DEfeating PEnile CAncer-2

In contrast to the developing world with the incidence of 2.8-6.8 per 100,000 men, penile cancer (PeCa) is an orphan disease in Western countries where the incidence is below 1.0 per 100 000 males (Douglawi-2019). A plethora of risk factors have been identified including lack of neonatal circumcision, phimosis, chronic inflammation, lichen sclerosus, socioeconomic status, obesity, smoking, psoralen UV-A phototherapy, premalignant lesions as well as impaired immune response (Douglawi-2019, Thomas-2020). Moreover, human papilloma virus (HPV) has been attributed to nearly 40-50% of cases (Diorio-2016, Backes-2009). The disease most commonly affects men in their 6th decade of life, whereas young males may be at a higher risk for more aggressive tumor characteristics if diseased (Paiva-2015). PeCa is a distinctly aggressive malignancy characterized by a rapid tumor growth as well as prompt lymphatic metastasis (Hakenberg-2015). Whereas for localized disease cure can be achieved in most patients, prognosis is literally fatal for metastatic PeCa (Thomas-2021). After failing the first-line cisplatin-based chemotherapy providing a progression-free survival of 20 weeks and a response rate of 30%, overall survival falls short of 6 months (Wang-2015). It is a matter of concern that contemporary reports from the USA, France, and Norway have shown that survival of PeCa patients remained unchanged over respective periods of 10, 20, and 60 years despite all efforts in the amelioration of diagnostic and therapeutic paradigms (Daubisse-Marliac-2017, Hansen-2018, Pham-2017). It is furthermore noteworthy that most currently used cytotoxic concepts for this less chemo-responsive condition have been introduced a decade ago at the earliest (Thomas-2021). Besides frequently encountered patient-related issues as delayed medical consultations impairing oncologic outcomes, several other aspects contribute to the lack of progress in the treatment of this malignancy (Gao-2016). One of the reasons is that biomarker and translational research, a prerequisite for the clinically successful disease management, is still in child's shoes in PeCa as compared to many other malignancies. Indeed, fundraising for preclinical research in this condition is challenging and often only possible when applying for funding exclusively dedicated to rare cancers hampering clinical advances as well. In addition, this orphan disease is not "appealing" for drug development pipeline of the pharmaceutical industry due to its rarity in the Western world (Taruscio-2011).

Beside aforementioned aspects, another well-known conundrum - a non-adherence of treating physicians to guideline recommendations - poses a threat to optimization of outcomes in PeCa since available evidence is often only insufficiently utilized in the routine care. A recent survey on local therapy of Tis, Ta-T1a, and T1b PeCa by the European PROspective Penile Cancer Study Group Survey (E-PROPS) distributed across 681 urologists yielded a disenchanted 42.4% adherence rate with a guideline-conform treatment across all tumor stages (Pallauf-2020). A survey assessment in German-speaking countries performed by the same group demonstrated that only 35.2% and 23.9% of 557 participating urologists correctly identified criteria for inguinal and pelvic lymphadenectomy (ILAD, PLAD), respectively (Suarez-Ibarrola-2021). These results are further substantiated by an analysis of the Surveillance, Epidemiology, and End Results and the National Inpatient Sample databases reporting on 24.7% adherence rate with guideline recommendations on ILAD in PeCa (Mistretta-2019). Of note, a recent study using data of 1,689 men diagnosed with pT1b-T3, cN0 PeCa included in the National Cancer Database revealed that only 25.3% of them were subjected to ILAD, omission of which turned out to be an independent predictor of overall mortality (Woldu-2018). This finding underscores the exceptional importance of the appropriate lymph node management in PeCa.

Accordingly, the most decisive prognostic factor for survival in males with PeCa is the presence and extent of nodal metastases, with a 5-year disease-specific survival of approximately 95%, 80%, 65% and 35% for N0, N1, N2 or N3 disease, respectively (Horenblas-1994, Ravi-1993, Wen-2018, Srinivas-1987). Thus, initial lymph node staging is aimed at identifying lymphatic metastasis as early as possible, since superior outcomes have been reported for men with T2-3 cN0 disease at high risk for (micro)metastases subjected to early (prophylactic) as compared to late (therapeutic) ILAD when groin metastases became clinically evident (Kroon-2005). In fact, systemic spread of PeCa occurs in a stepwise manner through the lymphatic system: initially to the inguinal nodes, followed by the pelvic nodes and finally to the retroperitoneal nodes and distant sites, while hematogenic metastasis is rare (Wood-2010, Lopes-1996). Superficial inguinal nodes located in femoral triangle are first affected during dissemination process. Daseler and coworkers divided the superficial inguinal lymph nodes into five regions centered around the saphenofemoral junction; central, lateral superior, lateral inferior, medial superior and medial inferior (Daseler-1948). Hereby, medial superior zone followed by the central inguinal zones contain sentinel inguinal nodes, i.e., those first affected by lymphatic spread (Daseler-1948, Leijte-2008, Omorphos-2018). From superficial lymph nodes further dissemination takes place into deep inguinal nodes located within the region of the fossa ovalis at the saphenofemoral junction as well as medially to the femoral vein up to the node of Cloquet that is located between the femoral vein and the lacunar ligament and marks the most cephalad inguinal lymph node connecting inguinal and iliac/pelvic lymphatics.

