Systemic Chemotherapy in Penile Squamous Cell Carcinoma: Mechanisms, Clinical Applications, and Evidence-Based Regimens

<b>Background/Objectives:</b> Penile squamous cell carcinoma (PSCC) is rare but aggressive. Systemic chemotherapy plays a crucial role in the management of node-positive or metastatic cases; however, the supporting evidence predominantly originates from small, non-randomized studies. This review provides a narrative analysis of the cytotoxic classes and regimens employed in PSCC and compares major clinical guidelines to facilitate informed decision-making in practice. <b>Methods:</b> English-language reports were identified in PubMed/Scopus/Google Scholar without date limits. Selection prioritized objective response, survival and toxicity outcomes, and guidance statements across neoadjuvant, adjuvant, and palliative settings. <b>Results:</b> Bleomycin-containing triplet regimens demonstrated efficacy but were associated with unacceptable pulmonary toxicity, leading to their discontinuation in clinical recommendations. Currently, cisplatin/taxane-based combinations remain fundamental in treatment protocols. The paclitaxel-ifosfamide-cisplatin (TIP) regimen achieves approximately 40-50% objective responses in phase II studies and may enable curative surgery, while taxane-cisplatin-5-fluorouracil (TPF) shows comparable efficacy with higher toxicity. For less fit patients, cisplatin-5-fluorouracil (PF) or carboplatin-taxane doublets are pragmatic alternatives. Single-agent taxanes or vinflunine offer modest second-line benefits. Although EAU-ASCO 2023, ESMO-EURACAN 2024, and NCCN v2.2025 are broadly in consensus, recommendations differ regarding eligibility thresholds and regimen preferences. Overall, the quality of the evidence remains low. <b>Conclusions:</b> TIP remains the reference neoadjuvant option for chemotherapy-fit patients with bulky nodal disease; doublets are reasonable when cisplatin fitness is limited; and bleomycin should be avoided. Harmonized eligibility criteria, biomarker-enriched studies, and coordinated multicenter trials are needed to improve outcomes in this rare malignancy.