Treatment of Metastatic Penile Cancer: Chemotherapy

267 Treatment of Metastatic Penile Cancer: Chemotherapy

Abhishek Marballi and Teresa Gray Hayes

Penile cancer is a rare malignancy, representing less than 1% of all cancers in men in the United States. It is relatively more common in parts of Southeast Asia, South America, and Africa. The rate of penile cancer increases with age, the mean age of diagnosis being 60 years. Penile cancer arises from the inner prepuce or glans and squamous cell carcinoma (SCC) accounts for the majority (>95%), although other histological subtypes occur.

Human papillomavirus (HPV) is a risk factor and about 30% to 40% of cases of penile cancer are associated with HPV-related carcinogenesis. HPV 16, HPV 6, and HPV 18 are the most frequent types encountered in penile SCC. There is conflicting data regarding the prognostic implications of presence of HPV. Other risk factors include penile injury, genital warts, presence of phimosis, lack of circumcision, and tobacco exposure.

Penile cancer initially spreads via lymphatics in a very predictable manner. Lymphatic spread from the primary penile tumor can be unilateral or bilateral. The superficial and deep inguinal lymph nodes are the first to be affected, followed by ipsilateral pelvic lymph nodes. Pelvic lymph node spread without ipsilateral inguinal lymph node involvement has never been reported. Involvement of para-aortic and paracaval lymph nodes is considered to be systemic metastatic disease. Distant metastases (e.g., bone, lung, liver, or brain) are rare and detected late in the course of the disease.

The aim of treatment for early stage disease is radical tumor removal with maximal possible organ preservation. Treatment approach depends upon tumor, node, and metastasis (TNM) classification and grade of differentiation.

268LOCALLY ADVANCED DISEASE

The 5-year cancer-specific survival is 90% to 100% in patients with pN0 disease, between 70% and 80% in patients with pN1 stage disease, and less than 30% for stage pN2-3 disease (1). In a study by Pandey et al, case records of 128 patients who underwent groin dissection for penile cancer were reviewed (2). It was noted that patients who had metastasis only to inguinal nodes had a 5-year overall survival (OS) of 65%, but patients with pelvic nodal metastasis had a 5-year OS of 0%. On multivariate analysis, the factors adversely influencing survival were: ≥ 4 positive inguinal nodes, bilateral nodal metastases (N2), extranodal extension, and pelvic nodal metastasis (N3). Based on these findings, it is desirable to consider a multimodality approach to patients with these adverse factors. To explore this strategy, a prospective phase 2 trial included 30 patients with N2 or N3 disease without distant metastases. These patients received neoadjuvant paclitaxel 175 mg/m² on day 1, ifosfamide 1,200 mg/m² days 1 to 3, and cisplatin 25 mg/m² on days 1 to 3 (TIP) for four cycles with intent to undergo lymphadenectomy. Results revealed an objective response of 50% with 30% alive at 34 months. There were no chemotherapy-related deaths. OS was significantly associated with response to chemotherapy. Authors recommend neoadjuvant TIP as a part of multimodal treatment in these patients (3). In another prospective clinical trial, patients were treated with bleomycin, methotrexate, and cisplatin. Although an overall response rate of 32% and median OS of 28 weeks were found, the benefits were offset by a 14% treatment-related mortality (4). Since there isn’t sufficient data to form conclusions regarding adjuvant chemotherapy, the recommendations are based on extrapolation of neoadjuvant data mentioned earlier. As per National Comprehensive Cancer Network (NCCN) guidelines, adjuvant TIP for four cycles is reasonable for patients who didn’t receive preoperative chemotherapy and have any of the high-risk features such as pelvic node metastases, extranodal extension, involvement of bilateral inguinal lymph nodes, or ≥ 4 cm tumor in lymph nodes.

269METASTATIC DISEASE

Stage IV penile cancer is defined as N3 (palpable fixed inguinal nodes or involved pelvic lymph nodes) or M1 (distant metastases) according to the TNM system (5). In order to identify prognostic factors, Pond et al conducted a retrospective analysis of 140 patients with locally advanced or metastatic prostate SCC receiving first-line chemotherapy. The multivariate model of poor prognostic factors included visceral metastases and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 1 for progression-free survival (PFS) and OS. It was noted that patients with one or both risk factors had an OS of 8 and 7 months respectively, whereas for patients with 0 risk factors the median OS was not reached. About 73% of patients received cisplatin-based combination chemotherapy. If all cisplatin-based regimens were combined, there was an improved hazard ratio of 0.49 for survival compared to patients who did not receive cisplatin, after adjusting for visceral metastases and ECOG PS. The conclusion was that ECOG PS ≥ 1 and visceral metastases were poor prognostic factors and cisplatin-based regimens induced better outcomes compared to non–cisplatin-based regimens in patients with advanced penile SCC (6). A retrospective analysis by Di Lorenzo et al included 25 patients with newly diagnosed or recurrent penile cancer not amenable to either radical surgery or neoadjuvant chemotherapy followed by radical intent surgery. All patients received first-line chemotherapy with cisplatin on day 1 followed by 5-fluorouracil (5-FU) as continuous infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. A median of six cycles were administered and there were no deaths or interruption of treatment for toxicity. Treatment was well tolerated overall. Partial responses were observed in 32% and stable disease in 40% of patients. Median OS was 8 months. The authors concluded that this regimen is associated with a moderate response and tolerated well in patients with metastatic penile SCC (7). Based on extrapolation from neoadjuvant data (3), TIP is the preferred regimen in the metastatic setting with 5-FU + cisplatin as an acceptable alternative.

270Endothelial growth factor receptor (EGFR) is highly expressed in penile SCC as demonstrated by a retrospective analysis. Using immunohistochemistry, the expression of EGFR in histological samples of 44 patients with penile SCC was evaluated. Results revealed that 40/44 samples (91%) showed a strong positive expression of EGFR (8). To evaluate efficacy of EGFR-targeted therapy in penile SCC, Carthon et al retrospectively analyzed 24 patients treated at MD Anderson Cancer Center. All patients had penile SCC with clinical T4 or N2, N3 or M1 disease. Of patients, 67% received cetuximab in combination with cytotoxic chemotherapy, mostly a platinum agent. Others received erlotinib or gefitinib. Results revealed a partial response in 23% of patients, with median time to progression (TTP) of 11.3 weeks and median OS of 29.6 weeks. Gefitinib and erlotinib didn’t induce objective responses. The most common toxic effect was grade 1 and grade 2 rash. The study concluded that cetuximab has antitumor activity in metastatic penile SCC and may enhance the effect of cisplatin-based chemotherapy (9).

After First-Line Chemotherapy Failure

Out of 30 patients who received neoadjuvant TIP for Tx, N2 or N3, M0 disease as described earlier in the prospective phase 2 trial (3), 19 patients had tumor progression or recurrence. A retrospective analysis evaluated the response to subsequent treatment and survival. Seventeen patients went on to receive salvage therapy. Four patients underwent salvage surgery and all of them experienced disease progression. Only two out of five patients who received bleomycin, methotrexate, and cisplatin had an objective response. There were no other documented responses to systemic therapy. OS was 5.6 months for patients who received cisplatin-based treatment and 4.3 months for those who didn’t (10). The conclusion is that patients with recurrent disease or progression after first-line chemotherapy experience poor responses to salvage treatments. With a median survival of less than 6 months, these patients should be placed on clinical trials or referred to hospice.

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