If no suspicious nodes are present at palpation (cN0 disease), approximately 20-25% of patients with PeCa may still harbor occult metastases necessitating further risk-adapted staging procedures (Woldu-2018). By now, no validated tumor markers or nomograms are available to predict lymphatic dissemination in PeCa. Since imaging modalities like CT, MRI or 8FDG-PET do not reliably detect metastases < 10 mm, they are not generally recommended in cN0 PeCa, in which the focus is directed at detection of the micrometastatic disease (Jakobsen-2021, Sadeghi-2012). Consequently, surgical staging still maintains its role as the standard care for detection of subclinical metastasis. Due to the morbidity of this strategy, risk categories are used to reduce potential overtreatment for up to 80% of males with cN0 PeCa being free of micrometastatic disease. Well-differentiated (G1), pTa, pTis and pT1 tumours without lymphovascular/perineural invasion and not poorly differentiated (pT1a) are considered low-risk tumours with a neglectable probability of metastases rendering invasive staging unnecessary. Moderately differentiated (G2) pT1a tumors are considered intermediate-risk and are associated with a 6-8% probability of (micro)-metastatic lymph node disease, whereas in pT1b G2 tumors, the risk is 22-30% (Fankhauser-2022). Therefore, all tumors that are stage T1b, or higher, are considered high-risk tumors bearing an up to 80% risk of occult metastasis (Chaux-2015, Solsona-2001). Considering these probabilities, current European Association of Urology (EAU) and American Society of Clinical Oncology (ASCO) Collaborative Guidelines on Penile Cancer recommend surgical lymph node staging for all patients at high risk, while for men at intermediate risk both surgical staging and surveillance with a strict follow-up represent acceptable disease management options (EAU-ASCO Penile Cancer Guidelines). National Comprehensive Cancer Network (NCCN) Guidelines recommend bilateral ILAD as primary surgical staging even in both intermediate and high risk cN0 disease (NCCN Guidelines Penile Cancer 2023).

In patients with palpable nodes in the groin (cN+ disease), nodal metastases are present in approximately 45-80% of cases (Hughes-2009, Lutzen-2016). Notably, for pN1 disease ILAD has been demonstrated to yield similar outcomes as patients with pN0 disease (Martin-2012). Since cure can be achieved in limited lymph node positive disease confined to the regional nodes, radical ILAD is the treatment of choice for males with cN1-2 disease (Brouwer-2023).

The present study is a prospective, investigator-initiated, randomized, open-label phase II trial. Male patients with a histologically proven diagnosis of PeCa and either pT1a G2 cN0, pT1b-3 any G cN0 or pT1-3 any G cN1-2 disease without bulk lymph nodes (< 4cm), constituting the indication for prophylactic or therapeutic inguinal lymphadenectomy, will be enrolled.

The eligible patients will be randomized 1:1 in one of two arms. Patients in the conventional treatment Arm A will receive open inguinal lymphadenectomy and patients in the experimental Arm B will receive robot-assisted inguinal lymphadenectomy. All patients will be followed up for 36 months after last patient in or until death, withdrawal of consent, or loss to follow-up (whichever occurs first).

Investigators will recruit patients directly during regular clinical consultation visits in the respective center. All trial related investigations and enrolment of patients will only be performed after a written informed consent was collected using the ethics committee approved patient information and consent forms.

All patients who gave written informed consent will be captured online in the electronic case report form (eCRF) as screening patients to obtain a patient number which is used for pseudonymized identification throughout the trial.

Provided that all other inclusion and exclusion criteria are met, the patient will be allocated and is allowed to start the trial treatment. If one or more inclusion and/or exclusion criterion is/are not met, the patient will be marked as a screening failure in the eCRF.

Patients will be randomized 1:1 into one of the study arms and stratified by lymph node status (cN0 vs. cN1-2) and body mass index (< 25 vs. ≥ 25). Randomization will be conducted following the allocation by an adaptive randomization procedure implemented in the EDC system.

Inclusion criteria

• 1. Patient has provided written informed consent.
• 2. Male patient ≥ 18 years at time of signing the informed consent form.
• 3. Patient has histologically proven penile squamous cell carcinoma.
• 4. Patient has indication for prophylactic (intermediate or high-risk primary tumor and cN0) or therapeutic (cN1/2) inguinal lymphadenectomy, i.e.:

• pT1a, G2, cN0 OR
• pT1b- pT3, any G, cN0 OR
• pT1-pT3, any G, cN1-2
• 5. Patients has adequate hepatic, renal and bone marrow function:

• Hemoglobin ≥ 8.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 109 /L
• Platelets ≥ 100 x 109 /L
• International normalized ratio (INR) / activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants. Anticoagulation is accepted according to the surgeon's practice.
• 6. Patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
• 7. Performance status of the patient is judged by the treating physician as appropriate to undergo surgery.

Exclusion criteria

• 1. Patients has inguinal bulky disease ≥ 4 cm (determined by ultrasound or cross-sectional imaging).
• 2. Patient has distant metastases.
• 3. Patient receives or is scheduled for neoadjuvant chemotherapy for PeCa.
• 4. Patient received previous major inguinal surgery (transabdominal laparoscopic inguinal hernia repair is permitted), lymph node resection or radiotherapy in the groin or pelvic area.
• 5. Patient participates in competing trials affecting the effects of the surgery or outcome measures.
• 6. Patient has addictive or other medical conditions that do not allow the subject to appreciate the nature and scope of the clinical trial and its potential consequences.
• 7. Patient has any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
• 8. Patient has been incarcerated or involuntarily institutionalized by court order or by the authorities.
• 9. Patient is unable to consent because he does not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts.