Penile Cancer

6. DISEASE MANAGEMENT

6.1. Treatment of the primary tumour

Besides its role in sexual functioning and urination, a fully functional penis is central to a patient’s sense of wholeness, desirability and masculinity. Hence, the aims of the treatment of the primary tumour are complete tumour removal with as much organ preservation as possible, without compromising oncological control.

There are no RCTs or observational comparative studies for any of the treatment options for localised penile cancer. Penile preservation appears to be superior in functional and cosmetic outcomes as compared to partial or total penectomy and is considered to be the primary treatment method for localised penile cancer, based on retrospective studies.

Histological diagnosis and local staging must be obtained before non-surgical treatments can be considered. For small tumours, excisional biopsy can equal treatment, while for larger lesions which necessitate more complex or mutilating surgery, an incisional biopsy is advised (see Section 3.4.6). Histology provides confirmation of the diagnosis before treatment and informs on the risk group of the primary tumour which has important consequences for invasive staging of the groins. With surgical treatment, negative surgical margins for invasive carcinoma must be obtained. Treatment of the primary tumour and of the regional nodes can either be simultaneous or staged.

Local treatment modalities for small and localised penile cancer include topical therapy, laser ablation, excisional surgery, external beam radiotherapy (EBRT) and brachytherapy. Unfortunately, the SR of the Guidelines Panel revealed a complete absence of both RCTs and prospective trials assessing and comparing the effectiveness of interventions for managing the primary tumour [3]. Treatment recommendations can therefore only be based on retrospective data and expert opinion. In the absence of comparative evidence supporting treatment modalities, patients should be informed about all appropriate treatment options for their specific tumour and situation, and the potential advantages and disadvantages for each technique which are discussed per disease stage in the following sections.

6.1.1. Treatment of superficial non-invasive disease (PeIN, Ta)

Penile intra-epithelial neoplasia can progress to invasive lesions in 2.6–13% of patients, despite treatment; hence, definitive eradication and diligent follow-up monitoring are important [127-129]. Most PeIN lesions are located on the mucosal surfaces of the glans or prepuce whilst lichen sclerosus also affects the prepuce [128]. Thus, circumcision should be the primary surgical option [129]. Following circumcision, the glans mucosa keratinizes over a period of 3–6 months and any residual PeIN or lichen sclerosus may resolve. Close monitoring before starting additional therapy has been advocated, but to date, data supporting this concept are limited [129]. Considering a median time to progression to malignancy of thirteen months [128], this approach seems reasonable to test in future clinical trials.

6.1.1.1. Topical therapies

Topical therapy with imiquimod (IQ) or 5-fluorouracil (5-FU) are effective non-invasive first-line treatment options which use is increasingly reported [130]. 5-Fluorouracil exerts its effects through inhibition of the enzyme thymidylate synthase. Although no standard protocol exists, leaving the 5-FU ointment on for 12 hours every 48 hours during a 4 to 6-week treatment course is often recommended in reported series of PeIN therapy [131]. Imiquimod acts through several pathways including activation of immune cells via toll-like receptor 7, creating an inflammatory response, and is commonly used 3 times per week for 12 weeks. There is no consensus or comparative data on the optimal treatment schedules for these therapies and the evidence for these treatments is heterogenous as it only relies on retrospective studies. A SR based on the aforementioned low-quality data illustrated that topical agents showed response- and recurrence rates of 40–100% and 20% for IQ, vs. 48–74% and 11% for 5-FU, respectively [132]. Because use of 5-FU typically results in marked erythema, erosions, and crust lasting for a month or longer, decreased patient compliance with treatment regimens may result in diminished effectiveness. Similarly, IQ use is complicated by the resultant tissue effects, including erythema, oedema and erosions, ulceration and crust, that are not consistent from one individual to the next [133]. Discontinuation of topical agents because of side effects was observed in 12% of cases [132]. It is advised that treatment effects must be clinically assessed and in cases of doubt evaluated by biopsy and long-term surveillance is warranted. Insufficient responses and recurrences may signify underlying invasive disease, hence, if topical treatment fails, it should not be repeated.

6.1.1.2. Laser ablation

Laser ablation is an alternative treatment option. Energy-based therapies discussed in the literature include Neodymium:Yttrium-Aluminium-Garnet (Nd:YAG, penetration 4–61398042195mm, wavelength 1064 nm) or Carbon dioxide (CO₂, penetration < 1 mm, wavelength 10600 nm) lasers and photodynamic therapy [134]. Laser treatment has shown total response rates of 52–100% with recurrence reported in 7–48% of patients [132]. Altered penile sensitivity following laser treatment has been described, including increased sensitivity in 50% and decreased sensitivity in 15% of patients. Reports show relatively high rates of local recurrence, possibly owing to inadequate penetration, difficulties in assessing borders of affected areas and missing lesions that have invaded the subepithelial tissue [10,135,136]. Repeat laser treatment for recurrence has been described in some series without compromising long-term oncological outcomes, which is likely a result of the low risk of the lesions treated in those series [137,138]. For cryotherapy, with or without topical therapy, and photodynamic therapy, which induces photo-selective cell death, there are only limited data for the treatment of PeIN.

6.1.1.3. Surgery

Extensive PeIN, residual PeIN in resection margins or recurrent disease after ablative or topical therapy, can be treated by surgical excision. Glans resurfacing consists of full thickness removal of the glandular epithelium followed by reconstruction with a graft (split skin [139] or buccal mucosa for urethral reconstruction [140]). Grafts tend to have excellent engraftment rates on this well-vascularized wound bed [141]. Recurrences are reported to be low (0–20%) and cosmesis is acceptable [139,141,142]. If feasible, preservation of the coronal ridge helps maintain sexual function and provides excellent cosmetic outcomes as shown by a small retrospective report [143]. Resection, as opposed to ablative or topical treatments, provides the advantage of complete histopathological local staging and detection of areas of invasion; in one study in cases of glans resurfacing for presumed PeIN, up to 20% of patients were found to have invasive disease on histopathological examination [139]. Surgeons and pathologists are urged to discuss appropriate specimen handling (e.g., pinning down the skin as resected) and pathological reporting of these cases to aid further management and avoid over-reporting of positive margins [144].

6.1.2. Treatment of invasive disease confined to the glans (cT1/T2)

When feasible, small and localised invasive lesions should receive organ-sparing treatment. Resection of the primary lesion not only eradicates all disease in localised invasive tumours but also provides definitive pathological staging without the risk of understaging and of missing intra-tumour heterogeneity encountered with incisional or punch biopsy [10]. Foreskin tumours are treated by ‘radical’ circumcision. For glandular and coronal lesions, wide local excision, partial glansectomy or total glansectomy with reconstruction, are surgical options while additional circumcision is advised in glandular tumours. External beam radiotherapy and brachytherapy are radiotherapeutic options for these patients. Laser therapy of small lesions has been reported but the risk of invasive disease must be recognised, and the recurrence risk is high, possibly as a result of the limited tissue penetration depth of laser ablation. Further research is needed to better establish the comparative safety and effectiveness of surgical and nonsurgical therapies for penile cancer.

Treatment choice depends on tumour size, histology, stage and grade, localisation and patient preference. Over the recent decades, a shift towards organ-sparing surgery has been observed, based on the assumption that local recurrence has little influence on long-term survival. However, in a large series looking at higher-risk tumours treated with glansectomy [145] or partial penectomy [146], it was observed that patients experiencing local recurrence have poorer survival, also in multivariate analysis correcting for poor prognosticators. This, however, does not indicate that these patients may have fared better with more radical excision, as local recurrence in those cases may be a display of a more aggressive disease biology in general. On the other hand, large series are available showing lower local recurrence rates after amputative surgery despite more aggressive tumours, supporting a wider resection [147].

