Chapter 38: Penile Cancer

Incidence in United States

Penile cancer most commonly affects men between 50 and 70 years of age. The tumor is not unusual in younger men; in one large series, 22% of patients were younger than 40 years, and 7% were younger than 30 years (¹). In 2015, there were an estimated 1,820 new cases in the United States (²).

Epidemiology

Penile carcinoma accounts for less than 1% of all malignant neoplasms among men in the United States and Europe, but it may represent up to 20% of malignant neoplasms in men in some Asian, African, and South American countries (¹). These differences are thought to be related to the prevalence of neonatal circumcision, human papillomavirus (HPV) infection, and hygienic practices. Rates of HPV vaccination will likely become a factor in the future (³).

Incidence and Significance Worldwide

Among uncircumcised tribes of Africa and within uncircumcised Asian cultures, penile cancer may amount to 10% to 20% of all malignant neoplasms in men (¹). Carcinoma of the penis is particularly rare among the Jewish population, for whom neonatal circumcision is a universal practice (⁴). The annual number of new cases in total per year worldwide has been estimated at approximately 26,000 (⁵). Squamous cell carcinoma is the most common histologic subtype, accounting for over 95% of cases (Table 38-1) (⁶).

Lack of Circumcision

The risk of penile cancer varies according to circumcision practice, hygienic standard, phimosis, number of sexual partners, HPV infection, exposure to tobacco products, and other factors (^1,5). Neonatal circumcision has been well established as a prophylactic measure that removes most of the risk of penile carcinoma because it eliminates the closed preputial environment where penile carcinoma most commonly develops. Phimosis is found in 25% to 75% of patients with penile carcinoma described in most large series. Reddy et al (⁷) studied the foreskins of 26 men undergoing circumcision because of phimosis and found epithelial atypia in one-third of the specimens. Data from most large series show that neonatal circumcision is protective, whereas circumcision delayed until after puberty is not (⁸).

Human Papillomavirus

Although HPV is not a reportable sexually transmitted disease, the number of new genital HPV infections has been estimated at 500,000 to 1 million annually in the United States (⁹). The terms genital condyloma, venereal warts, genital warts, and genital HPV infection all refer to a sexually transmitted disease caused by HPV. Factors associated with higher rates of infection with HPV include presence of foreskin, increasing numbers of sexual partners, lack of condom use, and smoking (¹⁰). The overall prevalence of HPV in females was found to be 26.8% among US females aged 14 to 59 years and was highest among women aged 20 to 24 years (44.8%) (¹¹). Human papillomavirus is recognized as the principal etiologic agent in cervical dysplasia and cervical cancer (¹²).

On histologic examination, the koilocyte—a cell characterized by an empty cavity surrounding an atypical nucleus—is pathognomonic for HPV infection (Fig. 38-1) (¹³). DNA hybridization techniques have been used to identify and classify HPV infections, and some 60 genotypes of HPV virus have been identified that involve the genital tract (¹⁴). Virus types 6, 11, and 42 to 44 are associated with gross condylomata and low-grade dysplasia, whereas types 16, 18, 31, 33, 35, and 39 have a higher association with malignant disease (¹⁵).

In men, a personal history of genital condylomata has been associated with squamous cell carcinoma of the penis (¹⁰). Malignant transformation of condylomata to squamous cell carcinoma has been reported (¹⁶). Condylomata acuminata located in the perianal, scrotal, and oral areas have also demonstrated malignant degeneration. An increased incidence of penile intraepithelial neoplasia has been found in the male partners of women with cervical intraepithelial neoplasia (³).

More than 25 types of HPV infect genital sites. It appears that HPV-16 is the most frequently detected type in primary carcinomas and has also been detected in metastatic lesions (¹⁷). Thus, preventive strategies are relevant, and prophylactic HPV vaccines are available for both men and women (³). The prevalence of HPV vaccination in the United States, however, remains disappointingly low.

