Chemotherapy for Penile and Urethral Carcinoma Edouard J. Trabulsi, MD a, *, Jean Hoffman-Censits, MD b Systemic therapy for carcinoma of the penis and urethra is considered for locally advanced disease as part of a multimodal treatment regimen, or for suspected or proven metastatic disease. The mainstay of systemic therapy for these conditions has traditionally been cytotoxic chemotherapeutic agents, but may incorporate small-molecule tar- geted agents in the future as their use widens with other solid tumors. The field is limited, however, by the relative rarity of the disease in the Western world, and the lack of robust, large clinical trials to date. This article reviews the systemic therapy agents and data available for these conditions in the neoadjuvant or adjuvant setting as well as for metastatic disease, and high- lights the importance of stage and histology for these categories. PENILE SQUAMOUS CELL CARCINOMA Penile carcinoma is a rare tumor in the Western world, with only 1290 cases expected in the United States in 2009. 1 Unfortunately, because of the disease site, patient reluctance, and social mores, patients commonly present with advanced disease. 2,3 Therefore, effective systemic therapies are necessary and are commonly incorporated into multimodal treatment regimens. These strate- gies are palliative, to debulk advanced tumors in an attempt at local control, as well as potentially curative for lesser burdens of disease. Neoadjuvant Chemotherapy for Bulky/ Unresectable Disease Patients presenting with locally advanced penile tumors with clinically negative inguinal lymph no- des are typically treated surgically initially, with chemotherapy considered in the adjuvant setting for high-risk patients. If patients have unresectable locally advanced penile tumors, or bulky inguinal nodal disease, neodjuvant chemotherapy before surgical consolidation can be considered. Multiple cytotoxic agents have been reported to be active for penile carcinoma, either as single agent or in combination, including methotrexate, bleomycin, cisplatin, and 5-fluorouracil (5-FU). Small, retrospective, single-institution studies have investigated neoadjuvant chemotherapy for unresectable disease. Leijte and colleagues 4 re- ported on a 33-year experience from Amsterdam of 20 patients with unresectable inguinal lymph- adenopathy, with a total of 5 different chemo- therapy regimens used neoadjuvantly during that time period. In this series, single-agent bleomycin was used until 1985; from 1985 to 1999 combina- tion bleomycin, vincristine, and methotrexate (VBM) were administered; cisplatin and 5-FU were given from 1999 to 2001; and since 2001 a 3-drug regimen of cisplatin, bleomycin, and methotrexate has been used, with 1 patient receiving cisplatin and irinotecan on a separate protocol. There was an overall response rate of 63%, and 5-year survival of 32%. There was a Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Suite 1102, Philadelphia, PA 19107, USA b Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, 834 Chestnut Street, Suite 314, Philadelphia, PA 19107, USA * Corresponding author. E-mail address: edouard.trabulsi@jefferson.edu KEYWORDS  Penile carcinoma  Urethral carcinoma  Chemotherapy Urol Clin N Am 37 (2010) 467–474 doi:10.1016/j.ucl.2010.04.010 0094-0143/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved. urologic.theclinics.com