The Residual Role of Doxorubicin–Cisplatin in Endometrial Cancer in the TC Plus Immunotherapy Era

ABSTRACT: Doxorubicin plus cisplatin (AP) once played a central role in the systemic treatment of advanced and recurrent endometrial cancer and helped establish combination chemotherapy as a standard approach for extra-uterine disease. Contemporary practice, however, has shifted toward carboplatin plus paclitaxel (TC), which now serves as the cytotoxic backbone for first-line immunotherapy-based strategies. This transition should not be interpreted as the simple replacement of an ineffective regimen by a definitively superior one. No dedicated two-arm trial established the superiority or noninferiority of TC over AP across the full clinical spectrum. Rather, the change resulted from an accumulation of evidence: AP had established historical activity, the addition of paclitaxel to AP improved outcomes, and TC subsequently achieved similar efficacy to the three-drug regimen with better tolerability and practical feasibility. Molecular classification has further changed the treatment landscape. POLE-mutated, mismatch repair-deficient, p53-abnormal, and no specific molecular profile tumors differ in prognosis and therapeutic relevance, but no molecular subgroup has been shown to derive preferential benefit from AP rather than TC. TC also remains the platform for major first-line immunotherapy trials, whereas biomarker-directed and later-line options have further reduced the competitiveness of AP. Emerging biomarkers of cisplatin sensitivity and combinations of immune checkpoint blockade with PARP inhibition remain investigational and do not establish a new molecular niche for AP. AP should therefore be regarded as a historically important regimen with a narrow residual role as an exceptional fallback when established contemporary strategies cannot reasonably be used.