Although HPV infection is probably an important factor in the development of penile cancer, with evidence that 31% to 63% of tumors are HPV related, its presence is not invariable (¹⁸). Other factors must be involved in the development of the disease or its subtypes. Human papillomavirus is most associated with the basaloid and warty tumor subtypes, which were found to contain HPV DNA in 80% to 100% of cases.

Patients with HPV-related penile cancer appear to have a better prognosis than those with HPV-unrelated tumors. A population-based study found that the detection of HPV DNA in penectomy specimens was associated with a significant advantage in disease-specific survival (96% vs 82%) (¹⁹). Immunohistochemical detection of p16, which is a marker for HPV infection, was also associated with improved outcome (²⁰). Whether HPV is predictive of response to treatment (eg, chemotherapy) is unknown.

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) infection may predispose affected patients to rapid development of squamous carcinoma from preexisting condyloma infection (²¹). Poblet et al (²²) reported on two cases of coexisting HIV-1 and HPV infection and postulated that HIV-1 could synergize with HPV to increase the progression of HPV penile lesions into penile carcinoma. Whereas there is evidence supporting this effect in cervical and anal neoplasia (²³), definitive proof for penile cancer awaits further study.

Overview of Molecular Features

The viral genes E6 and E7 are overexpressed in HPV-transformed cells, and they are known to interact with the RB1 and TP53 tumor suppressor pathways. These molecular events are known to play a critical role in the development of cervical cancer (¹²), and a similar mechanism probably exists in HPV-related cases of penile cancer (^3,18).

The tumor suppressor gene TP53 is commonly mutated in human solid tumors, where the abnormal protein accumulates and can be detected by positive immunostaining. In penile cancer, positive p53 immunostain is an independent predictor of lymph node metastasis (²⁴). In a study by Lopes et al (²⁵), the p53-positive cases had a lower overall survival and higher incidence of lymph node metastasis. Martins et al (²⁴) studied 50 patients, of which 14 had clinically positive lymph nodes. After penectomy, tumors were stained for p53 and proliferating cell nuclear antigen (PCNA), and these results were compared with stage, grade, nodal status, and cause of death. Overexpression of p53 was associated with pT classification, grade, nodal metastasis, and cause-specific survival. Also, PCNA was associated with nodal metastasis but not survival. Of note, TP53 mutations would not be expected to occur in HPV-related tumors because p53 is inactivated by HPV viral proteins.

Matrix metalloproteinases (MMPs) and cellular adhesion molecules have been studied in penile cancer. Campos et al (²⁶) measured MMP-2 and MMP-9 expression and found that MMP-9 was an independent risk factor for disease recurrence. In the same study, low E-cadherin was associated with a greater risk of lymph node metastasis. A Chinese study (²⁷) found that 45% of tumors had low E-cadherin, and that it was associated with shorter cause-specific survival. These alterations have been found in both HPV-related and unrelated penile tumors (⁵).

Epidermal Growth Factor Receptor

Multiple studies have shown that the epidermal growth factor receptor (EGFR) is overexpressed in the majority of penile cancer cases (^28,29). Activating mutations of EGFR or KRAS, on the other hand are uncommon. Several published case reports and one case series suggested that EGFR is a useful target for therapy in metastatic penile cancer (^30,31,32).

Anatomy of Lymphatic Drainage

Penile cancers have a predictable pattern of local, regional, and systemic spread. The earliest route of dissemination from the penis is metastasis to the regional femoral and iliac nodes. The lymphatics of the prepuce form a connecting network that joins with the lymphatics from the skin of the shaft. These tributaries drain into the superficial inguinal nodes. The lymphatics of the glans join the lymphatics draining the corporal bodies, and they form a collar of connecting channels at the base of the penis that also drain by way of the inguinal lymph nodes. From there, drainage is to the pelvic nodes (external iliac, internal iliac, and obturator). Multiple cross connections exist at all levels of drainage, so that penile lymphatic drainage is bilateral to both inguinal areas (³³).

Frequency of Metastases: Prognostic Factors

Tumor grade, lymphovascular invasion, and perineural invasion appear to be the most important pathologic prognostic factors for nodal spread and mortality (³⁴). Other frequently cited risk factors are pT classification, tumor thickness, anatomical site (proximal vs distal), pathologic subtype, urethral invasion, and positive margins of resection.

