Site-specific therapy in cancers of unknown primary site: a systematic review and meta-analysis

Background: Cancer of unknown primary site (CUP) is a term applied to characterize pathologically confirmed metastatic cancer with unknown primary tumor origin. It remains uncertain whether patients with CUP benefit from site-specific therapy guided by molecular profiling. Patients and methods: A systematic search in PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials. gov, and of conference abstracts from January 1976 to January 2021 was performed to identify studies investigating the efficacy of site-specific therapy on patients with CUP. The quality of included studies was evaluated using the Cochrane risk of bias tool and NewcastleeOttawa scale. Eligible studies were weighted and pooled for meta-analysis. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were assessed to compare the efficacy of site-specific therapy with empiric therapy in patients with CUP. In addition, subgroup analyses were conducted. Results: Five studies comprising 1114 patients were identified, of which 454 patients received site-specific therapy, and 660 patients received empiric therapy. Our meta-analysis revealed that site-specific therapy was not significantly associated with improved PFS [HR 0.93, 95% confidence interval (CI) 0.74-1.17, P = 0.534] and OS (HR 0.75, 95% CI 0.55-1.03, P = 0.069), compared with empiric therapy. However, during subgroup analysis significantly improved OS was associated with site-specific therapy in the high-accuracy predictive assay subgroup (HR 0.46, 95% CI 0.26-0.81, P = 0.008) compared with the low accuracy predictive assay subgroup (HR 0.93, 95% CI 0.75-1.15, P = 0.509). Furthermore, compared with patients with less responsive tumor types, more survival benefit from site-specific therapy was found in patients with more responsive tumors (HR 0.67, 95% CI 0.46-0.97, P = 0.037). Conclusions: Our results suggest that site-specific therapy is not significantly associated with improved survival outcomes; however, it might benefit patients with CUP with responsive tumor types.