Abstract
Penile cancer is a rare and biologically heterogeneous malignancy in which extensive regional nodal or distant metastatic disease is associated with poor survival. This structured narrative review summarizes current evidence for systemic treatment in the neoadjuvant, adjuvant, first-line palliative, and later-line settings, together with emerging biomarkers and molecularly directed strategies. PubMed/MEDLINE, Embase, Scopus, Web of Science, and ClinicalTrials.gov were searched through 2010 to June 2026. The evidence base remains dominated by retrospective cohorts and small, single-arm phase II studies, while mature randomized phase III data are lacking. Locally advanced disease and/or lymph node metastases carry a poor prognosis. Systemic treatment is crucial in improving the outcome and chemotherapy remains the main and first treatment option. Two triple drug regimens based on cisplatin and taxanes are recommended by guidelines, but response cannot be predicted. The most advantageous use is in combination with lymphadenectomy either as a neoadjuvant or an adjuvant approach.
Targeted therapies and immune-checkpoint inhibitors have shown signals of clinical activity, particularly in combination strategies, but they have not yet established a universal standard of care. Future progress will depend on international prospective trials, biomarker-integrated patient selection, and rational multimodal combinations.
Keywords
Penile cancer, Chemotherapy, Immunotherapy, Targeted treatment, Radio-chemotherapy, Molecular oncology, p16, p53, Human papillomavirus, Adjuvant, Neoadjuvant, Palliative