Lymphovascular invasion in the primary tumor has significant prognostic importance. Studies have assessed its presence or absence and found that it was an important predictor of nodal metastasis (³⁵). The pathologist should specifically comment on the presence or absence of vascular invasion in the surgical specimen. Perineural invasion was found to be present in 36% of cases analyzed in a multi-institutional data set of 134 patients and was also a strong predictor of lymph node metastasis (³⁶).

Distant Metastasis and Mortality

Metastatic penile cancer is characterized by a relentlessly progressive course, causing death for the majority of untreated patients within 2 years (³⁷). Metastatic enlargement of the regional nodes eventually leads to skin necrosis, chronic infection, and death from sepsis, hemorrhage secondary to erosion into the femoral vessels, and failure to thrive.

Clinically detectable distant metastatic lesions to the lung, liver, bone, or brain are uncommon at initial presentation. Such metastases usually occur late in the course of the disease after the local lesion has been treated. Distant metastases in the absence of regional node metastases are unusual.

Staging System

The American Joint Committee on Cancer (AJCC) seventh edition TNM staging system for penile cancer (Table 38-2) differs from the sixth edition in that pT1 tumors are stratified regarding whether there is high-grade histology or lymphovascular invasion (pT1b) (³⁸). Considering pathologic nodal factors further, the seventh edition distinguishes patients with a single positive node (N1) from those with multiple or bilateral nodes (N2) and further recognizes the ominous prognosis (5%-18% 5-year survival) associated with extranodal extension of cancer.

Limitations of the Staging System

A study from the Netherlands Cancer Institute evaluated the practical and prognostic value of the sixth edition TNM classification for penile carcinoma (Table 38-3) (³⁹). The current T2 category combines tumors that invade either the corpus spongiosum or the corpora cavernosa (³⁸). The 5-year disease-specific survival for tumors invading the corpus spongiosum in the Dutch series was 77.7% and for tumors invading the corpora cavernosa was 52.6%, suggesting that the capacity of a tumor to penetrate the tunica albuginea covering the corpora cavernosa is a more invasive characteristic. The Dutch investigators also suggested that the T3 category appears to be obsolete because a distally located tumor that invades the urethra can still be treated with good prognosis; they proposed that invasion of the corpora cavernosa should be designated T3 (⁴⁰).

The Dutch study did not find a significant difference in 5-year disease-specific survival between the N1 and N2 category (70.2% and 58.3%, respectively; P = .18), and the authors proposed designating all unilateral inguinal (mobile) lymph node metastases as N1, bilateral inguinal (mobile) lymph nodes as N2, and any fixed groin mass as N3 (³⁹). They also noted the difficulty of distinguishing superficial from deep inguinal lymph nodes, which is not always possible to do either clinically or on histopathologic analysis of a surgical specimen. The seventh edition TNM does not distinguish superficial from deep inguinal lymph nodes and does recognize the prognostic significance of a fixed groin mass as N3. The N2 category, however, still includes two or more unilateral, mobile lymph nodes, where the prognosis with two to three nodes is probably better than with more than three nodes involved (^38,40).

Thus, the 2010 TNM classification, while an improvement over previous versions, still necessitates caution with respect to prognosis in the assessment of deep inguinal lymph nodes (regarding whether they are truly inguinal or pelvic lymph nodes) and in considering laterality as well as the number of inguinal lymph nodes involved. Also, bulky inguinal lymph nodes that are mobile and suspected of having extranodal extension based on imaging are still classified as N1 or N2; such cases would likely be pN3 on histopathologic confirmation of extranodal involvement (⁴¹). Patients with clinical N1 or N2 and computed tomographic (CT) scan appearance suggestive of extranodal extension should be regarded as being at higher risk.

