The myth of eradicating peritoneal surface malignancies: How ultramicroscopic disease undermines the potential benefits of hyperthermic intraperitoneal chemotherapy.

Peritoneal carcinomatosis (PC) remains a challenging clinical condition associated with poor outcomes in digestive and gynecologic malignancies. The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival in selected patients and represents the current standard locoregional treatment. This approach is based on the concept that elimination of residual microscopic disease after complete cytoreduction may prevent recurrence. Despite optimal patient selection, complete macroscopic cytoreduction, and standardized HIPEC protocols, peritoneal recurrence rates remain high. This observation indicates that relevant disease components may persist beyond the reach of conventional locoregional therapies. Increasing preclinical and translational evidence supports the role of ultramicroscopic disease, composed of subcellular elements such as exosomes and circulating tumor DNA (ctDNA), in driving treatment failure. These components are not directly targeted by CRS or HIPEC and are believed to contribute to tumor cell survival, chemoresistance, microenvironmental remodeling, and disease dissemination. This review summarizes current evidence on the biological role of exosomes and ctDNA in peritoneal carcinomatosis, critically examines the limitations of CRS + HIPEC in controlling ultramicroscopic disease, and discusses emerging diagnostic and therapeutic strategies aimed at these targets. Recognition of ultramicroscopic disease provides a biological explanation for persistent recurrence after technically successful CRS + HIPEC and supports the development of integrated treatment strategies combining locoregional therapy with molecular and systemic approaches to improve long-term outcomes.