Node-positive and metastatic penile cancer

Penile squamous cell carcinoma spreads in an orderly way from the primary to the superficial and deep inguinal nodes, then to the pelvic nodes and only later to distant sites, which is why inguinal lymphadenectomy can still cure patients with limited node disease. The 2023 EAU-ASCO guideline recommends radical inguinal lymphadenectomy for a positive sentinel node or a palpable, biopsy-proven node, with pelvic lymphadenectomy when two or more inguinal nodes are involved or a node shows extranodal extension. Survival falls steeply with the number of nodes, bilateral disease, extranodal extension and pelvic involvement, and lymphadenectomy itself carries high rates of wound breakdown and lymphoedema, which minimally invasive and robotic techniques aim to reduce.

Systemic therapy is borrowed from small trials. The TIP regimen (paclitaxel, ifosfamide and cisplatin) produced responses in half of 30 patients given it before lymphadenectomy in a phase 2 trial at MD Anderson (Journal of Clinical Oncology 2010) and became the guideline neoadjuvant regimen for bulky or fixed nodes; paclitaxel and cisplatin with or without fluorouracil are alternatives. Adjuvant chemotherapy or chemoradiotherapy is offered after lymphadenectomy for pelvic node disease or extranodal extension, but the order and value of these treatments has never been randomised, which is what the international InPACT trial (International Penile Advanced Cancer Trial) is designed to answer. For metastatic disease platinum chemotherapy gives short responses, and phase 2 trials of pembrolizumab or cemiplimab, alone or with chemotherapy (HERCULES, EPIC), have shown responses in a subset, especially HPV-positive or PD-L1-positive tumours; the TG4001 HPV 16 vaccine with avelumab is also being tested in HPV 16-positive recurrent cancers.