Evaluation of Palpable Lymph Nodes

Palpable inguinal lymph nodes are found at presentation in 28% to 64% of patients with penile cancer, but not all of these represent metastatic tumor. Lymphadenopathy is caused by metastasis in 47% to 85% of cases, whereas the rest are secondary to inflammation (³⁵). Approximately 25% of patients with palpable lymph nodes will have bilateral metastases. Careful note should be made of the uni- or bilateral location of palpable adenopathy, diameter, number in each inguinal area, whether mobile or fixed, relationship to other structures (eg, skin) with respect to infiltration or perforation, and presence of leg or scrotal edema. The National Comprehensive Cancer Network and European Association of Urology guidelines for penile cancer recommend fine-needle aspiration (FNA) of palpable inguinal lymph nodes (^42,43).

Staging Groin Dissection

While treatment of the primary tumor and a period of antibiotics may be useful to help sterilize the inguinal region, this practice is no longer advocated as a tool to select patients who either should or should not undergo lymphadenectomy. One alternative to immediate lymphadenectomy for all patients has been to observe patients with normal findings on inguinal examination. Lymphadenectomy is subsequently reserved for those patients who develop palpable lymph nodes. The reluctance to advocate automatic ilioinguinal lymphadenectomy in all patients with penile cancer stems from the substantial morbidity the procedure can produce. Early complications of phlebitis, pulmonary embolism, wound infection, flap necrosis, and permanent and disabling lymphedema of the scrotum and lower limbs were frequent after both inguinal and ilioinguinal node dissections (³⁵). Postoperative complications have been reduced by improved preoperative and postoperative care and advances in surgical technique. The mortality of complete inguinal lymph node dissection by an experienced surgeon is about 3% (⁴⁴).

Several studies have analyzed the survival of men undergoing early versus delayed lymphadenectomy according to pathologic evaluation of nodal status. McDougal et al (⁴⁵) reported a series of 23 patients with invasive primary lesions and nonpalpable nodes; 9 patients were treated with immediate adjunctive lymph node dissection (6 were positive), and 14 were treated with surveillance and delayed lymph node dissection. The 5-year survival in the node-positive immediate adjunctive lymphadenectomy group was 83% (5 of 6 patients), whereas in the surveillance group, the 5-year survival was 36% (5 of 14 patients). A third subset in this series had palpable nodes at presentation and had immediate therapeutic lymph node dissection, with 10 of 15 patients (66%) surviving 5 years. The best results were from immediate adjunctive lymph node dissection (83%), with the next best from immediate therapeutic lymphadenectomy (66%). The worst results were from the surveillance and delayed lymphadenectomy group (36%), in whom dissection was delayed until palpable nodes developed. The interval of opportunity for cure in this third group appears to have been lost.

Similarly, Fraley et al (⁴⁶) reported that immediate adjunctive lymphadenectomy resulted in a 5-year disease-free survival in 6 of 8 node-positive patients (75%) compared with 1 of 12 patients (8%) who had been followed up and then treated by delayed lymphadenectomy when nodal enlargement occurred. Six other patients in that series also presented with unresectable adenopathy after initial surveillance, and all died of disease. Although only two of six immediate lymphadenectomy patients had more than two positive nodes, all the patients treated by delayed lymph node dissection had three or more positive nodes.

A series from MD Anderson Cancer Center (⁴⁷) compared 5-year disease-free survival of 14 patients undergoing early lymphadenectomy for clinically suspicious and histologically node-positive disease with that of 8 patients who were followed up and later underwent lymphadenectomy when clinical nodal enlargement was undisputed. The primary tumors were of similar stage. The 5-year disease-free survival was 57% for early lymphadenectomy compared with 13% for delayed node dissection. Of note, the number of involved nodes in the immediate lymphadenectomy group (median 2) was half that of the delayed lymphadenectomy group (median 4), and no patient with more than two positive nodes survived more than 5 years.

Data from these and other studies suggest that a policy of immediate adjunctive or early lymphadenectomy gives greater assurance that surgical intervention will occur when tumor volume is small. For patients at highest risk of lymph node metastases based on features in the primary tumor, surgical staging can be performed by complete bilateral inguinal lymph node dissection, which may also be curative in cases of small-volume metastases. Moreover, experience has suggested that lymphadenectomy in the setting of microscopic disease may be less likely to produce complications than node dissection in the presence of bulky nodal metastases. This is presumably due to the reduced amount of lymphatic tissue removed, preservation of venous drainage, and blood supply compromised, which affect the viability of skin flaps and lymphatic flow.

