Penile squamous cell carcinoma (PSCC) is relatively rare in Japan, with an incidence of 0.4 per 100,000 of the male population [1]. The majority of PSCCs are diagnosed when they are still localized. Although localized PSCC has a good prognosis after radical resection, cases of unrespectable, recurrent, and metastatic disease, with a poor prognosis, can also be seen [2-5]. The penile cancer guidelines of the National Comprehensive Cancer Network (NCCN) recommend neoadjuvant chemotherapy, radiotherapy, or chemoradiotherapy followed by consolidation surgery for the management of advanced and recurrent disease, provided that the disease is stable or a clinical response is demonstrated [6]. However, there are currently no guidelines for the management of PSCC in Japan. Hence, many Japanese urologists treat PSCC patients based on the guidelines from NCCN or European Association of Urology [2,6].

Chemotherapy regimens for PSCC have switched from monotherapy with a single anticancer agent to cisplatin-based combination chemotherapy. We used a combination regimen of cisplatin, methotrexate, and bleomycin (CMB) for advanced, recurrent, or metastatic PSCC patients (n=12) between 2002 and 2009. The CMB regimen was first described by Corral et al. [7]. Sixteen of the 29 advanced-stage genitourinary SCC patients treated with this regimen had an objective response and the median overall survival (OS) of patients who were disease free following surgery or external beam radiotherapy was significantly longer than that of patients who were not disease free [7]. Subsequently, this regimen has been widely used as one of the effective chemotherapy regimens for advanced PSCC. In this study, we retrospectively analyzed the efficacy and toxicity of CMB chemotherapy in PSCC patients.

Patients and Methods

The CMB regimen was administered to 12 patients with advanced, recurrent, or metastatic PSCC in our department at Yokohama Municipal Citizen’s Hospital, National Sagamihara Hospital, and Yokosuka Kyosai Hospital between February 2002 and July 2009. Patients received 20.0 mg/m² of cisplatin intravenously on days 2-6; 200.0 mg/m² of methotrexate intravenously on days 1, 15, and 22; and a bolus of 10.0 mg/m² of bleomycin on days 2-6 [7]. The CMB regimen consisted of 21-28 days of treatment per cycle.

Of the 12 patients included in this study, 7 had advanced-stage PSCC and 5 had recurrent (n=4) or metastatic (n=1) PSCC. Four advanced-stage PSCC patients received 1 cycle of neo adjuvant CMB therapy followed by surgical resection and 1 or 2 cycles of adjuvant CMB therapy. The remaining advanced-stage PSCC patients (n=3) received 1 cycle of adjuvant CMB therapy.

The 5 patients with recurrent or metastatic PSCC received 1 or 2 cycles of CMB therapy. Of these, 1 patient had inguinal lymph node and lung metastases. The remaining 4 patients had local recurrence or lymph node metastasis after the initial surgery. One patient received adjuvant CMB therapy after inguinal metastatic lymph node dissection. Four patients with recurrent or metastatic PSCC, who responded to CMB or had stable disease during CMB treatment, were continued on CMB until there was evidence of disease progression or adverse effects were observed (Table 1).

A maximum of 3 courses of this regimen were administered to avoid exceeding the maximum permissible dose for bleomycin. Adverse effects were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0 [8]. When patients had disease in an evaluable region, the response was assessed after each cycle of chemotherapy, according to changes in the radiographic evidence of the disease. Responses were classified as follows: a complete response, a partial response (>50.0% reduction), a minor response (25.0-50.0% reduction), stable disease, or progressive disease, using the sum of the products of the perpendicular diameters of the measured lesions [9].

The surviving patients were followed-up and assessed at 3-month intervals for the first 2 years and at 6 month intervals thereafter. The cancellation criteria for CMB were as follows: (1) development of progressive disease after treatment; up to 3 courses were administered for stable disease; (2) occurrence of an adverse event of Grade 3 or higher. Patients were staged according to the 2009 edition of the TNM classification system [10]. OS was measured from the date the initial cycle of CMB therapy was started to the date of the last follow-up. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test.

All statistical analyses were conducted using Statistical Package for the Social Sciences for Macintosh, software version 22.0 (IBM Corp., Armonk, NY, USA). A p value <0.05 was considered statistically significant. This study protocol was approved by the appropriate Ethical Review Board committee of Yokohama City University Medical Center (Yokohama, Japan) (IRB approval number D1209028). Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. All participants provided informed written consent.

Patients’ characteristics, effects of the CMB regimen, and survival information are summarized in Table 1 and 2.

Table 1: Patient characteristics and outcomes [NA: Not Applicable; PR: Partial Response; MR: Minor Response; SD: Stable Disease; PD: Progressive Disease; NED: No Evidence Disease; DOD: Died of Disease; LN: Lymph Node; ILND: Inguinal Lymph Node Dissection; PLND: Pelvic Lymph Node Dissection; EBRT: External Beam Radiation Therapy; CMB: Cisplatin, Methotrexate Bleomycin].

Table 2: Effect of cisplatin, methotrexate, and bleomycin (CMB) chemotherapy on our cases.