The SR by the Panel found a cumulative 5-year recurrence free rate (RFR) of 82% in case series and 76.7% in non-RCTs for organ-sparing surgery. Similarly, the cumulative 5-year RFR of amputative surgery is reported 83.9% in case series and 93.3% in controlled studies. These variations reflect the differences of study designs as well as the different cohorts analysed at each instance; a larger proportion of patients treated with amputative surgery typically present with advanced disease (> T3: 29.4% vs. < T3: 7.8%). The higher RFRs observed after amputative surgery needs to be weighed against the impact on sexual function and QoL. Hence, the limits of organ-sparing surgery are not completely clear, and the higher risks of local recurrence should be discussed with the patient when making a treatment plan.

6.1.2.1. Width of negative surgical margins

The concept of organ-preserving surgery is based on observations of how the distance between tumour and resection margin affects local recurrence. A study found that most lesions do not spread > 5 mm beyond the macroscopic margin and, in line with this finding, subsequent reports show that an excision margin of between 5 mm and 10 mm results in acceptably low recurrence rates [148-150]. Another study from a supra-regional referral centre found that local recurrence rates only increased considerably when the distance from tumour to margin was < 1 mm [151]. However, comparative evidence is lacking for this topic and there is no clear evidence as to what constitutes an oncologically safe width of macroscopic negative surgical margins. Based on the observation that in lower-risk tumours (1) a local recurrence does not impact survival and (2) minimal section margins > 1 mm do not result in a higher risk for local recurrence, macroscopic margins can indeed be minimal, specifically in smaller and less aggressive lesions. Hence, to ensure complete removal with histologically negative margins, standard excision must include a margin of clinically normal-appearing skin around the tumour and surrounding erythema. However, for bulky or higher-grade lesions where local recurrence may have an impact on survival, adoption of a wider margin or partial penectomy may be prudent and should be discussed with the patient [145,150].

6.1.2.2. The use of intra-operative frozen section assessment

The role of frozen section and its value in the interpretation of excision margins remains uncertain, potential benefits of adopting frozen section assessment include a decreased risk of local recurrence and a smaller safety margin, allowing maximum preservation of penile tissue. A study in 169 patients treated in a tertiary referral centre in the UK showed that frozen section use during organ-sparing surgery contributed to a very low definitive positive margin rate of 0.6% and a local recurrence rate of 5.3% [152,153]. These data, however, are contradicted by a large contemporary series, also from a tertiary referral centre in the UK, showing similarly low local recurrence rates of 4% without routine intra-operative frozen section analysis [151]. A SR conducted in 2017 stated that routine frozen section analysis results in lower rates of local recurrence but failed to correct for patient selection, and hence a causal relationship between frozen section analysis and low local recurrence rates is lacking, as is comparative research. Data from one multi-centre study suggests that differentiated PeIN, squamous hyperplasia and lichen sclerosis present at the surgical margins are frequent findings and are not relevant for CSS [77]. As negative surgical margins are aimed for, in cases of doubt on the radicality of the resection, it is the Panel’s opinion that frozen section analysis is a helpful tool to achieve definitive tumour-free margins, whereas it is not recommended to be used routinely.

6.1.2.3. Laser ablation

In line with results achieved in non-invasive and superficially-invasive penile lesions, laser ablation has been proposed as an option for smaller invasive lesions. Typically, a CO₂ laser can resect the tumour with ample millimetres of margin, while for coagulation of the tumour bed a Nd:YAG laser is the better option as it provides deeper uniform tissue coagulation. Healing time is fastest after CO₂ laser treatment, with re-epithelization almost complete by three to six weeks post-treatment. Because of the greater depth of tissue coagulation, the healing time for Nd:YAG laser treatment is longer, often up to six weeks [134]. Penetration depth depends on laser type and settings and most commonly used settings are 15–20 W for CO₂ and 15–25 W for Nd:YAG lasers but only very few publications provide technical details [134].

In the Panel’s SR, seven studies reported outcomes of laser therapy for invasive penile cancer limited to T1 (81.2%) or T2 (18.5%) disease in a total of 389 patients [3]. Five-year RFR ranged from 34.2-94%. The cumulative mean 5-year RFR was 69.4% (270/389). Three studies reported a 5-year RFR per disease stage of 42.9–73.9% for T1 and 23.5%–84.2% for T2 disease. In nine studies (n = 512), the penile preservation rate following laser therapy was 50–100% (mean 89.2%), indicating that a large proportion of recurrences had to be managed with total amputation, which raises caution on the use of such technique and its use is likely best limited to T1 tumours. Tang et al., demonstrated that nodal recurrence was high in a multi-institutional cohort of patients treated with laser ablation as monotherapy, illustrating the importance of pre-ablation biopsy for risk stratification and nodal staging. Clinicians should be aware of the risk of understaging as a result of incision biopsy followed by ablation vs. complete resection [10,154], and it is advised that patients be informed that laser therapy may result in higher local recurrence rates when compared to surgical excision.

Three studies reported on laser-related complications, with preputial oedema and dysuria reported most frequently. Meatal stenosis was reported in 7.4% and post-operative bleeding in 1–7% of patients. Three studies assessed the sexual function after laser treatment and 46.0–56.5% of men report an impact on their sexual life. A single trial including 46 men found that 72% reported no change in erectile function, 22% reported decreased erectile function and 6% reported improvement [155].

6.1.2.4. Moh’s micrographic surgery

Moh’s micrographic surgery is a surgical technique by which tissue is excised and processed with en face histological margins in real time to give a complete circumferential and deep margin. It aims at maximal organ-preservation by adopting margin-guided excision. Three studies reported the 5-year RFR in 51 men, most with T1 disease. Recurrence-free rates ranged from 71.4 to 100% with a cumulative mean 5-year RFR of 88.2% (45/51) [3]. As data are very limited, it is not routinely recommended, and the Panel feels it is important to involve a clinician experienced in penile cancer management before referral for Moh’s surgery.

6.1.2.5. Wide local excision and circumcision

In addition to treating preputial penile cancer, circumcision combined with topical treatment, laser therapy or brachytherapy, facilitates follow-up examinations [153]. For small, distal preputial penile cancer, circumcision alone usually presents adequate treatment. However, lesions located on the corona or glans, limited in size, may be treated with wide local excision which should include a margin of clinically normal-appearing skin around the tumour and surrounding erythema (see Section 6.1.2.1). Few data on wide local excision are available, the technique has, so far, only been described in retrospective series combining various types of organ-sparing treatments.

6.1.2.6. Glans resurfacing

Besides its established effects in the therapy of PeIN, total or partial glans resurfacing has been reported to be employed for superficially-invasive lesions combined with deeper resection at the site of invasion. The literature is heterogeneous with many studies reporting miscellaneous techniques of organ-sparing surgery including glans resurfacing without specification of tumour invasiveness in these patients specifically. Five studies have reported results of glans resurfacing specifically in invasive penile cancer in a total of 68 patients, with most being pT1 and a few instances of T2 lesions displaying RFR ranging from 75–96.6% [143,151,156-158]. Similar to glans resurfacing as applied to carcinoma in situ, graft-related complications are scarce and cosmesis, as assessed by patients, is generally good. Cakir and colleagues have described a small series using a technique for glans resurfacing with preservation of the coronal sulcus for distal tumours not invading the sulcus and show that this option can be considered when aiming for maximally preserved erogenous sensation [143].