In patients with nonpalpable inguinal lymph nodes, if ultrasound-guided FNA of any questionable lymph node is tumor negative, dynamic sentinel lymph node biopsy (DSNB) can be performed if the equipment and expertise are available (^35,48). In patients at intermediate risk of inguinal lymph node metastases, sentinel lymph node biopsy or modified (superficial) inguinal lymph node dissection may be performed if DSNB is not feasible.

Computed Tomographic Imaging

Patients with clinically palpable lymph nodes should undergo imaging to define the full extent of disease. Both CT and magnetic resonance imaging (MRI) scanning techniques depend primarily on lymph node enlargement for detection of metastases but are unable to define the internal architecture of normal-size nodes (⁴⁸). Because CT and MRI have similar accuracy in detecting lymphadenopathy in other cancers, CT has often been the imaging modality chosen in penile cancer to examine the inguinal and pelvic areas as well as to rule out more distant metastases (Fig. 38-2).

Computed tomographic scanning facilitates the examination of the inguinal region in obese patients or in those who have had prior inguinal surgery, for whom the physical examination may be unreliable. In addition, in patients with known inguinal metastases, CT-guided biopsy of enlarged pelvic nodes may provide important information for consideration of neoadjuvant chemotherapy. Otherwise, the addition of CT imaging does not appear to improve the sensitivity or specificity of lymph node detection when compared to physical examination in patients with a normal inguinal examination.

Positron Emission Tomographic Imaging

Scher et al (⁴⁹) evaluated positron emission tomography (PET)/CT among 13 patients with penile cancer. Five of thirteen patients had metastatic disease, and PET/CT detected four of five patients (80% sensitivity). There may be a role for PET/CT in the detection of lymph node disease in penile cancer; however, the sensitivity of PET/CT is limited for smaller size lymph nodes (Fig. 38-3).

Local Control

Surgical amputation of the primary tumor remains the oncologic gold standard for rapid definitive treatment of the penile primary tumor; local recurrence rates range from 0% to 8% (⁴⁵). Amputation is often necessary for bulky stage T2-T4 tumors, but it has been shown to decrease sexual quality of life (⁵⁰). It is generally accepted that patients with penile primary tumors exhibiting favorable histologic features (stages Tis, Ta, T1; grades 1 and 2 tumors) are at a lower risk for metastases. These patients are also best suited for organ-sparing or glans-sparing procedures, with the goal of preserving glans sensation where possible or at least to maximize penile shaft length. Such approaches include topical treatments (fluorouracil or imiquimod cream for Tis only), radiotherapy, Mohs surgery, limited excision strategies (eg, circumcision), and laser ablation (^{51,52,53,54,55}).

Partial or total penectomy should be considered in patients exhibiting adverse features that defy adequate control by organ preservation strategies. These include tumors of size 4 cm or more, grade 3 lesions, and those invading deeply into the glans, urethra, or corpora cavernosa.

Therapeutic Lymph Node Dissection

The biology of penile cancer is such that it exhibits a prolonged locoregional phase before distant dissemination. Lymphadenectomy alone can be curative and should be incorporated into the treatment planning for most patients. However, due to the morbidity of traditional lymphadenectomy, especially among those patients with clinically negative groins, contemporary controversial issues include the following: (1) the selection of patients for lymphadenectomy versus careful observation; (2) the types of procedures to correctly stage the inguinal region with low morbidity; and (3) multimodality strategies (eg, neoadjuvant chemotherapy, see further in the chapter) to improve survival among patients with bulky inguinal metastases.

