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Immunotherapy in Advanced Head and Neck Squamous Cell Carcinoma: A Retrospective Evaluation in Latin America

The standard of care in first line treatment for advanced Head and Neck Squamous
Cell Carcinoma (SCCHN) includes polychemotherapy based on platinum and Cetuximab.


Introduction
Squamous Cell Carcinoma of the Head and Neck (SCCHN) includes neoplasms in the oral cavity, pharynx and larynx and accounts for 90% of all head and neck cancers [1][2][3]. Despite multimodal therapy including platinum-based chemoradiotherapy, more than 50% of patients with locoregionally advanced SCCHN have recurrence or develop metastases (or both) within 3 years of treatment [4][5][6]. Patients with recurrent/metastatic (R/M) SCCHN who progress within 6 months after platinum-based therapy have poor long-term prognosis and limited treatment options, with a median Overall Survival (OS) of ≤6 months [7,8]. Platinumbased combination chemotherapy regimens and cetuximab are commonly used in the first-line recurrent and metastatic settings [9]. Until 2017, treatment options for recurrent and metastatic disease following progression on a platinum-based regimen were limited to single-agent chemotherapy or cetuximab, which yield a median overall survival of 7 months or less [10][11][12].
Inhibitors of the Programmed Death 1 (PD-1) pathway, which is implicated in tumor immune escape, have emerged as valid treatment options in patients with squamous cell carcinoma of the head and neck based on their antitumor activity and safety profiles [13][14][15][16][17][18][19]. On the basis of these data, we initiated a retrospective, multinstitutional, descriptive analysis, to evaluate the efficacy and safety of different immunotherapeutic drugs, in a "real world" subset of patients with R/M SCCHN that progressed during or after platinum-based chemotherapy.

Objectives
To describe the clinical-pathological characteristics, efficacy (overall survival -OS-, objective response rates -ORR-and Progression Free Survival -PFS-) and toxicity of pts with advanced SCCHN treated with immunotherapy.

Methods
Retrospective multinstitutional descriptive analysis of patient treated with immunotherapy for advanced SCCHN from 03/2017 to 05/2018, in Argentinian academic centers (Hospital Alemán, Hospital Italiano de Buenos Aires, Instituto Ángel Roffo, Hospital Posadas, Instituto Alexander Fleming and Centro de Atención Integral del Paciente Oncológico Tucuman). Treatment setting were defined as Platinum refractory (progression within 6 months after multimodal therapy using platinum regimen); first and subsequent lines for metastatic disease. Statistix 8.0 was used for statistical analysis. Descriptive statistics (including mean, standard deviation, median, range, frequency, and percentage) were calculated to characterize the patient population. Tumor responses were measured radiographically using Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1. Follow-up assessments were conducted by telephone or at the outpatient clinic. Survival time was calculated from the date of diagnosis until the date of last contact or death. The Kaplan-Meier method was used to assess the survival outcome. Univariate and multivariate analyses were performed using Cox regression. Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) were calculated.

Discussion
The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer is generally poor. The median survival, in most series, is 6 to 12 months depending upon patient and diseaserelated factors. Systemic therapy is indicated in conjunction with best supportive care for most patients with metastatic or advanced recurrent head and neck cancer. The choice of a systemic regimen is influenced by whether patients have received prior treatment as part of a combined modality approach postoperatively or for functional organ preservation as part of their initial management or whether they had previously received systemic therapy for metastatic or recurrent locoregional disease. Treatment options include single-agent therapy and combination regimens using either conventional cytotoxic chemotherapy and/or molecularly targeted agents combined with best supportive care. Checkpoint inhibitor immunotherapy is an option for patients with progressive disease after their initial chemotherapy regimen.
Pembrolizumab and nivolumab, checkpoint inhibitors of programmed cell death protein 1 (PD-1), have shown clinically significant activity in patients who progressed on or after platinumbased regimens and these agents are approved for this indication [15,17]. In this group of patients, there was no difference related to the Human Papilloma Virus (HPV) status. Treatment is associated with immune-related adverse events (irAEs) that typically are transient but occasionally can be severe or fatal. The most common and important irAEs are dermatologic, diarrhea/colitis and endocrinopathies [15,17]. Patient-reported outcomes on a quality of life questionnaire found that there was no clinically meaningful deterioration associated with treatment with nivolumab immunotherapy, in contrast to chemotherapy, where quality of life significantly decreased in 8 of 15 domains [20].
For those with R/M SCCHN without prior exposure to systemic therapy, the combination of pembrolizumab plus chemotherapy improves overall survival beyond that seen with cetuximab plus chemotherapy. For those with high Programmed Cell Death ligand 1 (PD-L1) expression, single-agent pembrolizumab also improves overall survival compared with cetuximab plus chemotherapy. These results have been presented in abstract form, and regulatory authorities are evaluating the use of pembrolizumab for this indication [21]. The results of this descriptive analysis solidify the role of PD-1 checkpoint inhibition in the treatment of head and neck squamous cell carcinoma. Of course, our results should be assessed critically. Limitations of the data include the retrospective evaluation. Despite of the small sample size, our data are in accordance with the published one, with a higher proportion of patients with fewer previous treatment lines. Another weakness of the study is the lack of a biomarker analysis (not required for the use of these drugs in this pathology in the second line or after). At the other hand, In spite of the weakness for being a retrospective analysis, it highlights the multi-institutional cooperation, relevant for the study of this disease. To our knowledge, this is the first published experience with a "real world" group of patients with R/M SCCHN in Latin America.