6.1.2.7. Glansectomy

Patients with tumours confined to the glans and prepuce that are not eligible for wide local excision or glans resurfacing are good candidates for glansectomy. Patients with poor vascular function, diabetes, immunosuppression, or previous radiation to the groin area are less suitable for graft application due to higher failure rates which should be discussed with the patient when making the decision between graft application for primary closure. For cases in which the lesion is confined to the glans and is clearly away from the corporal tips according to imaging or clinical examination, an approach that uses dissection over Bucks’ fascia can be used to excise the glans, while in cases of doubt, a plane under the Bucks fascia can be used. In the Panel’s SR, glansectomy with or without resection of the outermost tips of the corpora cavernosa was assessed in six studies including 1,681 men, 86.4% of whom with T1–T2 disease. The 5-year RFR ranged from 78.0–95.8% [3]. A split-thickness skin graft is commonly used to reconstruct a neo-glans and the graft loss rate was 1.5–23.5%. The incidence of meatal stenosis in a recent SR was 2.8–14.3%. Good cosmetic outcomes and normal erections were reported in 95–100% and 50–100% of cases, respectively [159]. In a large retrospective study by Roussel and colleagues, describing a multicentre cohort including 230 pT1, 534 pT2 and 108 pT3 patients treated in high-volume centres, the authors found high-grade disease and pT3 to be independent risk factors predicting local recurrence. Three-year local RFS rates were 94.8%, 87.3% and 69.7% in patients with no, one, or both, risk factors, respectively. Moreover, in this population, local recurrence remained a significant predictor of decreased overall- and CSS, even when excluding margin-positive cases, patients with pT3 disease, and patients with clinical LN involvement. Hence, these issues should be discussed with the patient prior to surgical intervention when choosing between glansectomy and the more aggressive partial penectomy.

6.1.2.8. Partial penectomy

Amputative and partial amputative surgery is reserved for more advanced disease. Results of partial or total penectomy were reported in 5 heterogeneous studies with a total of 243 patients. 71.6% of men were staged as T1–T2 and the 5-year RFR was 75.8-95.4%. The cumulative mean 5-year RFR was 83.9% (204/243). Two cases series including T1 and T2 men, reported 92% and 95.4% 5-year RFRs after partial penectomy [3]. There is no comparative evidence between partial penectomy and glansectomy for T1–T2 lesions, however most case series report similar RFRs between penile-sparing surgery and amputative surgery. In a series of T1 and T2-only disease, 5-year RFR after amputative surgery were superior to penile-sparing surgery, indicating that a wider resection is protective against local recurrence and should always be discussed as an alternative option, although the higher RFRs observed after amputative surgery needs to be weighed against the impact on sexual function and QoL.

6.1.2.9. Radiotherapy for T1 and T2 disease

Radiotherapy is an organ-preserving approach with good results in selected patients with T1–2 lesions [3]. It can be given as external radiotherapy with a minimum dose of 60 Gy EQD2 combined with a brachytherapy boost or as brachytherapy alone [160,161]. Brachytherapy has been studied only for lesions < 4 cm hence its use should be limited to tumours not exceeding this size. Reported results are best with brachytherapy with local control rates ranging from 70–90% [160,161]. The American Brachytherapy Society and the Groupe Européen de Curiethérapie-European Society of Therapeutic Radiation Oncology consensus statement for penile brachytherapy also reported good tumour control rates, acceptable morbidity, and functional organ preservation for penile brachytherapy for stages T1 and T2 disease [160]. Penile preservation rates of 70–88% have been reported [162], with overall penile conservation rates of 87% and 70% at 5 and 10 years. Pulsed-dose-rate brachytherapy can be used interchangeably with traditional low-dose rate and 15% local recurrences have been reported in one series [163]. High-dose rate brachytherapy has been introduced but experience is still limited [164-169].

The Panel’s SR identified 21 studies evaluating the efficacy of radiotherapy for the management of primary tumour in men with penile cancer. A total of 1,222 men had low-, pulse-, or high-dose rate brachytherapy after circumcision [3]. The cumulative mean 5-year RFRs were 78.6% (861/1,096) after brachytherapy and 55.2% (37/67) after EBRT. Four studies (including some EBRT and some brachytherapy cohorts) reported RFRs per disease stage, with 5-year RFRs for T1 ranging from 59–94%, 50–67% in T2, and 17–77% in T3 disease [167,170-172].

In the few studies comparing surgical treatment and radiotherapy, results of surgery were slightly better. In a meta-analysis comparing surgery and brachytherapy, 5-year OS and local control rates were 76–84% for surgery and 73–79% for brachytherapy, respectively [173]. The organ preservation rate for brachytherapy was 74% and there was no difference in survival. Local recurrence after radiotherapy can be salvaged by surgery [170].

Specific complications of radiotherapy for penile cancer are urethral stenosis (20–35%), glans necrosis (10–20%) and late fibrosis of the corpora cavernosa [174]. With brachytherapy, meatal stenosis has been reported to occur in up to 40% of cases but was much lower in a contemporary series of 73 patients with only 6.6%. In that series, 2.6% of patients reported pain with sexual intercourse and 5.3% dysuria over a follow-up of 5 years. Penile amputation for necrosis was necessary in 6.8% of patients [175].

Functional outcome after radiotherapy has not often been reported. In one report, 17/18 patients with normal erections before treatment maintained these after treatment [176]. After a minimum of 3 years (median 5.9) follow-up after brachytherapy treatment, 29/34 patients (median age 63 years) answered a self-reporting questionnaire. Urethral dilatation had been necessary in 30% of patients, self-catheterisation in 13%; erectile dysfunction was mild and 70% continued to maintain sexual activity, and QoL was good.

6.1.3. Locally advanced disease (T3–T4)

6.1.3.1. Resectable disease

In cT2 disease where there is doubt of corporeal or tunica albuginea invasion, rather than continuing the dissection over Buck’s fascia to perform glansectomy combined with distal corporectomy, dissection superficial to the tunica albuginea can be adopted after dividing the neurovascular bundle. In these instances, frozen sections of the corporeal tips and urethra may be helpful in assessing the radicality of the procedure peri-operatively. Pre-operative MRI or US can assist in surgical planning as discussed in Chapter 5. For cT3 patients with obvious involvement of the corpora cavernosa, partial amputation is standard. Patients can be offered reconstructive options such as urethral centralisation and/or neo-glans formation with the use of a graft. Two studies in higher-risk patients treated with radical glansectomy or partial penectomy show that local recurrence in these instances is associated with poor survival. Patients should be informed that a wider resection (i.e., partial or radical penectomy) provides a lower risk of local recurrence at the cost of functionality of the penis [145,177]. Radical amputation and diversion of urination with a perineal urethrostomy is reserved for those patients in whom a resection with a safe margin would result in the inability to void standing upright or without wetting the scrotum. Radiotherapy for locally-advanced penile lesions should be undertaken with concurrent chemotherapy. As with disease in the LNs, traditional radiotherapy dosing recommendations are being reconsidered [178]. Complex treatment planning will be necessary in most cases of T3–T4 primary lesions, with patient-unique immobilization to spare testes and scrotum. A total phallic reconstruction may be offered to patients undergoing total/subtotal amputation. Extensive partial amputation with wide margins or total penectomy with perineal urethrostomy is the standard advisable treatment. In case of locally-advanced and ulcerated cases which are resectable, composite myocutaneous flaps or advancement flaps may be needed to cover the surgical defect [179].