The presence and the extent of metastasis to the inguinal region are the most important prognostic factors for survival in patients with squamous cell carcinoma of the penis. The survival rates for therapeutic lymph node dissection in patients with established regional lymph node metastases are variable, averaging about 60% (range, 0%-86%) (^35,46,48). This variability in survival rates is directly attributable to the extent of nodal metastasis. Patients with pN1 or pN2 with a minimal number of lymph nodes involved have an average 5-year survival of 77%, compared with only 25% when a greater degree of nodal involvement is present. In one study (⁵⁶), the 5-year survival of patients with extranodal involvement was only 6% (1 of 17 patients). The combined results of several small series suggest an average 5-year survival of 15% when pelvic lymph nodes are present.

Taken together, these data suggest that the pathologic criteria that predict long-term survival (ie, 80% 5-year survival rate) after attempted curative surgical resection of inguinal metastases are (1) minimal nodal disease (up to two involved nodes in most series); (2) unilateral involvement; (3) no evidence of extranodal extension of cancer; and (4) absence of pelvic nodal metastases.

Chemotherapy for Stage IIIB/IV Penile Carcinoma

The first candidate drugs for the chemotherapeutic treatment of stage IIIB/IV penile carcinoma included cisplatin, vincristine, methotrexate, fluorouracil, mitomycin, and bleomycin (^37,57). In a multicenter study conducted by the Southwest Oncology Group (SWOG) (⁵⁸), 26 patients with metastatic penile cancer received single-agent cisplatin at a dosage of 50 mg/m² on days 1 and 8 of each 28-day cycle. Only four patients (15%) experienced responses that persisted for 1 to 3 months.

The combination of bleomycin, methotrexate, and cisplatin (BMP) was studied in phase II clinical trials. In a single-institution study conducted at MD Anderson Cancer Center (⁵⁹), 30 patients with squamous cell carcinoma of the urinary tract, including 21 men with metastatic penile carcinoma, received bleomycin at a dosage of 50 mg/m² on days 2 to 6, cisplatin at 20 mg/m² on days 2 to 6, and methotrexate at 200 mg/m² with leucovorin rescue on days 1, 15, and 22 of each 28-day cycle. There were 12 responses (55%) in the group with penile carcinoma, and the median duration of response was 4.7 months for the entire study. A second phase II study was conducted by the SWOG (⁶⁰), in which patients received bleomycin at a dosage of 10 U/m² on days 1 and 8, methotrexate at 25 mg/m² on days 1 and 8, and cisplatin 75 mg/m² on day 1 of each 21-day cycle. Among 40 evaluable patients, there were 5 complete and 8 partial responses for an overall response rate of 32.5%, which narrowly exceeded the predetermined target rate of 30%. The median response duration was 16 weeks, and the estimated median survival time was 28 weeks. The toxicity of the regimen was considerable, however, with five treatment-related deaths due to bleomycin lung toxicity, other pulmonary causes, and infection. The BMP regimen and bleomycin in particular are no longer recommended for the treatment of penile cancer because of the unacceptable toxicity.

Other cisplatin-based drug combinations demonstrated response rates of 8% to 50% (Table 38-4) (^{61,62,63,64,65}). A regimen would be of interest if it has an overall response rate greater than 30% with acceptable toxicity. The study of irinotecan/cisplatin conducted by the European Organization for Research and Treatment of Cancer (⁶¹) was a prospective study with 26 evaluable patients, but was interpreted as having a negative result by the authors because the response rate had an 80% confidence interval of 18.8% to 45.1%, extending well below 30%. In another study, paclitaxel, ifosfamide, and cisplatin was given to patients with metastases limited to the inguinal and pelvic lymph nodes (⁶²). In this neoadjuvant study, patients with response or stable disease after four courses underwent surgery with curative intent. The response rate was 50%, and the safety profile of this regimen was an improvement over BMP, with no treatment-related deaths. In another study of taxane drugs for the treatment of metastatic penile cancer, docetaxel, 5-fluorouracil, and cisplatin resulted in a response rate of 38.5% (⁶³). The response rate was not high enough to recommend this regimen in preference to 5-fluorouracil and cisplatin, and grade 3 and 4 toxicities were frequent.

