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      Deintensification of Adjuvant Treatment After Transoral Surgery in Patients With Human Papillomavirus-Positive Oropharyngeal Cancer: The Conception of the PATHOS Study and Its Development

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          Abstract

          PATHOS is a phase II/III randomized controlled trial (RCT) of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery (TOS) for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The study opened in the UK in October 2015 and, after successful recruitment into the phase II, transitioned into phase III in the autumn of 2018. PATHOS aims to establish whether the de-intensification of adjuvant treatment in patients with favorable prognosis HPV-positive OPSCC will confer improved swallowing outcomes, whilst maintaining high rates of cure. In this article, we will outline the rationale for the study and how it aims to answer fundamentally important questions about the safety, effectiveness and functional outcomes of minimally invasive TOS techniques followed by adjuvant radiotherapy (RT) or chemo-radiotherapy (CRT) in this patient population.

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          Most cited references52

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          Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual.

          Answer questions and earn CME/CNE The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior seventh edition. This article details several of the most significant modifications, and the rationale for the revisions, to alert the reader to evolution of the field. The most significant update creates a separate staging algorithm for high-risk human papillomavirus-associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer with other causes. Other modifications include: the reorganizing of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck-specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph node category (N) in all but the viral-related cancers and mucosal melanoma. The Head and Neck Task Force worked with colleagues around the world to derive a staging system that reflects ongoing changes in head and neck oncology; it remains user friendly and consistent with the traditional tumor, lymph node, metastasis (TNM) staging paradigm. CA Cancer J Clin 2017;67:122-137. © 2017 American Cancer Society.
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            Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

            Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.
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              Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).

              In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment. Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials. Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis. Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy. (c) 2005 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                01 October 2019
                2019
                : 9
                : 936
                Affiliations
                [1] 1Velindre NHS Trust , Cardiff, United Kingdom
                [2] 2University Hospitals Bristol NHS Foundation Trust , Bristol, United Kingdom
                [3] 3Centre for Trials Research, Cardiff University , Cardiff, United Kingdom
                [4] 4Department of Molecular and Clinical Cancer Medicine, University of Liverpool , Liverpool, United Kingdom
                Author notes

                Edited by: Jordi Giralt, Vall d'Hebron University Hospital, Spain

                Reviewed by: Irene Brana, Vall d'Hebron Institute of Oncology (VHIO), Spain; Philippe Gorphe, Institut Gustave Roussy, France; Alicia Lozano, Catalan Institute of Oncology, Spain

                *Correspondence: Sarah Hargreaves sarah.hargreaves@ 123456wales.nhs.uk

                This article was submitted to Head and Neck Cancer, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2019.00936
                6779788
                31632901
                47e57415-bd60-4f0e-9350-8ca36b2935bf
                Copyright © 2019 Hargreaves, Beasley, Hurt, Jones and Evans.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 May 2019
                : 06 September 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 63, Pages: 9, Words: 7873
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                hpv-related head and neck squamous cell carcinoma,pathos,deintensification,transoral surgery,adjuvant

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