6.1.3.2. Non-resectable disease

In non-resectable disease, induction chemotherapy offers the ability to downstage disease and thereby enable surgical resection among responders, even among men with advanced penile cancer. Several retrospective- and prospective series have evaluated the effects of combination regimens using paclitaxel or docetaxel with cisplatin and ifosfamide or 5-FU. The combination of irinotecan and cisplatinum, and vinflunine as monotherapy, have also been investigated. Although there is considerable heterogeneity in the regimens and cohorts combining advanced nodal disease and unresectable primary tumours, objective responses are observed in 29–60% of patients [177,180-186] . In two recent SRs pooled ORR were 53–57% [187] with pooled objective response rates of 57% (95% CI: 46–67%) for taxane-platinum combinations and 54% (95% CI: 31–76%) for non-taxane platinum combinations [188], and pathological complete responses in 4–10% [188], at the cost of considerable toxicity. This approach is discussed in more detail in Section 6.4.1.1. In case of not obtaining a response sufficient for resection, palliative chemo-radiotherapy is an option.

Accumulated evidence in anal and vulvar cancer supports the notion that definitive chemo-radiotherapy is an effective treatment for anogenital SCC [189]. In a single study in six node-positive SCC penile cancer patients, 4 of the 6 patients were recurrence-free and two had developed recurrence, of which one patient died [189]. In a currently unpublished observational cohort study in 40 loco-regionally advanced penile cancer patients fit for chemo-radiotherapy and treated with curative intent, Ottenhof and colleagues observed that only half of the patients proceeded to surgery, and one- and 2-year PFS was 32% with a > grade 3 toxicity rate of 40% [190]. Their regimen consisted of integrated boost intensity modulated radiotherapy with a dose of 59.5 Gy to the primary tumour in fractions of 1.8 Gy with mitomycin C on day one and capecitabin on radiation days. In comparison to peri-operative chemotherapy studies, the omission of surgery is a potential advantage of chemo-radiotherapy. As this strategy has only been evaluated in a single observational study without a published full text at the moment of writing, no recommendation can be made supporting this approach in patients suitable for other options.

6.1.4. Local recurrence after organ-sparing surgery

A second organ-sparing procedure can be performed if there is no corpus cavernosum invasion [136,149,191-193]. For large or high-stage recurrence, partial or total amputation is required, unless unresectable or concurrent with nodal or distant metastatic recurrence (see respective sections).

6.1.5. Summary of evidence and guidelines for local treatment of penile carcinoma

6.2. Regional lymph node management: clinically evident disease (cN1–cN3)

6.2.1. Introduction

The development of lymphatic metastases in penile cancer follows the route of anatomical drainage from the primary tumour to the superficial and then deep inguinal LNs (which can occur on both or either side), followed by the ipsilateral pelvic LNs. The superficial nodes are located under the subcutaneous fascia and above the fascia lata within Scarpa’s triangle. The deep nodes lie within the region of the fossa ovalis where the superficial saphenous veins anastomose with the femoral vein at the saphenofemoral junction. The Cloquet’s node (or Rosenmuller’s node) is located medial to the femoral vein around the entrance to the femoral canal and marks the transition between inguinal and pelvic regions. Daseler et al., divided the superficial inguinal LNs into five regions centred around the saphenofemoral junction; central, lateral superior, lateral inferior, medial superior and medial inferior [194]. Studies of radical ILND (rILND) as well as single-photon emission computed tomography (SPECT) imaging suggest that sentinel inguinal nodes, i.e., those first affected by lymphatic spread, appear to be located in the medial superior zone followed by the central inguinal zones [194-196].No solitary lymphatic spread has been observed from the penis to the two inferior groin regions and no direct drainage to the pelvic nodes, either [194-196].

Pelvic nodal disease does not occur without ipsilateral inguinal LN metastasis. Also, crossover metastatic spread, from one groin to the contralateral pelvis, is rare [197]. Further lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic, para-caval) is classified as systemic metastatic disease [198].

The management of regional LNs is decisive for patient survival. The presence and extent of nodal involvement is singulary the most important prognostic factor in patients with penile cancer. Cure can be achieved in limited LN-disease confined to the regional LNs. Radical LND is the treatment of choice. Multimodal treatment combining surgery, chemotherapy, or radiotherapy is often indicated for more advanced disease.

In clinically positive LNs (cN1/cN2), more extensive LN metastasis is highly likely and LN surgery with histology is required. Given the very high chance of recurrence, enlarged fixed inguinal LNs (cN3) or clinically evident pelvic metastases require multimodal treatment by induction chemotherapy and consolidative surgery in responding patients. Even if present in only one node, extra-capsular extension/ENE, or pelvic LN metastasis found at surgery carries a high risk of progression and is classified as pN3 and requires multimodal treatment.

Given the complexities of regional node management, the intent of the Panel in the following sections (i.e., Sections 6.2–6.4) is to describe the available evidence-based strategies in the management of clinically evident LN metastases (i.e., cN1–cN3). These include inguinal/pelvic LND, chemotherapy, radiotherapy ± chemotherapy and integrated strategies such as neoadjuvant and adjuvant therapies combined with surgery. The reader is encouraged to review the text sections, summaries of evidence, and recommendation tables collectively in order to better understand recommendations for single vs. multimodal treatment and currently available data utilising various strategies.

6.2.2. cN1–N2 disease: radical inguinal lymph node dissection

6.2.2.1. Indication for radical inguinal lymph node dissection

Radical ILND remains the standard of care for patients with cN1–2. In low-volume disease (pN1) rILND is curative with a suggestion of equivalent outcomes in those patients without nodal disease [199-201].

Despite this, several studies have demonstrated continuing non-adherence to accepted international guidance [202-205]. Cindolo et al., evaluated adherence of twelve European and American centres to the EAU recommendations [205]. They reported a 26.3% rate of non-adherence in terms of LN management. For those patients managed as per guidance with LND there was a statistically significant association with OS (adjusted HR: 0.48; 95% CI: 0.24–0.96, p = 0.038) [205].

6.2.2.2. What is an acceptable definition?

Daseler’s original description of a rILND in 1948 is considered the classical description of a radical inguinal LN dissection (rILND) (see Table 6.1) [194]. Despite this, considerable variation exists across high-volume centres. In an international survey of surgeons’ practice in European high-volume centres, consensus was not found in the definition of the superior and lateral borders of the dissection, and whether the fascia lata and saphenous should be preserved [206]. This variation in practice is likely a reflection of clinicians and patients desire to reduce the significant burden of morbidity acknowledged in the literature associated with rILND (see later section on complications). A SR of the literature by the Panel identified only one other description of a modified template used in clinical N1–2 disease by Yao et al. [207] (see Table 6.1). This retrospective cohort study of 201 fascial-sparing inguinal dissections (fsILND) with < N2 disease, demonstrated comparable oncological outcomes to rILND with 3-year DFS of 92.1% (100% for pN0, 91.3% for pN1, 80% for pN2, and 33.3% for pN3 disease, respectively) and a complication rate of 29.3%. To date, however, no direct comparison exists between rILND and fsILND in this group of patients (Table 6.1).

Table 6.1: Variations in radical inguinal lymphadenectomy

fsILND = fascia-sparing inguinal lymph node dissection; RILND = radical inguinal lymph node dissection.

6.2.2.3. Quality metrics

To standardise the quality of resections, several studies have attempted to look for surrogate markers to infer complete oncological resection including LN yield (LNY), LN density (LNDen), and time to completion of surgery.

