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Introduction Penile cancer (PeCa), though rare, presents significant challenges in diagnosis, treatment and management. Despite medical advancements and therapeutic strategies, outcomes vary due to factors like geographic disparities, clinical practice differences, socioeconomic influences and varying levels of healthcare provider awareness. 1 Unveiling these variations in PeCa care is crucial to ensure all patients receive evidence-based, effective treatment. Furthermore, understanding the current landscape—including existing protocols, treatment modalities and patient access to care—will highlight areas that necessitate further research and collaborative efforts. This narrative review explores the existing disparities in PeCa management, with a focus on aspects that lack consensus or have limited data; thus, identifying knowledge gaps and establishing research priorities to standardise practices and enhance patient outcomes.Diversity in disease presentation and management Founded in 2019, the Global Society of Rare Genitourinary Tumours (GSRGT) recognised the global disparity in PeCa presentation and management, and the need for collaborative efforts to standardise management protocols via a survey conducted among more than 100 PeCa experts worldwide. 1 Geographically, patients in South America, Africa and Asia are less likely to have primary tumours suitable for penile preservation compared with patients in North America and Europe. This highlights how socioeconomic issues, difficult healthcare access and lack of centralised PeCa care can contribute to delayed patient presentation.2–4 A similar contrast was also noted in the nodal status at presentation with the majority of patients in Europe, North America and Asia being clinically node-negative (cN0); while node-positive (cN+) patients were higher in Africa and South and Central America.In managing cN0 patients, definitions of ‘cN0’ varied. Some experts relied on clinical examination alone, while others incorporated imaging and fine needle aspiration cytology. A stark difference was also noted in the preference for the inguinal staging approach for high-risk cN0 patients. Dynamic sentinel lymph node biopsy was preferred in Europe, while North and Central American respondents preferred modified and superficial inguinal nodal dissection. All three approaches were almost equally preferred in Asia and South America.For the radical inguinal nodal dissection in cN+patients, a recent survey by the European Reference Network on urogenital diseases and conditions reported the lack of consensus regarding the boundaries of the template for inguinal nodal dissection.5 In the GSRGT survey, there was no consensus on the threshold for assessing ipsilateral pelvic nodes. Also, most surgeons preferred neoadjuvant chemotherapy followed by surgery for bulky inguinal or pelvic nodal disease, with adjuvant chemotherapy used less frequently. Adjuvant radiotherapy (RT) was sparsely used. Due to this global variation in practice, collaborative efforts and consensus are needed to establish standardised and shared protocols.Pathology and staging of penile carcinoma: current status and issues Human papillomavirus infection and PeCa: incorporation in WHO classification and clinical implication The role of human papillomavirus (HPV) infection in PeCa development is poorly understood but increasingly recognised. 6 The 2016 WHO classification of penile squamous cancer unveiled a paradigm shift based on the relationship of PeCa to HPV infection. The 2022 update reaffirmed this, emphasising HPV-associated and HPV-independent PeCa.7 The same applies to premalignant penile lesions designated as penile intraepithelial neoplasia (PeIN), recognising an HPV-independent differentiated PeIN and an HPV-associated PeIN.8 Chronic inflammatory conditions like lichen sclerosus and long-lasting balanoposthitis contribute to the development of differentiated PeIN via mediators like Cyclo-oxygenase-2. Furthermore, a high prevalence of TP53 mutations has been recognised in differentiated PeIN and HPV-independent PeCa.9 The most common HPV-associated PeIN and the related invasive counterparts included as ‘subtypes’ are the basaloid and warty subtypes.9 Although there are no clear prognostic or treatment differences, some studies suggest that HPV-associated PeCa may have better responses to radiation therapy.10The integration of HPV detection and serotyping in PeCa care is crucial for prevention and treatment strategies. Several methods exist for HPV detection with varying sensitivity, specificity, applicability and cost. The details of the techniques are summarised in table 1.Table 1Summary of commonly used methods for HPV detection