Key points

Introduction

Squamous cell carcinoma (SCC) of the penis is a rare disease, with an estimated 2020 cases and 340 deaths in the United States this year. Prognosis is good if disease is diagnosed at a localized stage, but up to 40% of patients present with locally advanced or metastatic disease and outcomes for these patients have historically been poor. The disease typically spreads in a locoregional manner, first to the draining inguinal lymph nodes, then to pelvic nodes, and then to viscera. The organized nature of spread makes the disease a candidate for a multimodal therapeutic approach, which has been successfully used to treat other SCCs, such as head and neck, anus, or vulva. The rarity of penile cancer in the United States and Western Europe, however, has hampered clinical study into the treatment of locally advanced or metastatic disease and there are currently no randomized data in this setting.

The TNM staging system for penile cancer is shown in Table 1 . Advanced disease implies spread beyond the local tissues (ie, T3-4 and/or N1-3 and/or M1 disease); 28% to 64% of men with penile cancer present with clinically palpable inguinal lymph nodes. In such cases, metastatic disease underlies lymphadenopathy in 47% to 85% of such individuals, with the remainder due to inflammatory nodal reaction, and the risk of pelvic nodal metastases is 22% to 56% if the inguinal nodes are involved. The most important prognostic factor in penile cancer is the presence of inguinal lymph node metastases, with the number of positive lymph nodes, bilateral inguinal nodal disease, pelvic nodal involvement, and extranodal metastatic extension imparting a worse prognosis. When inguinal lymphadenopathy is not clinically apparent, micrometastatic disease is present in approximately 25% of cases, with predictive risk factors including tumor stage, grade, and lymphovascular invasion.

Introduction

Squamous cell carcinoma (SCC) of the penis is a rare disease, with an estimated 2020 cases and 340 deaths in the United States this year. Prognosis is good if disease is diagnosed at a localized stage, but up to 40% of patients present with locally advanced or metastatic disease and outcomes for these patients have historically been poor. The disease typically spreads in a locoregional manner, first to the draining inguinal lymph nodes, then to pelvic nodes, and then to viscera. The organized nature of spread makes the disease a candidate for a multimodal therapeutic approach, which has been successfully used to treat other SCCs, such as head and neck, anus, or vulva. The rarity of penile cancer in the United States and Western Europe, however, has hampered clinical study into the treatment of locally advanced or metastatic disease and there are currently no randomized data in this setting.

The TNM staging system for penile cancer is shown in Table 1 . Advanced disease implies spread beyond the local tissues (ie, T3-4 and/or N1-3 and/or M1 disease); 28% to 64% of men with penile cancer present with clinically palpable inguinal lymph nodes. In such cases, metastatic disease underlies lymphadenopathy in 47% to 85% of such individuals, with the remainder due to inflammatory nodal reaction, and the risk of pelvic nodal metastases is 22% to 56% if the inguinal nodes are involved. The most important prognostic factor in penile cancer is the presence of inguinal lymph node metastases, with the number of positive lymph nodes, bilateral inguinal nodal disease, pelvic nodal involvement, and extranodal metastatic extension imparting a worse prognosis. When inguinal lymphadenopathy is not clinically apparent, micrometastatic disease is present in approximately 25% of cases, with predictive risk factors including tumor stage, grade, and lymphovascular invasion.

Adjuvant chemotherapy in node-positive disease

A multimodal approach can be used to treat men who are found node-positive after undergoing radical inguinal lymphadenectomy. Although there is evidence to support the use of adjuvant chemotherapy in men with pN2 or pN3 disease, this is based on small numbers of patients and single-center or multicenter retrospective data.

The largest patient series reporting outcomes of adjuvant chemotherapy for penile cancer was recently published and combined data from 4 tertiary centers in the United States, Netherlands, Italy, and China. The investigators identified 84 men who underwent lymph node dissection for SCC of the penis between 1978 and 2013 and who were found to have positive pelvic lymph nodes (ie, pN3). In this cohort, 36 men received adjuvant chemotherapy, with a majority (78%) treated with platinum-based regimens (most commonly docetaxel, cisplatin, and 5-fluorouracil [TPF]), whereas 48 were not. At a median follow-up of just over 12 months, median overall survival was significantly greater in those who had received chemotherapy compared with those who had not (21.7 months vs 10.1 months, P = .048) ( Fig. 1 ). Furthermore, receipt of adjuvant chemotherapy (hazard ratio [HR] = 0.40 [0.19–0.87], P = .021) was the sole independent predictor of overall survival in a multivariable analysis adjusting for age, pathologic stage, bilaterality of nodal disease, and timing of pelvic surgery.

