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

## TL;DR

This review summarizes chemotherapy options for advanced penile cancer, highlighting effective regimens and the need for better evidence.

## Contribution

The paper provides a comprehensive comparison of chemotherapy regimens and guidelines for penile squamous cell carcinoma.

## Key findings

- Bleomycin-containing regimens are no longer recommended due to severe lung toxicity.
- Cisplatin/taxane-based combinations like TIP and TPF are effective but vary in toxicity.
- Doublets like PF or carboplatin-taxane are suitable for less fit patients.

## Abstract

Penile squamous cell carcinoma (PSCC) is a rare but aggressive malignancy. In its advanced stages, systemic chemotherapy plays a pivotal role; however, the evidence remains limited, and treatment strategies are frequently extrapolated from other cancer types. This review provides a concise and comprehensive overview of the cytotoxic agents used in PSCC, outlining their mechanisms of action, historical development, and current clinical applications. Moreover, major international guidelines are compared to highlight the similarities and differences relevant to daily practice. This review seeks to assist clinicians and researchers in understanding the dynamic landscape of chemotherapeutic options for the treatment of penile cancer.

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.