The purpose of this study is to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) versus chemotherapy alone for patients with stage IV esophageal squamous cell carcinoma (ESCC). Eligible patients were retrospectively enrolled at the authors’s institution from January 2010 to October 2015. Of the 141 patients enrolled, 55 (39.0%) received CCRT and 86 (61.0%) received chemotherapy alone. The outcomes and adverse events (AEs) were compared between the two groups. The baseline clinical characteristics of the two groups were similar. However, the CCRT group showed a significantly better primary tumor objective response rate (ORR) than that of the chemotherapy group (74.5% versus 45.3%, p = 0.001). The 1-year, 2-year, 3-year overall survival (OS) rates and median OS were 58.0% versus 43.0%, 25.5% versus 14.0%, 10.7% versus 4.7%, and 14 months versus 11 months for patients treated with CCRT or chemotherapy, respectively (p = 0.007). The 1-year and median progression-free survival (PFS) were 29.8% versus 14.9% and 8 months versus 6 months (p = 0.005). Multivariate analysis identified CCRT (p = 0.013) and solitary metastasis (p = 0.037) as independent factors for greater OS. The frequency of leucocytopenia (grade 3 or higher) was significantly higher in the CCRT group than in the chemotherapy-alone group (p = 0.040), whereas the rates of other AEs did not differ. In this study, it is suggested that CCRT is more effective than chemotherapy alone for stage IV ESCC, yielding better primary responses and survival outcomes with tolerable side effects.

The clinical advancement of cancer nanomedicine is significantly hindered by its limited accumulation in tumors, a key factor behind the frequent failure of nanodrugs in clinical trials. The effectiveness of these nanodrugs is closely tied to their route of administration, whether oral, transdermal, intravenous, or intracerebral, as each path presents unique physiological barriers that impede bioavailability and precise tumor targeting. Among the major causes of poor accumulation are rapid clearance by the mononuclear phagocyte system, opsonization accompanied by protein corona formation, renal filtration, and the abnormal, heterogeneous nature of tumor vasculature that restricts passive targeting via the enhanced permeability and retention (EPR) effect. In response, active targeting (AT) strategies have been widely explored, including surface modification with ligands, antibodies, or aptamers designed to bind specifically to overexpressed receptors on cancer cells or blood vessels. Despite these efforts, challenges such as the dense extracellular matrix, elevated interstitial fluid pressure, and the notable inconsistency of the EPR effect between animal models and human patients continue to limit therapeutic penetration. This review offers a systematic examination of nanodrug delivery pathways and the reasons behind their inadequate accumulation, highlighting the potential of both active targeting and combined passive-active strategies to enhance tumor-specific delivery. Overcoming these biological barriers through refined nano-design is crucial for developing the next generation of nanomedicines with improved tumor accumulation and treatment outcomes.