and serotyping, including their principles, sensitivity, specificity, clinical applicability and relative cost in penile cancer careDetection methodSensitivitySpecificityPerformed onCommentLimitationsp16 IHC100%71%FFPE tissueDetects p16INK4a antigenValuable for initial screeningModerate specificity, may miss some HPV-related cases.72 73DNA PCR98%84%FFPE tissueProvides information about genotypes, thereby helping in determining the specific strainMay not differentiate between active and dormant infection.74E6/E7 mRNA RT-PCR97%100%Fresh/frozen tissueThe gold standard for research purposesDetects presence and active infectionTime-consuming, can only be performed on non-FFPE tissues (fresh/frozen), more expensive, RNA fragility issues.75HPV DNA ISH85%88FFPE tissueMost reliable method to confirm HPV presence when compared with other techniquesRequires expertise, less commonly available, relatively expensive compared with IHC.74Novel hybrid techniquesMultiplex HPV RNA ISH/p16 IHC74FFPE, Formalin-Fixed Paraffin-Embedded; HPV, human papillomavirus; IHC, Immunohistochemistry; ISH, Insitu Hybridization.Integrating HPV detection and serotyping into PeCa care could revolutionise diagnosis and treatment. While routine serotyping is not currently done, it could enhance our understanding of HPV’s role in PeCa. Since HPV vaccines target serotypes linked to cervical cancer, it is unclear if they offer the same benefits in preventing PeCa in males.11 Thus, integrating HPV serotyping could lead to more targeted vaccination strategies for both genders.12 As knowledge of the role of HPV in PeCa advances, standardising detection methods and prevention strategies is essential.Implication of the change in American Joint Committee on Cancer staging of the primary and potential areas of improvement The American Joint Committee on Cancer (AJCC) tumour-node-metastases (TNM) staging system serves as a critical tool for guiding treatment decisions while predicting patient prognosis and outcomes across various cancers. The 8th edition has significant changes from the 7th, and these have been summarised in table 2.Table 2Summary of the key changes in the AJCC TNM staging system (8th edition) compared with the 7th edition, highlighting updates relevant to treatment decisions, prognosis and patient outcomesAJCC TNM7th Edition8th EditionStudiespT staging changespT1=single stage for all tumours. pT2 includes involvement of either or both corpora. pT3 includes urethral involvement.pT1 subdivided into pT1a (low grade, no LVSI/PNI) and pT1b (high grade, with LVSI/PNI).76 pT2 and pT3 stages modified based on corpus involvement.77Leitje et al found no significant difference in 5-year survival between pT2 and pT3 disease (seventh AJCC), suggesting no impact of urethral involvement on survival. (79) Sun et al observed lower inguinal lymph node metastasis risk in tumours involving the corpus spongiosum compared with the corpus cavernosum, supporting the separation of tumours into pT2 (corpora spongiosa) and pT3 (corpora cavernosa), regardless of urethral involvement. (80) Sali et al recommend histological grade, LVSI and PNI in pT2/pT378pN staging changespN1≤2 inguinal lymph nodes with/without extranodal extension; pN2≥3 inguinal lymph nodes with/without extranodal extension.pN1=1–2 inguinal lymph nodes involved without extranodal extension; pN2≥3 unilateral inguinal metastases or bilateral metastases.79Similar survival in ≤2 lymph node metastasis without extranodal extension; poorer outcomes for ≥3 lymph nodes 11 80AJCC, American Joint Committee on Cancer; LVSI, lymphovascular space invasion; PNI, perineural invasion; TNM, tumour-node-metastases.The recent update to the AJCC staging system has improved tumour stratification, yet the current PeCa grading system still has limitations. Penile SCCs are graded using the three-tiered WHO/International Society of Urological Pathology classification, where a grade three tumour is defined by any anaplasia.7 This can affect clinical decision-making, as the grade from a biopsy may differ from the final grade of the resected specimen since grade heterogeneity is known to exist in PeCa.13 Other important prognostic factors include the anatomical level of infiltration, such as vascular, lymphatic and perineural invasion, as well as inguinal lymph node metastasis, all of which are incorporated in PeCa staging.14–16A key modification in the current AJCC staging could be separate staging for HPV-related and non-HPV-related tumours, as HPV status impacts both the pathogenesis and prognosis of PeCa. A retrospective study by Chipollini et al used national registry data to assess clinical and survival outcomes in 1224 penile SCC patients with documented HPV staining.17 After excludingpatients with distant