6.2.2.3.1. Lymph node yield and density

In a SR commissioned by the Panel, several studies were identified examining the association between LNY/LNDen and survival as a surrogate marker of adequate dissection in penile cancer [203,208-212]. However, LNY varied from > 8 to > 15–16 and LND < 6.7 to < 22%. The variance in accepted values is likely because of different surgical templates, variable pathological assessment, and stage migration. Consequently, widespread adoption of LNY and LNDen as a predictor of survival and as quality markers cannot be recommended.

6.2.2.3.2. Timing of surgery

Several studies have highlighted the importance of expedient LN management in patients with cN0 disease vs. surveillance with LND on presentation of clinical disease. Two non-RCTs have demonstrated a survival benefit in patients who underwent early ILND compared with delayed ILND (within six weeks of primary surgical treatment vs. surgery following identification of positive nodes during surveillance), showing 3-year CSS 84% vs. 35% (p = 0.0017) and 3-year CSS 71% vs. 50%, respectively [98,213].

The evidence in pN1–2 regarding optimal timing of LN management is limited. Chipollini et al., examined the effects of early vs. late inguinal LN dissection (> three months following primary surgery) in 84 patients with cN0 and cN+ disease. Overall, those patients undergoing early ILND demonstrated a 5-year DSS of 64.1% vs. 39.5% for late dissection with an unadjusted HR of 0.66 (0.32–1.37). However, when sub-analysis was performed in cN+ patients, the 5-year DSS for early vs. late dissections failed to delineate a statistically significant benefit (31.8% vs. 35.3%, respectively) [214].

Gulia et al., examined 28 patients undergoing rILND stratified by < 6 months (group 1) and more than 6 months (group 2) from treatment of the primary tumour (70% and 50% palpable at presentation, respectively). The 5-year CSS was 91 and 13%, respectively (p = 0.007) [215].

6.2.2.4. Complications

Radical ILND carries a significant morbidity due to impaired lymph drainage from the legs and scrotum, however it can be lifesaving and therefore should not be avoided [216].

Historical morbidity of the procedure has been as high as 61% [217]. Contemporary large series of rILND suggest between 21–55% of men will suffer a complication [115,218,219]. The reduction in morbidity is likely due to a better understanding of pre-, intra-, and post-operative management (see Table 6.2). In a SR commissioned by the Panel the most reported complications in recent series were wound infections (2–43%), skin necrosis (3–50%), lymphoedema (3.1–30%), lymphocele formation (1.8–26%), and seroma (2.4–60%)
[115,199,215,218-225]. Table 6.2 lists several strategies and conditions associated with increase, decreased or uncertain effects on morbidity outcomes reported in penile cancer, urologic or in other cancers. Future studies specific to ILND and strategies to decrease morbidity are needed.

Table 6.2: Impact of pre-intra- and post-operative factors on morbidity following radical inguinal lymph node dissection

6.2.2.5. Open versus minimally-invasive approach

In recognition of the significant morbidity associated with rILND, clinicians have sought to reduce these through technical modifications. Expanding interest and experience in minimally-invasive techniques have led to the introduction of video-endoscopic inguinal LND (VEIL) and subsequently robot-assisted video-endoscopic inguinal LND (RAVEIL), using rILND or fsILND templates.

Ports are generally placed at the apex of the femoral triangle, although variations include lateral and hypogastric approaches allowing pelvic lymph node dissection (PLND) through the same incisions [242-244].

A review of the literature commissioned by the Panel identified a single incomplete RCT in 2012 which closed prematurely due to poor accrual, with patients preferentially choosing minimally-invasive approaches over open [245]. The remaining studies identified were either retrospective cohort- or comparative series. Narrative review would suggest that although operative time is longer, LN yields can be similar to open ILND, length of hospital stay shorter in VEIL/RAVEIL and wound complications lower, though lymphocele and readmission rates were equivalent [113,236,238,246-248].

Follow-up for the minimally-invasive approaches were short, and there was a high proportion of patients receiving VEILND or RAVEIL as prophylaxis as opposed to clinically node-positive disease, precluding incorporation in the current guidance. In addition, some studies where open rILND was used as a comparator, involved more morbid manoeuvres when using an open approach, such as Sartorius transposition and saphenous vein sacrifice, which were not replicated in minimally-invasive procedures.

6.2.2.6. Summary of evidence and guidelines for radical inguinal lymph node dissection in cN1-2 disease

6.2.3. Prophylactic pelvic lymph node dissection

Prophylactic PLND (pPLND) in most cases represents a staging procedure that can thus identify candidates for early adjuvant therapy, although in select patients may also provide a therapeutic benefit.

6.2.3.1. Indications for prophylactic pelvic lymph node dissection

6.2.3.1.1. Risk factors for pelvic nodal metastasis

To identify patients with pelvic LN metastasis in the absence of radiological evidence for LN involvement, several studies have tried to develop generalized estimating models based on inguinal characteristics using logistic regression and multivariate analysis. Among various predictors, the number of positive inguinal LNs (1–2 vs. 3, or more, with no extra-capsular extension) was associated with positive pelvic LNs in 0–6.5% of patients vs. 33–67% of patients [249,250]. The presence of extracapsular spread was also consistently significantly associated with positive ipsilateral pelvic LN metastasis in 4 studies [249-252] Strong immunoreactivity of p53, LN density > 30% and primary tumour grade are also reported as predictors of pelvic LN involvement [250].

6.2.3.2. What is an acceptable dissection?

In a study by Yao et el., the authors prospectively mapped the distribution of positive pelvic LNs at the time of PLND in 128 patients [197]. Most patients underwent bilateral PLND (86.7%). The median number of nodes retrieved per groin was 18 (interquartile range [IQR] 10–30), with the distribution of positive nodes in the external iliac, obturator, common iliac, internal iliac and presacral packages 50%, 36.6%, 7%, 6.4% and 0%, respectively. Notably two patients were observed to have crossover metastasis from one inguinal region to the contralateral pelvic region, defying the accepted understanding of the historical literature. When the extent of dissection was considered in context of overall- and RFS there was no statistically significant difference [197]. Similar data was seen in a study by Zhu et al., with the external iliac package being more commonly involved than the obturator and common iliac packages [253].

To evaluate the prognostic impact of LN yield on survival outcomes for penile SCC, Chipollini et al., examined 198 patients undergoing PLND [208]. In their cohort they found a LN yield of > 9 was a predictor of RFS (HR: 0.53, p = 0.032).

6.2.3.3. Survival and recurrence

The evidence that pPLND has an additional therapeutic effect over surveillance or adjuvant radiotherapy (see Section 6.4.2.2) is limited and significant controversy remains. Djajadiningrat et al., estimated the 5-year DSS in all patients treated with pPLND was 51%. Patients with positive pelvic nodes had a significantly worse 5-year DSS than those without pelvic involvement (17%, 95% CI: 6–47 vs. 62%, 95% CI: 50–76, p < 0.001) [251]. A retrospective multicentre study compared the outcomes of bilateral pPLND for N2 or N3 disease vs. no surgery and reported better 5-year OS in the pPLND group (35% vs. 25%) without reaching statistical significance [254]. In N2 patients, 3-year OS was significantly better in the PLND group as compared to the no-surgery group (83.3% vs. 50.2%, p = 0.03) [254]. This difference was not evident in N3 patients.

6.2.3.4. Complications

There is limited data available regarding the reporting of complications from PLND. This is complicated by the fact that most patients will have already undergone a rILND which carries a significant morbidity as discussed above. A single-centre experience of 89 patients, undergoing open PLND for penile cancer reported an overall complication rate of 18%. Nine patients had wound complications including infection, seroma, and dehiscence. The remaining 5 patients had non-wound-related complications such as pneumonia, delirium, and ileus [251].

