Risk factors for second primary esophageal cancer after head and neck squamous cell carcinoma: a systematic review and meta-analysis

Background Patients with head and neck squamous cell carcinoma (HNSCC) are at an elevated risk of developing second primary tumors. Esophageal second primary tumors (ESPTs) represent a significant clinical challenge due to their frequent late detection and associated poor prognosis. This systematic literature review aims to identify and synthesize current evidence on risk factors for synchronous and metachronous ESPTs in patients with HNSCC. This can help identify individuals at highest risk so that targeted screening strategies can be created, which could ultimately improve long-term outcomes through earlier diagnosis. Materials and methods A comprehensive search was conducted in PubMed, Web of Science, and Embase using a predefined search strategy. Eligible studies included observational, cohort, and case-control analyses involving adult patients with histologically confirmed HNSCC, either with or without an ESPT. Studies focusing exclusively on genome-associated risk factors, or those not addressing risk factors for ESPTs, were excluded. Meta-analyses were carried out when at least five studies reported on a specific risk factor. Results Of 1338 records screened, 22 studies met the inclusion criteria and were included. In the meta-analyses, the following risk factors were found to be statistically significant for the development of ESPTs among HNSCC survivors: male sex [odds ratio (OR) 4.73; 95% confidence interval (CI) 2.15-10.40; P = 0.0001], HNSCC location in the hypopharynx (OR 4.31; 95% CI 2.13-8.75; P < 0.0001) or oropharynx (OR 2.40; 95% CI 1.80-3.20; P < 0.0001), alcohol consumption (OR 5.45; 95% CI 2.29-13.38; P = 0.0001), and stage IV disease of the first primary HNSCC (OR 1.90; 95% CI 1.16-3.12; P = 0.0110). Conclusions Male sex, HNSCCs located in the hypopharynx or oropharynx, advanced tumor stage, and heavy alcohol consumption are associated with an increased risk of ESPT development. These findings may help identify susceptible patient subgroups who could benefit from future risk-adapted esophageal surveillance strategies.