The mean age of the 12 patients enrolled in our study was 61 (61.0 ± 8.7) years and the median follow-up duration was 50.8 ± 45.2 (range, 6.4-146.6) months. A total of 21 cycles of CMB therapy were administered. Of the 7 patients with advanced disease who received 14 cycles of CMB therapy as neoadjuvant and/or adjuvant treatment, partial and minor responses were each observed in 2 patients (33.3%). Five patients (41.7%) survived and 1 patient died of local recurrence and lung metastasis after treatment. One patient (8.3%) died of interstitial pneumonia due to adjuvant chemotherapy. In 5 patients with recurrent or metastatic PSCC, only 1 patient exhibited a minor response (8.3%). Progressive and stable diseases were observed in 1 (8.3%) and 2 patients (16.7%), respectively. Three of these 4 patients died of PSCC. One patient with lung metastasis died of interstitial pneumonia, after just 1 cycle of CMB therapy. Only 1 patient in this group survived with no evidence of disease for 81 months after receiving 2 cycles of adjuvant chemotherapy following inguinal metastatic lymph node dissection.

A Kaplan-Meier curve for OS of the 12 patients included in this study is displayed in Figure 1. The median OS of the 8 patients who were disease free was significantly longer than that of the 4 patients who still had the disease (54.3 months vs. 19.3 months, p=0.028). Across the 21 cycles administered no adverse hematological effects of Grade 3 or higher were observed. Non-hematological toxicities of Grade 3 or higher included interstitial pneumonia in 2 patients (9.5%), urticaria in 1 patient (4.8%), nausea in 1 patient (4.8%), anorexia in 1 patient (4.8%), and stridor (diagnosis was not interstitial pneumonia) in 1 patient (4.8%). Two patients (9.5%) with interstitial pneumonia died (Table 3).

Figure 1: Kaplan-Meier curve of overall survival for penile squamous cell carcinoma patients who were disease free (n=7) and those who were not (n=5).

Table 3: Adverse effects of cisplatin, methotrexate, and bleomycin (CMB) treatment observed in our study.

There are currently no guidelines for the management of PSCC patients in Japan. A treatment system for PSCC has recently been developed through the introduction of the European Association of Urology [2] and NCCN [6] guidelines in Japan.

According to the European Association of Urology guidelines [2], adjuvant chemotherapy is recommended for patients with N2-3 metastases. In patients with bulky or fixed inguinal lymph node metastasis or distant metastasis, neoadjuvant chemotherapy followed by surgery is also recommended. Cisplatin-based chemotherapy regimens have been shown to improve outcomes in patients with advanced-stage disease compared to non-cisplatin-based chemotherapy regimens [2,11]. Furthermore, taxanes can enhance the efficacy of the regimen [2,12].

Conversely, according to the NCCN guidelines [6], neoadjuvant chemotherapy should be considered as the standard treatment for patients with initially unresectable primary tumors or inguinal lymph nodes of >4 cm, if fine needle aspiration is positive. The NCCN guidelines recommend paclitaxel, ifosfamide, and cisplatin combination therapy [6], with regimens containing bleomycin no longer recommended [12]. Although the outcomes of adjuvant chemotherapy are yet insufficient to support its use, it is reasonable to administer 4 cycles of the paclitaxel, ifosfamide, and cisplatin regimen in an adjuvant setting [6].

The CMB regimen was first described by Corral et al. [7]. The authors treated 29 advanced-stage genitourinary SCC patients with the CMB regimen. Sixteen patients (55.2%) had an objective response and the median OS of patients who were disease free following surgery or external beam radiotherapy was significantly longer than that of patients who were not disease free (34.4 vs. 7.0 months) [7].

Haas et al. reported the effects of combination chemotherapy with CMB in 45 patients with advanced or metastatic PSCC [13]. Although the drug dose and schedule of administration were different from those reported by Corral et al. [7], of the 45 patients enrolled, 5 exhibited a complete response and 8 exhibited a partial response, giving a total response rate of 32.5%. However, 5 patients died due to the toxicity of the regimen [13]. Hakenberg et al. treated 13 patients with advanced or metastatic PSCC with a similar regimen to ours, and reported that 3 of the 8 patients treated with adjuvant chemotherapy had no evidence of disease [14]. However, 5 patients with metastatic PSCC died of the disease. The authors also reported that 2 patients died of pulmonary toxicity due to chemotherapy.

Our study comprised 7 patients with advanced-stage PSCC and 5 patients with recurrent or metastatic PSCC. Although 5 of the 7 (71.4%) patients who received adjuvant and/or neoadjuvant CMB therapy survived without evidence of recurrence, 4 of the 5 patients with recurrent or metastatic disease who were treated with CMB therapy died of their disease with little effect of the CMB regimen. Patients who achieved a disease-free status survived significantly longer than those who did not.

Our study had some limitations, including the small sample size (12 patients) and the retrospective nature. However, in Japan, patients with PSCC are extremely rare [1] and there have been limited studies about PSCC. Hence, we believe that collaborative multi-center research is necessary to determine new treatments for advanced PSCC in Japan.

In conclusion, our findings suggest that the CMB regimen is effective as adjuvant and/or neoadjuvant chemotherapy for advancedstage PSCC patients, but not for recurrent or metastatic PSCC patients, corroborating the findings by Hakenberg et al. [14]. Additionally, 2 patients died of interstitial pneumonitis due to chemotherapy. Although generally only bleomycin is considered to induce interstitial pneumonitis, methotrexate has also been reported to induce pulmonary toxicity [15]. Given that pulmonary toxicity is a life threatening adverse effect and safer and comparably effective treatments are emerging [16], we recommend that the CMB regimen should not be used as a first-line treatment option in patients with advanced-stage or metastatic PSCC.

We wish to thank Editage (www.editage.jp) for English language editing.

The authors declare no conflict of interest and no funding has been received for this work.