6.2.3.5. Minimally-invasive versus open pelvic lymph node dissection

In a SR commissioned by the Panel there were no reported studies that examined the role of minimally-invasive pPLND in the setting of penile cancer and PLND. There is, however, a significant body of evidence that exists in other common urological malignancies that demonstrates equivalent oncological outcome as well as improved morbidity profile and recovery profile.

6.2.3.6. Summary of evidence and guidelines for prophylactic pelvic lymph node dissection

6.3. Clinical N3 disease (cN3)

6.3.1. Diagnostic evaluation

Patients with clinical N3 disease as defined by the presence of a fixed inguinal mass (i.e., to skin or underlying structures) or pelvic lymphadenopathy based upon imaging should undergo a complete staging evaluation including cross sectional imaging (i.e., PET/CT or CT, see Section 5.2.3), if not already performed [255]. Biopsy of the inguinal mass in the setting of a patient with a known diagnosis of penile cancer is not required but should be performed in a previously undiagnosed patient, as needed, to establish the diagnosis and facilitate accurate staging.

6.3.2. Management strategy

Neoadjuvant chemotherapy (NAC) is a reasonable strategy among cN3 patients based on the results of a recent SR which reported radiological response rates of approximately 53% and pathological complete response in approximately 12.8% of patients [187,256]. This review consisted mostly of retrospective series; complete response rates in the intention to treat population were 10% (paclitaxel, ifosfamide, and cisplatin [TIP]) and 4% (docetaxel, cisplatin and fluorouracil [TPF]) in prospective trials [177,180]. In responding patients, and those with no evidence of disease progression, surgical resection to remove all residual disease utilizing radical inguinal and PLND techniques is the preferred strategy. For a detailed examination of peri-operative chemotherapy please see Section 6.4.1.

Pre-operative radiotherapy was used in a single study among a cN3 cohort of 12 patients and reported an objective response in only 2 patients with 7 of 12 patients subsequently undergoing ILND. Only 2 patients (17%) survived 5 years [257]. It is worth recognising that this data, however, utilises historical radiotherapy techniques precluding meaningful extrapolation to modern practice (see Section 6.4.2 for further details).

Surgery as the initial treatment in patients with a fixed inguinal mass or clinically evident pelvic adenopathy (cN3) at presentation or recurrence is discouraged in routine management. While often technically feasible a “surgery first approach” often results in large skin/soft tissue defects, the need for myocutaneous flap reconstruction, prolonged hospital stays (mean or median 8.5–23 days) and is associated with high overall complication rates (65–77%) [258,259]. In a single-centre study among 24 patients treated with surgical debulking alone in the advanced disease setting, the median CSS and DFS were only six and three months, respectively [259]. In the same study 17.5% of patients exhibited rapid progression of disease post-surgery and never received adjuvant therapy [259].

6.3.3. Patient selection for consolidative radical inguinal/pelvic lymphadenectomy

Patients whose tumours respond to NAC and subsequently undergo surgical consolidation represent a favourable subgroup of patients with a mean 5-year survival of 56.9% according to a SR [256]. Among cN3 patients who are not candidates for conventional multi-agent chemotherapy, pre-operative chemo-radiation/radiation can be offered in an attempt to downsize tumours to improve resectability. The evidence for this, however, is recognised to be weak but is being prospectively investigated in the InPACT study [260].

6.3.4. Surgical technique

6.3.4.1. Inguinal lymph node dissection

Surgical resection should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.

Pre-operative planning to remove all residual disease taking into consideration the size of the mass, involvement of surrounding structures, and the anticipated skin and soft tissue defects as well as plastic surgical consultation (as appropriate) is required for successful outcomes.

6.3.4.2. Lymphadenectomy boundaries

Surgical boundaries should follow that of a ‘radical inguinal lymph node’ dissection” (described in Table 6.1). Wide resection of involved skin is often required with en bloc ILND. Considering the extent of inguinal metastases along with fixation to adjacent structures, minimally-invasive techniques (i.e., robotic-, laparoscopic ILND) are considered inappropriate in cN3 inguinal metastases.

6.3.4.3. Pelvic lymph node dissection

Simultaneous PLND should be performed at the time of ILND if pelvic LN metastases were clinically evident at diagnosis. Ipsilateral PLND should also be performed in a simultaneous (preferred) or delayed fashion in the setting of advanced bulky inguinal metastases without clinically evident pelvic metastases as well (i.e., prophylactic). In the latter setting, microscopic pelvic metastases were noted quite frequently (44–100%) in the setting of extracapsular disease and especially when an inguinal mass was present in one series [249].

6.3.4.4. Surgical complications in cN3 disease

Resection of bulky/fixed inguinal masses with or without prior chemotherapy is associated with a variety of complications. Minor complications not requiring hospitalization or surgical intervention are common and tolerable when cure or significant palliation can be achieved. Major post-surgical complications requiring medical or surgical intervention or associated with disability, or death, in several series included infection/sepsis (1.5–4.5%), lymphocele requiring drainage (0–3.8%), wound dehiscence or necrosis requiring debridement (1.5–5.6%), pneumonia (0–2.9%), deep venous thrombosis/pulmonary embolus (0–8.7% and death (0–5.6%) [180,258,259]. Overall, in the three selected series of patients treated at experienced centres the incidence of major complications as described above was less than one in ten patients with 3/82 (3.9%) patients succumbing to sepsis or other early peri-operative complications.

6.3.5. Summary of evidence and guidelines for the surgical management of cN3 disease

6.4. Role of multimodal chemotherapy/radiotherapy in the management of (regional) lymph nodes

6.4.1. Systemic therapy

6.4.1.1. Neoadjuvant chemotherapy

Bulky inguinal LN enlargement indicates extensive lymphatic metastatic disease for which few patients will benefit from surgery alone. Neoadjuvant chemotherapy before inguinal LN surgery allows for early treatment of systemic disease and down-sizing of the inguinal LN metastases. In responders, complete surgical treatment is possible with reasonable clinical outcome.

Cisplatin/5-FU (PF) chemotherapy achieved a response rates of 25–50% with acceptable toxicity [261,262]. Over a period of 30 years, five different NAC regimens including PF were used in twenty patients, with long-term survival in 37% of responders who underwent radical LN surgery after NAC [263]. In the EORTC cancer study 30992, 26 patients with locally-advanced or metastatic disease received irinotecan and cisplatin chemotherapy. Although the study did not meet its primary endpoint (response rate), there were three cases of pathologically complete remissions (pCRs) [186].

Hypothetical similarities between penile SCC and head and neck SCC led to the evaluation in penile cancer of chemotherapy regimens with an efficacy in head and neck SCC, including taxanes. A phase II trial evaluated treatment with 4 cycles of neoadjuvant paclitaxel, cisplatin, and ifosfamide (TIP) in patients with clinical N2 or N3 LN metastases [180]. An objective response rate (ORR) of 50% was reported in 30 patients, including three pCRs. The estimated median time to progression (TTP) was 8.1 months and the median OS was 17.1 months. Long-term DFS was observed in 67% of responding patients and 7% of non-responding patients.