metastasis and those with incomplete data, 825 patients were included, of which 38.9% tested positive for HPV. HPV-positive tumours were linked to lower AJCC clinical cT stages, poorer differentiation and lower rates of lymphovascular invasion (LVI), but higher node-positive disease. For patients who underwent lymph node dissection, no significant differences were observed in the final pathologic stage, upstaging rate or the presence of extranodal extension. Interestingly, only tumour differentiation, the presence of LVI and performance scores emerged as independent predictors for locally aggressive disease. HPV status did not prove to be a predictive factor for overall survival (OS) (p=0.13). Similarly, a multi-institutional study found that HPV-positive patients had better median OS with adjuvant RT than HPV-negative patients, highlighting the importance of incorporating HPV status into the TNM staging system.10 Additionally, HPV-negative disease was associated with a higher frequency of p53 mutations. Yuan et al also showed improved locoregional control with adjuvant chemoradiation in HPV-positive patients compared with HPV-negative patients (83% vs 38%, p=0.038).18 HPV positivity in node-positive disease was also associated with better locoregional control. The International Penile Advanced Cancer Trial (InPACT) aims to explore the prognostic effects of HPV status, p53 mutations and smoking on outcomes as a secondary objective.19Overall, while the 8th Edition AJCC staging system has improved our understanding of PeCa, ongoing research and refinement are still needed.Management of the primary tumour The European Association of Urology - American Society of Clinical Oncology (EAU-ASCO) guidelines for the management of primary penile tumours emphasise organ preservation as a central aim—provided oncological outcomes are not compromised. 20 Although no randomised controlled trials (RCTs) or robust comparative observational studies are currently available, retrospective evidence suggests that for well-selected patients, penile-preserving approaches yield superior functional and cosmetic results than partial or total penectomy, with comparable oncological outcomes.21 For patients undergoing non-surgical treatments, accurate histological diagnosis and precise local staging are critical. In cases managed surgically, achieving negative margins is essential for invasive carcinomas, with regional lymph node management performed either simultaneously or in a staged manner. Local treatment options for small, localised PeCa include conservative surgery, external beam RT and brachytherapy (). In the absence of high-level comparative evidence, current recommendations are largely informed by retrospective data and expert consensus—highlighting the importance of individualised, shared decision-making between clinicians and patients.Role of RT for organ preservation The EAU-ASCO 2023 guidelines recommend RT for selected patients with T1-2 lesions, 20 delivered either as BT or external beam RT (EBRT). Despite its effectiveness, RT is underused due to limited awareness among both physicians and patients and general lack of expertise due to the rarity of the disease.BT for early disease BT offers effective local control (LC) to preserve penile tissue with good LC rates in appropriately selected patients. A meta-analysis by Hasan et al22 and a recent review by Garaz et al23 reported equivalent LC rates with BT as compared with surgery for patients with early-stage PeCa. Moreover, the local recurrences after BT were successfully treated with surgery resulting in no difference in OS. Several case series have reported LC rates ranging from 70% to 90% for T1-2 lesions with penile preservation rates varying between 70% and 88%.24–27 Though direct comparisons are lacking, BT appears to outperform EBRT: Hasan et al found superior LC (79% vs 50%) and OS (73% vs 58%) with BT.22The implant for interstitial BT can be performed either using a template or by free-hand insertion of flexible catheters in single or multiple planes avoiding the urethra. Figure 1 shows the steps of an interstitial penile implant sparing the urethra. Common toxicities include urethral stenosis (0 to 45%), soft tissue necrosis (10%–20%) and fibrosis.25 27 28 Urethral stenosis can be avoided by selecting tumours away from the meatus (which may not always be possible) and avoiding hotspots in the meatal area. More recently Achkar et al evaluated the outcomes of pulse dose rate interstitial BT (PDR-BT) for localised glans penis cancer, focusing on urethral dose-volume constraints. The findings supported PDR-BT as an effective organ-preserving treatment for glans penis cancer and identified urethral dose-volume thresholds associated with meatal