ABSTRACT
BACKGROUND: Although induction studies of TPF in SCCHN have not improved outcomes compared to chemoradiotherapy alone, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown promising results. Nano-albumin-paclitaxel (nab-paclitaxel) based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in squamous cell carcinoma of the lung with favorable toxicity. MATERIALS AND METHODS: Patients with treatment naïve SCCHN of any site with ≥N2b disease or that was unresectable by strict criteria were eligible. Patients were treated with nab-paclitaxel 100â¯mg/m2, CbP area under the curve (AUC) 2 and C225 400â¯mg/m2 week 1 then 250â¯mg/m2 for six weeks, followed by standard of care chemoradiotherapy (CRT). The primary endpoint was clinical response rate to induction therapy as defined by RECIST version 1.1. Secondary measures included toxicity, progression-free survival, overall survival and quality of life as measured by FACT-HN. RESULTS: 38 eligible subjects were treated. Primary sites were: oropharynx (OPX) (25), larynx (3) oral cavity (OC) (9), hypopharynx (1). The most common grade 3 or 4 toxicity during induction was acneiform rash (26%) followed by neutropenia (16%). RR was 76.3%. Median PFS and OS have not been reached (median follow-up of 3.3â¯years); they were superior in patients with response. CONCLUSIONS: The combination of nab-paclitaxel, CbP and C225 is feasible, tolerable and active against locally advanced SCCHN.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Head and Neck Neoplasms/drug therapy , Neoadjuvant Therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Albumins/administration & dosage , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Cetuximab/administration & dosage , Cetuximab/adverse effects , Chemoradiotherapy/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy , Drug Eruptions/etiology , Female , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , Induction Chemotherapy , Kaplan-Meier Estimate , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Neutropenia/chemically induced , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Progression-Free Survival , Radiotherapy, Intensity-Modulated/adverse effects , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/secondary , Squamous Cell Carcinoma of Head and Neck/therapy , Treatment OutcomeABSTRACT
Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.