The combination of PF plus a taxane has been used in neoadjuvant and adjuvant settings [183,184,264,265]. A phase II trial with docetaxel, cisplatin, and 5-FU (TPF) reported an objective response of 38.5% in 29 locally-advanced or metastatic patients, although the study did not meet its primary endpoint, and there was significant toxicity [184]. A prospective study testing neoadjuvant TPF in 26 patients with loco-regionally advanced penile cancer showed a pathologic complete response in one patient, with a 2-year PFS and DSS probability of 12% and 28%, respectively [177]. Treatment was discontinued in 23% of patients because of toxicity. In a recent meta-analysis analysing 10 studies (n = 182 patients, mostly retrospective), the pooled ORR was 53% (95% CI: 42–64), and the overall mortality was 55% (95% CI: 40–70) [187]. The available evidence favours a cisplatin- and taxane-based combination (doublet or triplet) as the preferred approach.

Overall, these results support the activity of pre-operative chemotherapy in patients with clinically-involved regional LNs from penile SCC. However, randomised studies are lacking and substantial concerns remain regarding the selection of patients who are best suited for a systemic therapy approach upfront. A large retrospective study including 743 patients who received a LND from several international institutions suggested patients with a clinical N3 stage constituted the cohort with the most appreciable benefit from NAC use, compared to LND alone [266]. Bilateral inguinal LN involvement emerged as a strong negative predictor of clinical outcome in patients with penile SCC, together with pelvic nodal involvement.

In summary, given the poor outcome of upfront surgery, NAC is a potentially-suitable approach for patients having pelvic LN (cN3) metastases or fixed inguinal LN involvement (cN3), or bulky or bilateral involvement (cN2). In nonresponding patients, the potential benefits of surgery should be re-evaluated as prognosis is poor in these patients. See also section on chemo-radiotherapy.

6.4.1.2. Adjuvant chemotherapy

There are known poor prognostic characteristics for a subset of patients with resected high-risk disease (such as involved pelvic LNs), indicating the likely presence of micrometastatic disease. Data exists on response rates for those with metastatic disease and there is possible benefit for pre-operative chemotherapy for those with unresectable locally advanced disease as described above. With extrapolation from other diseases, it stands to reason that systemic therapy following resection (i.e., adjuvant therapy) may improve outcomes.

A retrospective multicentre analysis of patients with resected pathologically involved pelvic LNs suggested a potential benefit of adjuvant chemotherapy [264]. In this series, 84 patients were analyzed. Patients who received chemotherapy for relapsed disease were excluded. Compared to those not receiving adjuvant chemotherapy, patients who received adjuvant chemotherapy were younger, had lower T stage, more likely to have unilateral (rather than bilateral) LN involvement, and were less likely to receive adjuvant radiation. On multivariable analysis, receipt of adjuvant chemotherapy was associated with improved OS (HR: 0.40, 95% CI: 0.19–0.87, p = 0.021). Additional series have also been reported, including a series of 611 patients from the National Cancer Database reported in abstract form [267]. After adjusting for co-variates, there was no difference in survival for those receiving adjuvant chemotherapy.

A recent meta-analysis examined this issue. After a systematic search, 7 studies were identified examining the use of peri-operative chemotherapy, 4 of which examined adjuvant chemotherapy (n = 771) [268]. There was no difference in survival for those receiving adjuvant chemotherapy vs. observation (HR: 0.95, 95%
CI: 0.48–1.80).

Upon examination of the overall data, there is no strong data supporting the use of adjuvant chemotherapy to improve OS following surgical resection of the primary tumour and involved LNs. However, given the fact that RFS is a relevant endpoint that has been suboptimally studied and there is a subset of patients at very high risk of recurrence, the Panel recommends a balanced discussion of risks and benefits of adjuvant chemotherapy in those thought to be healthy candidates. As previously stated for the neoadjuvant setting, the benefit from adjuvant chemotherapy is expected to be highest in the population of patients with pathological N3 stage, in particular for those patients with pelvic nodal involvement [266]. See also Section 6.4.1.2 on adjuvant radiation and chemo-radiotherapy.

6.4.1.3. Summary of evidence and guidelines for neoadjuvant and adjuvant chemotherapy

6.4.2. Radiotherapy

6.4.2.1. Pre-operative radiation therapy

The role of pre-operative chemo-radiotherapy is being investigated in the ongoing InPACT trial [260]. Since surgical therapy of enlarged LNs is of paramount importance, it is unlikely that pre-operative radiotherapy alone would provide sufficient benefit. Should a patient who is otherwise unfit for chemotherapy require treatment to LNs while awaiting surgery, radiotherapy alone may be considered using conventional daily fractionation to 45–50Gy. Radiotherapy to the groins in penile cancer conceptually requires inclusion of the pre-pubic fat a in order to cover in transit lymphatics [269].

6.4.2.2. Post-operative radiation therapy

Adjuvant radiation therapy for node-positive penile cancer remains controversial. Since there is no level 1 evidence to support the benefit of radiation therapy in terms of disease recurrence and survival, it is not recommended in prior guidelines [270,271]. Radiotherapy is being used in some institutions in the management of regional LNs for penile SCC, based on evidence and experience with other SCC sites (such as head/neck and vulvar carcinomas) [174,272,273].

Jaipuria et al., reported that following inguinal- and pelvic LND, patients with > 2 positive LNs but negative pelvic nodes (n = 32) had increased OS with adjuvant radiation therapy compared to adjuvant chemotherapy (48 months vs. 14 months p < 0.0001) [274]. Although 68% of patients had ENE, there were no in-field failures. The radiation dose was higher than that commonly used under these circumstances, 54 Gy for ENE and up to 57–60 Gy for gross residual disease. With a lower radiation dose of 50 Gy, Johnstone et al., reported a high rate of in-field failures (32/39) [275]. At this dose, adjuvant radiation therapy (either groin: p = 0.016 or inguinal-pelvic: p = 0.006) improved RFS only for patients without ENE. Ager et al., reporting on the experience with pN3 disease (either ENE or pelvic LN+) in two tertiary referral centres in the UK also found dose to be critically important [276]. A 121 of 146 patients received adjuvant radiotherapy. The 5-year RFS was 51%. Twenty-six of 55 recurrences were in-field, but the risk of in-field failure was twice as high for lower doses < 50 Gy.

For 92 patients with positive pelvic LN from 4 international centres, adjuvant radiation was found to prolong DSS by 6 months and delay the time to recurrence [277].

The data collated in Table 6.3 reveal variable results with conventional radiotherapy delivered in the adjuvant setting, potentially impacted by HPV status and presence/absence of ENE. Also notable in the data is the fact that traditional radiotherapy doses delivered to microscopic disease may be insufficient. Recent genomic data analyses have modelled that a higher radiation dose may be necessary for management of penile cancer primary lesions and nodal basins [278,279].

Table 6.3: Adjuvant conventional radiotherapy for node-positive penile cancer

ADj = adjuvant; aRT = adjuvant radiotherapy; CT = chemotherapy; ENE = extra-nodal extension; HPV = human papillomavirus; ILND = inguinal lymph node dissection; mo = month; n = number of patients; NCDB = National Cancer Database; OS = overall survival; RFS = recurrence free survival; yr = year.

HPV status could be a suitable selection factor for patients who will benefit from adjuvant radiotherapy after ILND (in analogy to other HPV-related cancers). Bandini et al., reported on 507 patients from 11 centres, 86 of whom were HPV+. Among patients receiving adjuvant radiotherapy, those harbouring HPV-positive tumours appeared to have an increased OS relative to HPV-negative patients. However, more (prospective) studies are needed to validate these findings [34].