stenosis to guide safer practice.29 Circumcision is mandatory to mitigate the risk of soft tissue necrosis. Quality-of-life data post BT are limited, with most studies lacking longitudinal patient-reported outcomes (PROs).30 There is a clear need for prospective, multicentre registries collecting validated PROs—focusing on sexual, urinary and cosmetic outcomes—for both surgery and BT.Figure 1(A) Penile lesion, (B) post interstitial implant, (C) dosimetry showing sparing of urethra, (D) after implant removal, (E) at 3 weeks post RT, (F) at 2 months post RT. RT, radiotherapy.Definitive EBRT for early disease Retrospective case series report a LC rate of 60% with a penile preservation rate of 36%–66% in patients with T1-T2 lesions. 22 RT planning can be complex and unconventional due to the need for penile immobilisation, often achieved using wax boluses or a water phantom. Electron beam therapy may be suitable for superficial tumours. A minimum dose of 65–70 Gy equivalent dose in 2-Gy fractions is generally recommended, as lower doses (<60 Gy) are linked to inferior LC rate.31Techniques to optimise penile preservation surgery in men with buried corpora to avoid a total penectomy A particular challenge arises in patients with a buried penis, frequently associated with abdominal obesity, where partial penectomy risks resulting in total shaft loss. In these cases, the goal is to preserve as much of the penile shaft as possible. Reconstructive techniques such as suspensory ligament division and escutcheonectomy have been developed to address this issue. Figler et al described escutcheonectomy, which involves excising the mons pubis and penile skin, followed by coverage with a free skin graft from the thigh. This approach enhances penile exposure and can be combined with inguinal lymph node surgery when indicated.32 In a small case series, Staniorski et al reported on five patients who underwent buried penis reconstruction alongside PeCa treatment, with no perioperative complications. However, two patients experienced local or regional recurrence requiring further surgical intervention.33 While reconstruction does not appear to affect oncological outcomes, it may improve surveillance by making recurrent lesions easier to detect. Although large studies are lacking, outcomes reported to date are encouraging, with 80%–90% patient satisfaction, significant improvements in urinary function and hygiene, and sexual function improvement in 50%–75% of cases.32 34 These techniques represent important adjuncts to PeCa management, enabling functional preservation and potentially avoiding total penectomy in carefully selected patients.Penile reconstruction for the survivors Penile reconstruction is essential but underused in survivors of locally advanced PeCa, especially after total penectomy for T3–T4 tumours or when cancer involves the penile root. Phalloplasty involves neophallus creation using local or distant flaps—most commonly the radial forearm free flap, 35 though alternatives like the anterolateral thigh, latissimus dorsi and abdominal flaps are used.35–37 Phalloplasty is usually performed in stages, starting with neophallus creation, followed by microvascular transfer and eventual prosthesis insertion for functionality. Distant flaps require microsurgical transfer, unlike pedicled flaps that retain blood supply.38 Despite limited data, Garaffa et al reported favourable outcomes in 15 patients using radial-artery free flaps, including high cosmetic satisfaction, standing voiding (n=14) and functional erections in prosthesis recipients (5 of 7), though complications like strictures and fistulae were noted.39 Penile reconstruction holds promise as an essential component of postcancer care, providing survivors with an opportunity for functional and cosmetic restoration, although more extensive research is needed to establish best practices and optimise outcomes.Inguinal nodal disease management for cN0 patients Management of cN0 penile carcinoma has evolved focusing on accurate staging and reducing morbidity. Clinical examination alone misses 20%–25% of pathologically positive nodes. While routine imaging is not recommended by international guidelines due to low accuracy, it may aid preoperative staging in obese or previously irradiated patients. Ultrasound combined with fine-needle aspiration cytology (FNAC) of morphologically suspicious nodes offers high specificity (100%) but limited sensitivity (39%). 