Management of Advanced Penile Cancer

Penile squamous cell carcinoma (PSCC) is a rare cancer, with approximately 2000 new cases in the United States and 35,000 globally every year. Multiple risk factors are involved in PSCC, but most importantly, the high-risk human papillomavirus infection is thought to be present in approximately 50% of cases. Penile squamous cell carcinoma presents as localized or locally advanced disease. Multiple prognostic markers have been explored over the past 3 decades, but lymph node status remains the strongest predictor of clinical outcomes. Surgical decisions are based on the primary tumor pathologic findings, nodal clinical examination, and imaging results. Most patients with high-risk advanced PSCC benefit from a multimodal treatment approach combining chemotherapy with consolidation surgical treatment. The role of neoadjuvant chemotherapy with radiation therapy has not been well explored in PSCC. Prospective clinical studies, like the International Penile Advanced Cancer Trial, have been launched to provide high-level evidence for multimodal treatment. The International Penile Advanced Cancer Trial is the first randomized clinical trial among patients with PSCC and is currently accruing, with the expectation to generate results in 2023. Unfortunately, most patients with high-risk locally advanced PSCC will have relapsed or refractory cancer after cisplatin-based combination chemotherapy. These patients have dismal outcomes with salvage chemotherapy, highlighting the major unmet need to expand our knowledge of the disease's biology and develop clinical trials that use novel systemic agents. This narrative review synthesizes relevant publications retrieved from PubMed. Our aim is to discuss current approaches in the management of PSCC, summarize ongoing efforts to improve care, and identify future areas for enhancing our understanding of the disease.