5-Fluorouracil and cisplatin were studied in a retrospective series of patients with metastatic penile cancer (⁶⁴). Partial responses had been seen in 8 of 25 evaluable patients (32%). While there have been no randomized controlled trials to establish a single standard of chemotherapy treatment for metastatic penile cancer, either 5-fluorouracil plus cisplatin or paclitaxel, ifosfamide, and cisplatin have been endorsed by contemporary guidelines (^42,43).

Multimodality Therapy

Neoadjuvant Chemotherapy

As discussed in the section on therapeutic lymph node dissection, the 5-year overall and disease-free survival rates with surgery alone are as high as 80% for unilateral, superficial inguinal lymph node involvement with no more than two nodes (stage N1 or limited N2), only 10% to 20% for stages N2 and N3 (multiple, bilateral, or pelvic lymph nodes involved), and less than 10% in the presence of extranodal extension (⁶⁶). Nearly all recurrences are detected within 2 years of surgery, and an aggressive, multimodality approach to the treatment of high-risk patients could result in better overall survival (^37,57,67).

In 1988, a team of Italian investigators reported their experience with adjuvant or preoperative (neoadjuvant) bleomycin, vincristine, and methotrexate for patients with penile carcinoma and metastases confined to the inguinal lymph nodes (⁶⁸). In the neoadjuvant group, five patients with fixed inguinal nodes received weekly bleomycin (30 mg intramuscularly), vincristine (1 mg intravenously), and methotrexate (30 mg orally). Three of those five patients had a sufficient tumor response that they could undergo surgical consolidation, and they were reported to be alive and disease free at 20, 27, and 72 months after surgery. The other two patients experienced less-than-partial responses, did not undergo surgery, and survived less than 12 months. This study, although small, demonstrated that perioperative chemotherapy for locally advanced penile carcinoma was feasible.

A group from the Netherlands reported on their retrospective analysis of 20 patients who had received preoperative chemotherapy to downstage unresectable disease (⁶⁹). Seventeen patients had had bulky lymph node metastases (Tx, N3), and the other three had had advanced primary tumors (T3-T4, N0-N1). The most commonly used regimens in the Dutch series, which spanned a 34-year period, had been BMP (n = 10); bleomycin, vincristine, and methotrexate (n = 5); and single-agent bleomycin (n = 3). Severe toxicity had occurred in four patients, including three treatment-related deaths. Twelve patients had experienced an objective tumor response; nine of the twelve had undergone surgery, and eight had achieved long-term disease-free survival. Two patients had no residual tumor in the surgical specimen. The finding of pathologic complete responses suggested that this finding could be used as a screen for efficacy.

A retrospective study from MD Anderson Cancer Center reported a series of 10 patients who had received neoadjuvant chemotherapy (⁷⁰). The reported experience spanned a 15-year period at one institution and was limited to patients who had undergone aggressive lymph node dissections after having experienced a response or stable disease after chemotherapy. The regimens given preoperatively had been BMP (n = 3); paclitaxel and carboplatin (n = 2); and paclitaxel, ifosfamide, and cisplatin (n = 5). Four patients had complete responses, and one had a partial response. Three patients had a pathologic complete response in the lymph nodes; all of these patients had received paclitaxel, ifosfamide, and cisplatin, and all had biopsy-confirmed metastases prior to chemotherapy. Four patients had experienced long-term disease-free survival.

Neoadjuvant chemotherapy was next studied prospectively in a phase II clinical trial conducted at MD Anderson Cancer Center (⁶²). Thirty patients with clinical TX N2-N3, M0 penile cancer received four courses of paclitaxel, ifosfamide, and cisplatin prior to a planned complete bilateral inguinal lymph node dissection and uni- or bilateral pelvic lymph node dissection. Fifteen patients (50%) experienced a partial or complete response to chemotherapy. Twenty-two patients (73%) were able to complete the neoadjuvant chemotherapy and surgery, of whom there were three patients (14%) with a pathologic complete response in the lymph nodes (see Fig. 38-4). Objective response to chemotherapy, absence of bilateral residual tumor, and absence of extranodal extension in residual tumor were associated with a higher rate of overall and progression-free survival in a univariable analysis (Fig. 38-5).

The overall and progression-free survival rates in N2-N3 disease achieved with neoadjuvant paclitaxel, ifosfamide, and cisplatin are an improvement over the expected survival with surgery alone. Despite the absence of a randomized controlled trial, contemporary guidelines have recommend neoadjuvant paclitaxel, ifosfamide, and cisplatin for patients presenting with bulky/high-risk regional lymph node metastases (⁴²).

Adjuvant Chemotherapy

Adjuvant chemotherapy has the advantage of allowing patient selection based on accurate pathologic staging. Unfortunately, a randomized controlled trial of adjuvant chemotherapy would not be feasible due to the low incidence of penile carcinoma and the large number of patients necessary to power such a trial. The development of neoadjuvant chemotherapy as standard treatment appears to be more achievable and has advantages of downstaging to facilitate surgery, better tolerance of chemotherapy in the preoperative setting, and earlier exposure of micrometastases to the chemotherapy agents. Tumor response can be detected in the neoadjuvant setting, but not in the adjuvant setting, and the histopathologic findings of postchemotherapy surgery provide an early indicator of the treatment effect and prognosis (Fig. 38-6) (⁷¹).

In cases where patients have undergone surgery without neoadjuvant chemotherapy and are found to have multiple inguinal or any pelvic lymph nodes involved or extranodal extension, then a regimen such as paclitaxel, ifosfamide, and cisplatin can be administered as adjuvant therapy on the basis of extrapolation from the neoadjuvant data.

Radiotherapy Combined With Surgery or Chemotherapy

Studies of radiotherapy in penile carcinoma have included penis-sparing treatment for small (T1-T2, <4 cm) primary tumors, treatment of lymph node metastases, postoperative radiotherapy, and chemoradiotherapy (^54,57). There are no published randomized trials of multimodality treatment with radiotherapy in penile cancer, as there are in squamous cell carcinomas from other sites. For example, radiotherapy with surgical lymphadenectomy has been studied in women with cancer of the vulva, a disease site that has natural history and nodal drainage similar to those of the penis. On the basis of these studies, the standard of care for metastatic vulvar cancer is radiotherapy to the pelvis rather than pelvic lymph node dissection (⁷²). Pelvic lymph node dissection remains the standard of care for penile cancer patients following definitive treatment of inguinal lymph node metastases (⁴²). Thus, a randomized trial in penile cancer would be informative concerning the optimal method for consolidation of pelvic lymph nodes.

International Randomized Trial

It has not been possible to conduct randomized controlled trials in penile cancer to answer basic questions. One of the studies currently being developed and discussed by the International Rare Tumors Initiative (IRCI) is a 400-patient trial to be conducted in the United Kingdom, United States, and Canada (⁷³). The International Penile Advanced Cancer Trial (InPACT) uses a Bayesian design for randomized treatment of patients with inguinal lymph node metastases from penile cancer. The trial has two independent randomizations, addressing key questions in the clinical pathway: first, the role of neoadjuvant therapy prior to standard surgery, by randomizing to chemotherapy, chemoradiotherapy, or no neoadjuvant therapy; and second, the role of prophylactic pelvic lymph node dissection following the standard surgery with therapeutic inguinal lymph node dissection. The primary outcome measure of the InPACT study is overall survival.

The treatment of men with squamous cell carcinoma of the penis has evolved considerably in recent years, along with our understanding of its molecular biology. Penis-sparing strategies for early-stage disease allow for better outcomes in terms of comfort, dignity, and quality of life. Neoadjuvant chemotherapy is now standard of care for patients presenting with bulky regional lymph nodes. An ambitious international randomized trial proposes to compare neoadjuvant and adjuvant as well as surgical and radiotherapeutic strategies in this clinical setting. Meanwhile, vaccination of both men and women against HPV offers to reduce the risk of cancer, particularly for uncircumcised men who are already at increased risk. Viral antigens are a promising target for the immunotherapeutic treatment of penile cancer and suggest a possible role in this disease for drugs that exert immune checkpoint blockade. On the basis of these considerations, one could conclude that we are entering a period of rapid development in the treatment of patients with penile cancer.