40Nevertheless, surgical staging stands as the optimal procedure in cN0 high-risk patients. Inguinal lymph node dissection (ILND) has long been the preferred staging option, as it provides accurate pathological staging, guides treatment and clears potential micro metastatic disease. An Indian retrospective series supports this statement as it found that patients with poor compliance to follow-up have improved cancer-specific survival () if they undergo an early ILND (at the same admission or within 2 months) when compared with patients undergoing a delayed procedure (91% vs 13%, p=0.007).41However, ILND in cN0 groins presents several drawbacks. Risk stratification is critical, as over 60% of high-risk cN0 patients do not have micro metastatic disease. Nomograms for predicting lymph node involvement have been formulated using tumour characteristics such as tumour thickness, growth pattern, grade, LVI, T stage and cN stage. The nomogram proposed by Ficarra et al showed a good concordance index of 0.876, but a lack of validation in other cohorts precludes its use in daily clinical practice.42 The importance of these pathology findings in predicting micrometastatic disease makes us rethink if the decision to address the groin can reliably be taken based on a biopsy which is unlikely to provide these details. Patel et al developed the Clino-radio-pathological Risk Scoring System to predict inguinal lymph node involvement in penile SCC, potentially sparing low-risk patients (scores 0–2) from bilateral groin dissection through close monitoring with ultrasonography and FNAC, while guiding intensified nodal treatment for high-risk groups (scores 5–9).43For cN0 disease, we need to strike the right balance between the false negative rate and complications. Dynamic sentinel node biopsy (DSNB) probably offers the best trade-off and is currently considered the first option for surgical staging of cN0 patients according to the new EAU-ASCO guidelines. However, it requires both expensive equipment and well-trained specialists and is consequently best suited for centres managing high volumes of this disease. A superficial ILND offers the least recurrence rate; and though it has higher morbidity than DSNB, it can be widely practised in countries without a centralised healthcare. Because the highest incidence of PeCa is in geographic regions which lack centralised healthcare, an emphasis on template-based nodal dissection to minimise the infield recurrence in cN0 PeCa can improve the outcome of this disease globally in the long term. There is also a lack of consensus on the extent of template-based dissection. The EAU-ASCO guidelines recommend modified inguinal lymphadenectomy without mentioning the false negative rate of this template. The only study comparing modified and superficial inguinal lymphadenectomy found an unacceptable false negative rate of 26.3% with the former in patients with high-risk disease. As expected superficial inguinal lymphadenectomy was associated with a higher complication rate (25% Clavien Dindo 3A).44Some unanswered questions in cN0 groins Imaging modality to be used to stage the cN0 groin.Adequacy of template (Modified Inguinal Lymph node Dissection or Superficial Inguinal Lymph node Dissection) during invasive staging.Long-term oncologic outcomes in minimally invasive procedures.Choice of agent (Patent blue, Tc nanocolloid, ICG), dual or triple tracer for DSNB.Duration of follow-up in groins kept on surveillance.Postoperative rehabilitation.Postoperative rehabilitation Postoperative rehabilitation is crucial for minimising complications after inguinal lymph node dissection. To reduce morbidity, more limited dissection techniques and minimally invasive approaches have been adopted, especially for cN0 patients. However, complications like lymphocele and lymphedema still occur, with rates ranging 9%–16% and 16%–50%, respectively. 45 46 Lymphocele can be minimised by carefully controlling lymphatics, while fibrin sealants have shown no significant benefit in reducing complications.47 Closed suction drains are recommended to prevent fluid accumulation, and patients should use compression stockings, engage in early ambulation and start physical therapy. Postoperative care also involves educating patients on self-care strategies, lymphatic drainage exercises and manual lymphatic drainage therapy. Psychological support is key to helping patients cope with body image and functional limitations. Comprehensive rehabilitation strategies enhance recovery, improve quality of life and support a smoother return to daily activities for PeCa patients. However, limited evidence exists about perioperative rehabilitation of PeCa patients and is a potential area of multiple research questions.The role of systemic and radiation therapy for node-positive disease Node-positive PeCa, especially with adverse risk features like extranodal extension (ENE), multiple inguinal node involvement or positive pelvic nodes has poor prognosis, with 5-year OS ranging from 0% to 42%. 