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Page 2 of 10                          Farlow et al. J Cancer Metastasis Treat 2019;5:18  I  http://dx.doi.org/10.20517/2394-4722.2018.100

               INTRODUCTION
               Head and neck squamous cell carcinoma (HNSCC) imparts significant morbidity and mortality as the
                                                  [1]
               sixth most common cancer in the world . In the United States alone, over 10,000 deaths and 51,000 new
                                                [1]
               cases were estimated to occur in 2018 . Nonspecific symptoms often lead to advanced stages at clinical
               presentation and thus poor survival outcomes, with an average 5-year survival in the United States of
                   [2]
               65% . Surgical extirpation is a widely employed curative approach for advanced HNSCC, but there is often
               a time lapse of several weeks for preoperative workup and planning. Window of opportunity or “window
               trials” [Figure 1] leverage this time, where normally no treatment is rendered, in order to trial novel agents
                                                     [3]
               without delaying standard of care therapy  in the context of a tumor microenvironment and human
               pathophysiology that cannot be replicated in preclinical models. Tissue is widely available for study, given the
               necessity of a biopsy for initial pathologic confirmation of the diagnosis and the subsequent curative therapy.
               Recent genomic studies have highlighted a number of potential molecular alterations in HNSCC, which can
               provide valuable targets which can be studied through window trials. Additionally, immunotherapies that
               have shown promise in recurrent or metastatic cases can be studied in treatment-naïve subjects through this
               approach. Of note, neoadjuvant trials typically do not qualify as window trials, as neoadjuvant therapies
               are given preoperatively typically with the goal of a measurable pathologic or clinical response. Some recent
               neoadjuvant trials in HNSCC, however, have followed window trial methodology, in that a tumor response
               to therapy did not preclude or delay surgery. These trials have shed light on the safety, possible efficacy,
               and potential patient selection biomarkers for the therapies employed. Thus, in this article, we review select
               neoadjuvant and window trials in HNSCC and discuss potential future directions.



               RECENT WINDOW TRIALS OF TARGETED THERAPIES
               Genomic methodologies have characterized numerous molecular alterations in HNSCC, many critical in
                                                                                               [4-6]
               tumor cell survival and proliferation pathways, that could form the basis for targeted therapies . However,
               translation of these findings into clinical practice has been slow.


               ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR BASED WINDOW TRIALS
               Currently, the only molecularly targeted drug approved for HNSCC is cetuximab, a monoclonal antibody
               that targets the EGFR, an antiapoptotic transmembrane protein which is amplified or overexpressed in the
                                                                      [7]
               vast majority of HNSCC and is correlated with reduced survival . In a phase III trial, cetuximab has been
               shown to improve overall survival in HNSCC when combined with radiotherapy, although only a fraction
                                     [8]
               of patients receive benefit . Thus, identifying biomarkers that predict response to cetuximab is an ongoing
               area of study that potentially can be explored in a window of opportunity setting.

                          [9]
               Schmitz et al.  administered cetuximab to 33 subjects planned for curative surgery and compared radiologic
                                                                             18
               tumor response via 18-fluorodeoxyglucose positron emission tomography ( FDG-PET) and tumor cellularity
               to 5 control subjects who did not receive any drug preoperatively [Table 1]. No treatment-limiting adverse
                                                                        18
               events were noted, and there was a high rate of tumor response by  FDG-PET (90% in cetuximab group vs.
                                                                     18
               0% in the control group). Tumor cellularity was correlated with  FDG-PET standardized uptake values. As
               expected, cetuximab administration decreased pEGFR and phosphorylated extracellular signal regulated
                                                                       18
               kinase expression, but neither of the biomarkers correlated with  FDG-PET avidity. Cetuximab was also
                                                                [10]
               studied in a window of opportunity setting by Ferris et al. , who noted an objective response in tumor size
               by computed tomography (CT) in a third of evaluable patients. Larger numbers of circulating EGFR-specific
                     [10]
                                                    [11]
               T cells  as well as HLA class I upregulation  were correlated with response to cetuximab.
               Erlotinib is another EGFR inhibitor that has been approved in other cancers such as non-small cell lung
               cancer and pancreatic cancer. An uncontrolled neoadjuvant trial conducted by Thomas et al administered
                                                                                           [12]
               erlotinib in 35 subjects with advanced nonmetastatic HNSCC who were awaiting surgery . Four subjects
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