Although surgery is the mainstay of curative treatment of carcinomas of the penis and urethra, there is a role for systemic cytotoxic chemotherapy for locally advanced, unresectable, or metastatic tumors. Although this field is limited by a paucity of clinical trials or prospective data, the available single institutional retrospective reviews indicate that multi-agent cisplatin-based combination chemotherapy regimens have significant activity and may allow curative surgery for patients with otherwise unresectable tumors. Toxicity remains a concern in this typically older patient population, and clearly new regimens are necessary. This article reviews the available literature on chemotherapy for carcinoma of the penis and urethra in the neoadjuvant, adjuvant, and metastatic setting.
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 targeted 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 highlights 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. Unfortunately, because of the disease site, patient reluctance, and social mores, patients commonly present with advanced disease. Therefore, effective systemic therapies are necessary and are commonly incorporated into multimodal treatment regimens. These strategies 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 nodes 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 reported on a 33-year experience from Amsterdam of 20 patients with unresectable inguinal lymphadenopathy, with a total of 5 different chemotherapy regimens used neoadjuvantly during that time period. In this series, single-agent bleomycin was used until 1985; from 1985 to 1999 combination 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 marked difference in survival between chemotherapy responders and nonresponders: 56% 5-year survival in responders versus all nonresponders died within 9 months. Of the responders, 9 underwent consolidative surgical resection, with 8 of these patients achieving durable long-term survival. The chemotherapy regimens did carry significant toxicity, however, with 3 toxic deaths and cessation of chemotherapy because of toxicity in 1 patient. Using a similar VBM regimen, investigators from Milan reported a small pilot neoadjuvant and adjuvant study of 17 patients, including 5 patients receiving neoadjuvant therapy. Of these 5 patients with bulky unresectable inguinal nodal disease, 3 (60%) had a partial response to VBM, allowing consolidative surgery with durable disease-free responses; the 2 nonresponders died within 1 year of diagnosis.
In a another study from Texas, Bermejo and colleagues reported on the MD Anderson experience with surgical resection after neoadjuvant chemotherapy for unresectable penile squamous cell carcinoma from 1985 to 2000 in 10 patients. These patients received several different chemotherapy combinations, including bleomycin, methotrexate, cisplatin (BMP), ifosfamide, paclitaxel, cisplatin (ITP), or paclitaxel/carboplatin. These 10 patients, drawn from a total cohort of 59 patients who presented with locally advanced or metastatic penile carcinoma, had a complete (4) or partial response (1) or stable disease (5) after chemotherapy; the remaining 49 patients remained unresectable after chemotherapy or had progressive disease. The 5-year survival for these 10 patients was 40%, with a median survival of 26 months. Notably, there were 3 patients with pathologic complete response (pN0), all of whom received ITP. All patients with 3 or more positive lymph nodes found at consolidative surgical resection after neoadjuvant chemotherapy ultimately died of their disease.
A notable phase II trial of chemotherapy, one of the few multi-institutional clinical trials ever conducted for penile carcinoma, was performed by the Southwest Oncology Group (SWOG), investigating a combination of cisplatin, methotrexate, and bleomycin (PMB) in 45 patients. This study followed an earlier phase II SWOG trial of single-agent cisplatin for advanced disease, which reported poor response rates for cisplatin monotherapy. There was a significant response rate to combination PMB chemotherapy, with an overall response rate of 33% and 5 complete responses. Similar to the retrospective analysis from Amsterdam, however, there was considerable toxicity with this regimen, with 5 treatment-related deaths and 6 grade 4 toxicities, and the investigators concluded that less toxic regimens were necessary.
More recently, a pilot study from Milan examined a combination regimen of paclitaxel, cisplatin, and 5-FU (TPF) in 6 patients, including neoadjuvant therapy in 2 patients, and in recurrent inguinal nodal disease after lymphadenectomy in 4, with consolidative lymphadenectomy planned in all patients. Two patients completed 4 courses of TPF and had a pathologically confirmed complete response, and 3 others had significant tumor responses to TPF, indicating that TPF is very active in penile carcinoma, within the limitations of such a small study.
In a review by Culkin and Beer, when combining the published literature of several cisplatin-based combination chemotherapy regimens, a response rate of 69% (24/35) was calculated in patients with unresectable nodal disease, highlighting the chemoresponsiveness of this disease. In summary, as advocated by the recent European Urology Association (EUA) practice guidelines, neoadjuvant chemotherapy for locally advanced disease does demonstrate significant response when combination chemotherapy is used, and can allow subsequent surgical resection of previously unresectable disease in up to half of cases. Surgical consolidation, however, is necessary to maximize long-term durable freedom of disease, even with dramatic clinical and radiographic responses to chemotherapy alone.
Adjuvant Chemotherapy
Despite aggressive surgery, the relapse rate and eventual cancer-related morbidity and mortality remain depressingly high for node-positive penile carcinoma. The 5-year survival for node-negative disease was 95% in a large retrospective single-institution review from India from 1962 to 1986, declining to 76% with positive inguinal lymph nodes, and no 5-year survivors when deep pelvic nodes were involved. Therefore, multiple chemotherapy agents and combinations have been described in the adjuvant setting when positive lymph nodes are discovered after lymphadenectomy. The number of lymph nodes involved is an important predictor of recurrence, and the recent EUA guidelines advocate adjuvant chemotherapy for pN2-3 disease, but not for pN1 disease.
The largest published series to date have come from the Milan group, where initially VBM was administered adjuvantly from 1979 to 1990, with improved long-term survival compared with historical controls. Since 1991, cisplatin with 5-FU has been the primary adjuvant regimen given, with improved survival and lower toxicity.
In another small retrospective review from Dresden, Germany, patients with penile carcinoma who received combination PMB chemotherapy were evaluated from 1996 to 2003. This study represented a mixed cohort of 13 patients, including 8 patients receiving adjuvant therapy after lymphadenectomy and 5 patients with metastatic disease. Of the 8 patients receiving PMB in the adjuvant setting, 3 patients (38%) had a durable response, with no evidence of disease at a mean of 54 months. Although the patients with metastasis fared very poorly in this study, the investigators concluded that there was benefit in the adjuvant setting, but as with other studies of PMB, the toxicity is high.
Induction Chemotherapy for Metastatic Disease
Single-agent experience
Data on chemotherapy treatment of locally advanced or metastatic penile carcinoma is limited and difficult to generalize. Most of the available data are retrospective case series or studies with small numbers using mixed populations, including patients receiving chemotherapy in the neoadjuvant, adjuvant, and recurrent settings. In addition, many studies include patients whose regimens were also combined with radiation therapy or salvage surgery for cure.
Reports of the use of single-agent chemotherapy were scattered in the literature in penile cancer in the 1960s to 1980s. Reports using bleomycin, methotrexate, and cisplatin alone showed modest efficacy of short duration.
Experience with bleomycin was first reported by a Japanese group in 1969. Biweekly intravenous or intramuscular bleomycin was delivered at 15 mg, and objective response was seen in 6 of 8 patients. One patient who showed complete response died of pneumonia while on treatment. Experience with bleomycin in combination with radiotherapy as a single agent, or in conjunction with vincristine and methotrexate, was also reported in 1983. The investigators found improved response in patients with well-differentiated squamous cell carcinoma but also reported significant pulmonary toxicity, with pneumonitis in 3 and fibrotic changes in 6 of the 19 patients treated.
Single-agent cisplatin was used in 9 patients treated at the Memorial Sloan Kettering Cancer Center (MSKCC) in the 1970s. Low (1.6–2.0 mg/kg) and high doses (3 mg/kg or 120 mg/m 2 ) of cisplatin were given every 21 days with an overall response rate of 33%, with 1 complete response lasting several months. An additional patient died 5 days following cisplatin administration. Permanent and transient renal insufficiency as well as tinnitus were observed. Before the availability of newer generation antiemetics, nausea and vomiting often delayed subsequent chemotherapy cycles.