48 This has led to the integration of systemic therapy and RT to optimise outcomes, though evidence for their role remains limited. The ongoing InPACT trial is evaluating the benefit of multimodal strategies incorporating surgery, chemotherapy and RT for patients with clinically or radiologically positive inguinal nodes.Role of neoadjuvant treatment in the management of nodal disease Upfront surgical resection is often not feasible in patients with bulky, fixed or bilateral nodal disease. Neoadjuvant chemotherapy (NACT) followed by surgical management is the recommended approach by EAU-ASCO and National Comprehensive Cancer Network guidelined. 20 49 NACT helps in the possible downstaging of bulky disease and can help in achieving better surgical outcomes. The largest study on NACT by Pagliaro et al investigated a regimen of paclitaxel, ifosfamide and cisplatin (TIP) in patients with cN2 or cN3 disease showed an improved OS and time to progression in patients with response to TIP and in those with a pathological complete response, without extranodal extension and skin involvement.50 The InPACT trial will shed more light on perioperative approaches in patients with a higher volume of disease.19 The role of neoadjuvant immunotherapy is also being explored. A phase II trial from China demonstrated that neoadjuvant toripalimab, nimotuzumab and taxol-based chemotherapy followed by consolidative surgery yields promising pathological complete response rates (close to 48%) and manageable toxicity in cN3 PeCa.51Role of adjuvant treatment in the management of nodal disease Role of adjuvant chemotherapy The role of adjuvant chemotherapy is less defined due to a lack of prospective trials. A retrospective analysis of 141 patients, of which 43% were eligible and received adjuvant chemotherapy for positive pelvic lymph nodes 52 found an estimated OS of 21.7 months (IQR 11.8–104) in the adjuvant chemotherapy arm versus 10.1 months (IQR 5.6–48.1 months) in no adjuvant chemotherapy arm (p=0.048). On multivariate analysis, adjuvant chemotherapy was also associated with improved OS (HR 0.40; CI 0.19 to 0.87; p=0.021). The NCCN presently recommends adjuvant chemotherapy if neoadjuvant chemotherapy was not given (level 2A) for patients with pN2, pN3 or ENE.49Role of adjuvant RT Adjuvant RT in node-positive PeCa is supported by both clinical rationale and emerging data. The 2023 EAU-ASCO guidelines recommend RT—with or without chemotherapy—for patients with pN2/N3 disease, including those previously treated with neoadjuvant chemotherapy, although with weak strength of recommendation. 20 The NCCN guidelines also suggest adjuvant RT in inguinal and/or pelvic node-positive PeCa.49Recent evidence reinforces its role: Jaipuria et al reported significantly improved OS (48 months vs 14 months; p<0.0001) in patients with >two positive inguinal nodes but negative pelvic nodes treated with RT versus chemotherapy, though the study did not address outcomes in the presence of ENE.53 A multi-institutional study by Tang et al reported improved CSS (14.4 months vs 8 months, p=0.023) and OS (12.2 months vs 8 months, p=0.044) with the addition of adjuvant pelvic RT in patients with positive pelvic nodes after pelvic node dissection.54Treatment intensification with multimodality adjuvant therapy Patients with pN3 cancer are at high risk of fatal locoregional recurrence and their prognosis remains poor. 55–57 Li et al reported improved CSS with a combination of adjuvant RT and adjuvant chemotherapy in patients with ENE after ILND as compared with adjuvant chemotherapy alone (28.5% vs 16.2%, p=0.036).58 Khurud et al studied the impact of various pathological and treatment factors on the outcomes in patients with pN3 PeCa. This relatively large study of 128 patients showed that multimodality treatment in the form of sequential chemotherapy and chemoradiation in pelvic node-positive patients resulted in superior DFS and OS.59 Thus, considering the poor prognosis associated with pN3 PeCa, intensification of treatment is warranted in this subset of patients to improve outcomes. The ongoing international penile advanced cancer trial (InPACT) (NCT02305654) aims to further clarify the optimal sequencing of surgery, chemotherapy and RT in node-positive PeCa.19Treatment intensification with higher RT dose and larger target volume The conventional adjuvant RT dose of 50 Gy in 25 fractions for node-positive PeCa may be suboptimal for achieving durable locoregional control. Johnstone et al reported high in-field failure in presence of ENE (52/64 sites) at 50 Gy,60 while Ager et al reported that patients receiving <50 Gy had double the recurrence risk compared with those receiving >50 Gy.61 Thus, escalating the RT dose beyond 50 Gy may potentially enhance the locoregional control in these patients. Yuan et al suggested genomic radioresistance characterised by heterogeneity in both primary and nodal disease, based on radiosensitivity indices (RSI).18 Genomic-adjusted radiation dose (GARD) integrates RSI into a radiobiological model to estimate the actual biological effect of a given radiation dose on an individual tumour.62 Integrating clinicopathological parameters with biology-based risk stratification like RSI and GARD may enhance treatment precision and outcomes. The impact of HPV status on radioresponsiveness of PeCa is being increasingly recognised. The multicentric study by Bandini et al found that patients who underwent ILND and perioperative RT, HPV+penile carcinoma patients had enhanced radiosensitivity that has been also related to the lack of TP53 mutations in this cohort of patients.63Optimal target volume remains undefined owing to the paucity of data on pattern of locoregional failure. The InPACT trial recently published international consensus guideline for radiation therapy in locally advanced PeCa, standardising target delineation, dose and technique to support consistent treatment across centres, with outcomes to be reported as recruitment progresses.64 Historically, inguinal node RT volume was defined using bony landmarks leading to poor coverage of deep-seated inguinal nodes and high normal tissue toxicity (skin, bladder, femoral head and neck and external genitalia).55Mittal et al evaluated 222 lymph nodes from baseline scans of 33 patients with inguinal node-positive PeCa and proposed contouring guidelines for Clinical Target Volume delineation of the inguinofemoral region using variable margins around femoral vessels. The guidelines were further validated prospectively and serve as a tool to comprehensively delineate inguinal CTV in operated and non-operated groin.57Combining immunotherapy with radiation therapy Despite the advances, the outcomes with conventional systemic therapy and surgery remain poor. The PERICLES study explored a novel strategy of combining atezolizumab with radiation therapy for patients with advanced PeCa. 65 However, this combination yielded only two complete responders and three partial responders out of a total of 30 patients. The study did suggest that biomarkers such as HPV intra-tumoral CD3+CD8+T cells infiltration may help select patients better.Primary chemoRT for advanced disease Another exploratory approach for locally advanced PeCa is to use primary chemoRT instead of multiagent systemic therapy and surgery. A recent prospective phase II study by Ottenhof et al evaluated 33 patients undergoing chemoradiotherapy as primary treatment for locoregionally advanced PeCa. They reported a 73% overall response rate (including 39% complete responses), 2-year progression-free and OS rates of 31% and 46%, respectively, and acceptable toxicity. HPV status was not associated with outcomes, and salvage surgery remained feasible in cases of residual disease.66Surveillance strategies following primary treatment Optimal surveillance protocols for PeCa are not well-defined. Although local recurrences can occur many years later, nodal and distant failures usually occur within the first 2 years.Surveillance strategy for cN0 groin Surveillance is typically recommended for low-risk patients (pTa, pT1a, G1). The incidence of recurrence is higher in patients managed by surveillance (9%) compared with those with invasive staging (2.3%). 67 The EAU-ASCO guidelines suggest 3-monthly clinical examinations for the first 2 years, followed by 6-monthly clinical examinations until 5 years after treatment.20 Abstracts published from two different high-volume centres have pointed out that 95% of the nodal recurrences occur within the first 2 years and there is possibly room for deintensifying the surveillance regime after 24 months. Suspicious nodes on palpation must be subjected to FNAC with or without Ultrasonography guidance.68 69There is a lack of studies on short-term and long-term quality of life, particularly regarding urinary and sexual function; and is an unmet need according to EAU-ASCO guidelines. Moreover, quality of life assessment tools specific to PeCa remain underdeveloped.Multinational collaborative efforts Multinational collaborative efforts in the field of PeCa have become increasingly vital for advancing clinical practice, research and patient care. By uniting experts from different countries, these efforts enable the sharing of resources and best practices to address the challenges of this rare cancer. Multinational studies allow for larger patient cohorts, enhancing the statistical power of research findings and fostering the development of standardised treatment protocols across diverse healthcare settings. Furthermore, these collaborations can help identify geographic disparities in disease incidence, presentation and management, ultimately leading to improved health outcomes for patients worldwide. Initiatives such as the GSRGT exemplify this commitment to international cooperation, focusing on improving awareness, education and research related to PeCa. Similarly, global initiatives like the InPACT study for locally advanced penile carcinomas are the way forward for answering questions about this rare cancer. 