Evaluating the role of adjuvant therapy in improving outcomes for patients with lymph node-positive penile cancer following surgical management.

Penile squamous cell carcinoma (PeCa) is a rare malignancy with poor outcomes in pN+ cases. Prognosis is particularly poor in patients with extranodal extension (ENE) or pelvic lymph node (PLN) involvement. Despite advancements in surgical techniques, the role of adjuvant therapy (AT)-including radiotherapy (ART), chemotherapy (ACT), and chemoradiotherapy (ACRT)-following radical lymphadenectomy (LAD) remains undefined, and optimal strategies are yet to be established. This review evaluates the impact of AT on survival and recurrence in pN+ PeCa, assesses associated toxicities, and explores personalized treatment approaches. A systematic search of PubMed, Web of Science, Cochrane Library, and Scopus identified studies published between January 2000 and December 2024. Eligible studies focused on AT after LAD, including radiotherapy, chemotherapy, targeted therapies, or combination regimens. ART improves locoregional control in patients with ≥ 2 positive inguinal lymph nodes, particularly in HPV+ tumors. ACT with TIP or TPF regimens enhances disease-free and overall survival in high-risk pN+ patients, including those with PLN involvement. ACRT provides modest benefits in ENE cases but is associated with significant toxicity. Emerging biomarkers, such as HPV status and p53 mutations, show potential for predicting treatment response, while novel agents and immunotherapies represent promising investigational areas. AT improves outcomes in pN+ PeCa but requires individualized strategies based on risk factors and molecular profiles. Prospective, collaborative studies are essential to refine AT protocols, reduce toxicities, and integrate immunotherapies, targeted agents, and biomarkers into treatment algorithms. Multidisciplinary management and centralized care are critical for optimizing outcomes in this malignancy.