Overall survival stratified by receipt of adjuvant (adj.) chemotherapy in chemotherapy-naïve men with pelvic node-positive penile cancer.

( From Sharma P, Djajadiningrat R, Zargar-Shoshtari K, et al. Adjuvant chemotherapy is associated with improved overall survival in pelvic node-positive penile cancer after lymph node dissection: a multi-institutional study. Urol Oncol 2015;33(11):496.e20; with permission.)

There are several important limitations of this study, however, the most important being that men who had received salvage chemotherapy after disease recurrence were excluded, which may have led to a systematic bias. The group who had not received adjuvant chemotherapy likely included men who had been unable to receive it owing to rapid postoperative disease recurrence or poor postoperative recovery. In contrast, the group who did receive adjuvant chemotherapy was probably enriched by men who had recovered quickly after surgery (and were thus able to tolerate chemotherapy) and then never recurred, thereby never requiring salvage chemotherapy. In addition to this and potentially other selection biases, the study was inadequately powered for a multivariable analysis.

Other data on the role of adjuvant chemotherapy for pathologic node-positive penile cancer come from smaller, single-center studies. The earliest data on adjuvant treatment came from a pilot study in Milan, Italy, that was published in the late 1980s. Twelve men who had undergone unilateral or bilateral lymphadenectomy for penile cancer, including 5 who had pelvic nodal disease, received weekly vincristine, bleomycin, and methotrexate (VBM) for 12 weeks, with 11 of the 12 patients (92%) alive and disease-free at a median follow-up of 42 months. There were 2 cases of bleomycin-induced lung injury, however.

Poorer survival outcomes were reported in a small German case series evaluating adjuvant bleomycin, methotrexate, and cisplatin (BMP). Three of 8 men (38%) with pN1-3 disease were alive and free of disease at a mean of 4.5 years after adjuvant treatment, and 1 individual died as a result of lung toxicity secondary to bleomycin. Doublet (rather than triplet) chemotherapy has also been investigated in the adjuvant setting in an effort to reduce toxicity and this approach was shown to achieve good outcomes in a retrospective study from Mumbai, India. A combination of paclitaxel with either carboplatin or cisplatin was used in 19 men with high-risk locally advanced disease (defined as perinodal extension, bilateral nodal involvement, and pelvic node disease and those with incomplete surgical resection) and produced a 2-year overall survival of 68%. At a median follow-up of 15 months, 6 men (32%) had suffered a locoregional relapse, and 3 died (2 due to disease and 1 treatment-related death secondary to diarrhea and neutropenic fever).

The latest data on adjuvant therapy from the Milan group recorded disappointingly poor outcomes in 19 men with pN2 or pN3 disease who received adjuvant cisplatin and 5-FU in combination with a taxane (paclitaxel or docetaxel), termed TPF, with a 2-year disease-free survival of 37%. Additionally, there was substantial hematologic toxicity, with 6 cases of grade 3 or 4 anemia, neutropenia, or thrombocytopenia. These investigators recently evaluated factors associated with better outcomes in men who received adjuvant TPF and found that that p53 immunohistochemical positivity in the nodal metastasis seemed to predict for poorer disease-free survival (HR = 3.76 [0.78–17.96], P = .096) and overall survival (HR = 4.29 [0.89–20.57], P = .067) in multivariate analyses, although results did not reach statistical significance. These preliminary results are hypothesis generating and merit further study in ongoing efforts to determine which men with advanced penile cancer might benefit most from adjuvant therapy.

Summary

Table 2 summarizes the current available evidence on the role of adjuvant chemotherapy in node-positive penile cancer. There are no randomized data, and reported follow-up is short, which raises questions on whether a survival benefit from adjuvant chemotherapy can be durable, while attempts to define predictive and prognostic factors are at a very early stage. Although a majority of patients received a platinum-based regimen, the optimal combination (doublet or triplet) is also yet to be defined. Nevertheless, taken together, adjuvant platinum-based therapy does have a role in the management of chemotherapy-naïve patients with pelvic node-positive penile cancer, given the premise that it offers the possibility of long-term survival in this cohort of men who might otherwise be expected to relapse without adjuvant treatment.

Table 2

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