25 By fostering a global dialogue, these collaborative efforts aim to enhance diagnostic accuracy, optimise treatment pathways and ultimately improve survivorship for individuals affected by PeCa. Additionally, they help address gaps in patient support services, highlighting the need for multidisciplinary teams, including mental health professionals, sexual counsellors and urologists. A survey from a large online support group revealed that over one-third of PeCa patients reported 93% experiencing negative psychological effects, with 75% feeling that counselling would have been helpful. However, only 38% had access to such support, underlining the importance of comprehensive care. Importantly, nearly two-thirds of participants regarded peer support as vital for coping with their condition, emphasising the need for comprehensive support services tailored to the unique challenges faced by PeCa patients.70In India, despite having the highest burden of PeCa globally, care remains decentralised as of 2025. Several factors contribute to this, including the absence of governmental regulations for patient centralisation, limited resources for patient mobilisation and disparities in the facilities available at tertiary centres.71Conclusion In summary, the management of PeCa is a multifaceted field with several key areas deserving further exploration and attention ( table 3). Key areas include the integration of HPV assessment into routine care, with attention to detection methods and serotyping at diagnosis, which could lead to more targeted and effective treatment strategies. The evolving AJCC staging system for primary PeCa is another critical aspect, necessitating ongoing investigation to assess its impact and potential areas for improvement. Penile-sparing techniques, especially in patients with buried corpora, offer the potential to avoid total penectomy and preserve functional outcomes. Similarly, penile reconstruction, though currently underused, should be given greater consideration as part of comprehensive care for survivors of PeCa. Research in this area can pave the way for improved quality of life and enhanced post-cancer rehabilitation. BT offers an organ-preserving alternative for early-stage PeCa, with LC rates comparable to surgery in well-selected patients. In patients with node-positive PeCa with adverse risk features, treatment intensification with multimodality therapy is playing an increasingly important role. Additionally, the promising results of immunotherapy and targeted therapy offer significant potential for improving outcomes in these patients. Together, these topics underscore the need for ongoing research and innovation in the field of PeCa management and care.Table 3Key areas in the management of penile cancer (PeCa) that warrant further exploration and attention.Research strategySubstrategies/details1Integration of HPV detection and serotyping in PeCa careIncorporation of HPV into AJCC staging system—understanding HPV epidemiology and effective vaccination strategies targeting the male population2Techniques to optimise penile preservation in men with buried corporaFocus on preserving penile function and structure while avoiding total penectomy3Penile reconstruction techniquesDevelopment of innovative approaches for both functional restoration (urinary and sexual) and cosmetic outcomes4Multinational registry to report PRO measures for patients undergoing penile-preserving approachesInclusion of patients undergoing surgery and brachytherapy—collecting PROs to guide future clinical decisions5Treatment intensification in N3 diseasea. Optimal sequencing of surgery, chemotherapy and radiotherapyb. Exploring the role of novel systemic therapies like immune checkpoint inhibitors and targeted agent monoclonal antibodies.c. Potential for improving outcomes with radiotherapy dose escalation and larger target volumesd. Personalisation of radiotherapy doses based on radiosensitivity index and biologic profiling including HPV status6Effective surveillance strategies following treatmentDevelopment of comprehensive surveillance protocols, particularly for patients with low and high-risk diseaseAJCC, American Joint Committee on Cancer; HPV, human papillomavirus; PRO, patient-reported outcome.