As in other SCC sites such as head and neck cancer, HPV status may also predict for increased responsiveness to combined chemo-radiotherapy. Yuan et al., reported improved loco-regional control (LRC) of 83% over 38% (p = 0.038) for node-positive p16+ patients receiving chemo-radiotherapy following LND [273]. Twenty-eight of 51 patients were LN+, of whom 14 received chemo-radiotherapy, 7 of whom were HPV-positive. Overall, regardless of HPV status, 2-year LRC was 54% for those receiving adjuvant chemo-radiotherapy vs. 13% (p = 0.006). Choo et al., found similar efficacy of adjuvant chemo-radiotherapy with improved CSS at one and 2 years, even though the patients selected for adjuvant chemo-radiotherapy had a higher number of positive LNs (64% > 5 vs. 8%), more pN3 disease (72% vs. 17%) and more ENE (45% vs. 17%) [281]. The OS was the same for the unfavourable group receiving adjuvant chemo-radiotherapy as it was for the more favourable earlier-stage patients not receiving chemo-radiotherapy.

Although PLND is recommended for patients with high-risk groin pathology (N2–N3), this is not the practice in all jurisdictions. Maibom et al., reported from Denmark on the use of inguinal-pelvic chemo-radiotherapy for 21 patients with a median follow-up of 74 months [282]. All patients had ENE and two-thirds had bilateral groin disease, with a median OS of 84 months and 57% 5-year survival. This concept is being tested in the currently accruing InPACT trial where men with high-risk groin pathology can be randomised to chemo-radiotherapy or PLND followed by chemo-radiotherapy [260].

6.4.2.3. Summary of evidence and guidelines for pre- and post-operative radiotherapy

6.5. Systemic and palliative therapies for advanced disease

6.5.1. Introduction

Much of our current standard of care for this rare disease has evolved based upon extrapolated experience with similar cancers. The most common regimens utilized today for advanced disease are similar to those routinely used in the peri-operative setting, consisting of platinum-based regimens. Most data come from institutional or retrospective studies, but cooperative groups have occasionally studied this disease via prospective phase II studies.

6.5.2. Chemotherapy

Phase II cooperative group studies with bleomycin, methotrexate, and cisplatin (BMP) and irinotecan cisplatin yielded response rates of 31–33% [186,283]. The median OS for BMP was 28 weeks. Toxicity was a concern with both regimens, especially pulmonary toxicity from bleomycin.

A retrospective study of cisplatin and 5-FU (PF) presented a response rate of 32% and median OS of 8 months. Toxicity was manageable for this patient population [284].

Addition of taxanes to cisplatin-based regimens was associated with promising activity including CRs. Docetaxel, cisplatin, and fluorouracil (TPF) was prospectively studied in a cohort with distant metastasis (28%) or locally-advanced disease (72%). The response rate was 38.5% and median OS of 14 months; there were 2/26 patents with CR [184]. The study did not meet its efficacy endpoint and toxicity of TPF was a concern. Another prospective study of TPF in exclusively metastatic (M1) disease showed an objective response rate of 38.5% and median OS of 7 months [285]. The latter study did meet its efficacy endpoint and toxicity was interpreted as acceptable.

Paclitaxel, ifosfamide and cisplatin (TIP) was prospectively studied in patients with metastases confined to LNs (N2–3, M0), having a response rate of 50% in this select population and 3/30 with surgically verified CRs [180]. Toxicity was manageable in this setting, but there are limited data available for TIP in distant metastatic disease.

A SR of cisplatin-based chemotherapy outcomes with and without taxanes suggested a higher toxicity rate with taxanes, 49% vs. 26% [187].

Vinflunine single-agent chemotherapy was prospectively studied in patients with advanced disease who were not eligible for curative surgery or NAC. Patients were required to have ECOG performance status < 2 and estimated glomerular filtration rate (GFR) > 60 mL/min. Median age was 70 years with a 27% response rate and median OS of 8.4 months. Toxicity was manageable.

A retrospective study of paclitaxel single-agent chemotherapy as second line reported a response rate of 20% and median OS 23 weeks [286]. Two studies of various second-line systemic therapy regimens found median OS of 4.5 – 5.6 months [287,288].

A retrospective study of 101 patients looked at the efficacy of chemotherapy as first-, second- and third-line treatment [287]. The median OS for first-line chemotherapy was 7.2 months and with best supportive care, two months. The second-line regimens in seventeen patients included paclitaxel/carboplatin (41%), cisplatin/capecitabine (12%), paclitaxel (12%), or other (36%). There were two objective responses (12%), three stable disease (18%) and seventeen with progressive disease (71%) as best response. Paclitaxel/carboplatin was also reported in adjuvant and neoadjuvant case series and was well tolerated [289,290].

These data support the recommendation of platinum-based chemotherapy as the preferred approach to first-line palliative systemic therapy. Choices include triplet regimens (TPF, TIP) and doublets (PF, paclitaxel/carboplatin), where doublets appear to have less toxicity. Both TPF and TIP combine two neurotoxic drugs and are not appropriate for patients with pre-existing neuropathy or low GFR. Other comorbidities and functional status should be carefully considered when selecting a regimen. While data for paclitaxel/carboplatin in advanced penile cancer are limited, it is reasonable to extrapolate from its use as palliative treatment of squamous-cell cancers from other sites. An alternative approach is single-agent chemotherapy with vinflunine or a taxane.

Effective second-line palliative chemotherapy regimens are lacking. Second-line chemotherapy in multiple studies was associated with median OS of 6 months or less. This is an unmet need that also applies to patients with tumour recurrence after adjuvant or neoadjuvant chemotherapy.

6.5.2.1. Immunotherapy

Immune-based therapies such as immune-checkpoint blockade, HPV-directed vaccines and adoptive T-cell therapies have emerged as potential treatment options for advanced penile cancer [291]. Given the relatively high expression of PD-L1 in penile SCC, several trials in progress assess checkpoint inhibition in advanced disease. None of these anti-PD(L)1 monotherapy trials has been published thus far. Trials presented at conferences reported response rates of 14–17% [292,293].

Basket studies testing combination therapies have included penile SCC patients. In a phase I-II study of nivolumab combined with cabozantinib, with or without ipilimumab, 3 penile SCC patients were included: one partial response (PR) and 2 stable diseases (SD) were reported [294]. In another study testing the combination of ipilimumab and nivolumab, 5 penile SCC were included reporting 2 patients having SD [295]. In general, inclusion of patients with advanced penile SCC after chemotherapy exposure into early-phase basket trials is highly recommended.

6.5.2.2. Targeted therapies

Beyond chemotherapy, currently limited additional systemic options exist. Specific actionable genetic alterations appear rare in this disease. Targeted therapy against epidermal growth factor receptor (EGFR) has been tested, similar to SCCs originating from other anatomical regions.

Evidence of sporadic activity of several EGFR inhibitors have been reported from a few small clinical studies or case-series [296-298]. Dacomitinib, an orally-available pan-HER inhibitor, was tested as monotherapy in a phase II study including patients with locally-advanced and distant metastatic penile SCC. Twenty-eight patients were included in this study, and the ORR was 32.1% with one patient benefiting with a complete response [299].

Despite PIK3CA gene alterations have been reported as the most frequently identified potentially ‘actionable’ genomic alterations in SCC of the pelvic region, no data currently support the use of selected targeted agents in this disease [300].

6.5.3. Role of radiotherapy in palliation

Radiotherapy is frequently necessary for palliation of penile cancer and should be customized for unique presentations as necessary: e.g., ulcerative fixed LNs or dermal lymphatic spread. While standard palliative regimens should be readily employed, providers should be aware that re-treatment may be necessary for durable disease control [301]. This radio-resistance in some cases has been noted [178].

6.5.4. Summary of evidence and guidelines for systemic and palliative therapies for advanced penile cancer