The SWOG published their data on single agent cisplatin a decade later. In this series of 26 patients, cisplatin at 50 mg/m 2 given weekly for 2 weeks on and 2 weeks off demonstrated little activity, with 4 partial responses lasting only 3 months. Toxicity included cytopenias, nausea, and vomiting. Entry criteria for the study included creatinine clearance greater than 60 mL/min. Following treatment 9 patients had a decline in creatinine clearance to less than 50 mL/min, and 2 patients had creatinine clearance less than 30 mL/min.
Success of single-agent high-dose methotrexate chemotherapy with leucovorin rescue was reported by Garnick and colleagues in a patient who had disease progression while undergoing radiation treatment. Complete pathologic response was noted after 10 weekly cycles lasting for 9 months, when the patient suffered sudden infectious pulmonary death. Sklaroff and Yagoda of MSKCC also reported on experience with high- and low-dose methotrexate. In this group of 8 patients, 5 had previously undergone radiotherapy or chemotherapy, and the overall response rate to methotrexate treatment was 38%. Five patients were treated with high-dose chemotherapy, of whom 2 achieved partial remission lasting as long as 11 months. The remaining 3 patients were given low-dose therapy, with 1 short-lived partial response.
In 1984 Ahmed and colleagues published the MSKCC experience of all men presenting with penile carcinoma since 1975 who treated with single-agent methotrexate, cisplatin, or bleomycin. Sixty-one percent of patients treated with methotrexate achieved response, which lasted for greater than 12 months in 2 patients. Responses were also seen in 3 patients who had prior cisplatin therapy. Of 12 patients thought to have received adequate cisplatin treatment, 1 achieved a complete response lasting 7 months and 2 had brief partial responses. Of the 14 men treated with bleomycin, 3 responses were seen, but unfortunately 1 developed treatment-related pulmonary fibrosis and died.
Combination chemotherapy
Similar to experience with other solid tumor malignancies, penile cancer investigators began to have success treating patients with cytotoxic combinations with backbone agents such as methotrexate and bleomycin based on previous success, as well as combinations used for other squamous cell carcinoma sites.
The first group to report on their experience with combination 5-fluorouracil and cisplatin were Hussein and colleagues in 1990. Five men with recurrent or unresectable squamous cell carcinoma of the penis and 1 of the urethra were treated with cisplatin day 1 followed by 5-fluorouracil infusions on days 2 to 6 ( Table 1 ). The patient with urethral squamous cell carcinoma achieved clinical complete response after 2 cycles of therapy. Microscopic disease was found at lymphadenectomy, and local recurrence 12 months later was treated successfully with chemoradiotherapy and the patient had a durable clinical complete response for more than 32 months. The 5 patients with penile squamous cell carcinoma had partial responses. One patient underwent inguinal dissection for cure followed by adjuvant radiotherapy. He succumbed 18 months later to local recurrence. The remaining patients were thought to be unresectable and underwent local radiation therapy, with median duration of overall survival of 15 months. Toxicities were reportedly mild and consisted of mucositis, nausea and vomiting, and renal insufficiency.
| Regimen | N | Response | Responder Survival | Treatment-related Deaths | References |
|---|---|---|---|---|---|
| Cisplatin 5-Fluorouracil | 6 | 1 complete 5 partial | 6 to 32 mo | 0 | Hussein et al |
| Cisplatin 5-Fluorouracil | 8 | 2 partial | 32 and 57 mo | 0 | Shammas et al |
| Cisplatin Methotrexate Bleomycin (CMB) | 14 | 2 complete 8 partial 3 minor | 6 to 24 mo (median = 10 mo) | 0 | Dexeus et al |
| Cisplatin Methotrexate Bleomycin (CMB) | 45 | 5 complete 8 partial | 9 to 57 mo (median = 28 wk) | 5 | Haas et al |
| Cisplatin Methotrexate Bleomycin (CMB) | 13 | 3 adjuvant without recurrence | N/A | 1 | Hakenberg et al |
| Cisplatin Irinotecan | 28 | 2 complete 6 partial | N/A | Theodore et al | |
| Cisplatin Gemcitabine (GC) | 2 | 2 partial | 11 mo | Power et al |
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