Survival outcomes with concurrent systemic therapy in patients with a medical contraindication to cisplatin in the non-operative management of locally advanced HNSCC, an NCDB Study

Standard-of-care non-operative management for locally advanced head & neck squamous cell carcinoma (HNSCC) is definitive radiation with concurrent cisplatin. NRG-HN004 demonstrated the benefit of concurrent cetuximab in patients with a medical contraindication to cisplatin including those older than 70 with a Charleson-Deyo (CD) score ≥ 1 and those under 70 with a CD score ≥ 2. In these populations, the survival benefits of concurrent systemic therapies may be limited due to medical co-morbidities. We evaluated overall survival (OS) of these populations in the National Cancer Database (NCDB) comparing radiation-treated patients who received concurrent chemotherapy against concurrent immunotherapy (most likely cetuximab given it is the only FDA-approved immunotherapy for this indication). The NCDB was queried for data from 2015-2023 to include stage III, IVa, and IVb non-metastatic HNSCC patients that met the HN-004 criteria. Histological subtypes of squamous cell carcinoma (SCC) were identified using ICD-O-3 codes 8070-8078. Patients with clinical T3-T4 and/or clinically node-positive disease with a known primary were included. Patients who received less than 60 Gy were excluded. Groups were stratified based on radiation with chemotherapy (RT-C) or radiation with immunotherapy (RT-I) without overlap. Concurrent systemic therapy was defined as having started within 30 days of the initiation of radiation. OS was evaluated using Kaplan-Meier (KM) statistics and differences were evaluated using log-rank testing. A p < 0.05 was considered statistically significant. To minimize the effect of informative censoring, patients without documented follow-up after January 1, 2023 were counted as deaths unless they had greater than 5 years of observed follow-up. Additionally, KM estimates were capped at 5 years. A total of 6299 patients were identified: 5657 treated with RT-C and 642 treated with RT-I. 2-year OS was 65.0% (95% CI, 63.8-66.3) and 52.9% (95% CI, 49.2-57.0) for RT-C and RT-I, respectively. 5-year OS was 20.7% (95% CI, 19.6-21.9) and 21.8% (95% CI, 18.7-25.5) for RT-C and RT-I, respectively. KM analysis ultimately showed no significant difference between the two treatment cohorts (log-rank p=0.059). In a subgroup of patients with medical contraindications to cisplatin, there was no statistically significant improvement in OS with concurrent chemotherapy over concurrent immunotherapy (likely cetuximab) for locally advanced HNSCC in this real-world dataset. Critically, early survival benefits seen with concurrent chemotherapy dissipate with long-term follow-up possibly due to deaths from other causes in this population with extensive co-morbidity. Further prospective study is needed to evaluate the benefit of concurrent chemotherapy over cetuximab in this frail population.