Current Management and Future Perspectives of Penile Cancer: An Updated Review - Beyond the Abstract

Over the last decades, the growing exposure to human papillomavirus (HPV) has contributed to a rising incidence of penile cancer (PeCa) in men, appearing as a major concern worldwide and more specifically in developing countries. Despite substantial improvements in diagnostics and treatment, the survival of patients with PeCa last constant with a reported five-year overall survival of around 60%.1. While the prognosis of newly diagnosed PeCa still relies on classical clinicopathological features, the identification of genomic and molecular biomarkers able to accurately predict treatment response remains an unmet medical need. In our recent review entitled “Current Management and Future Perspectives of Penile Cancer: An Updated Review”, we extensively provide useful information upon the optimal surgical and medical treatment in PeCa, as well as ongoing preclinical and clinical research that could translate into new therapeutic options in the near future. In this supplementary commentary, we want to shed light on additional key points and provide new insights into the evolving landscape of PeCa.

As we know, HPV represents one of the major risk factors in PeCa. The role of HPV infection in PeCa is not well elucidated. However, it can be either through the development of premalignant lesions or via overexpression of oncogenes. Therefore, and following the example of cervical cancer, HPV vaccination in boys is increasingly being implemented in national immunization programs around the globe, especially in developing countries.2,3 Moreover, a recent systematic review of the efficacy and effectiveness of the HPV vaccine in males reported a vaccine efficacy of approximately 47% against anogenital HPV 16 infections.4 Nevertheless, since only 30 to 50% of all penile cancer cases seem to be attributable to HPV, vaccination alone cannot constitute the final solution, and more research is needed.

Detection of positives nodes in men with moderate- to high-risk PeCa and impalpable inguinal nodes is an important step in the therapeutic pathway. While detection using the traditional international standard dynamic sentinel lymph node biopsy (DSLNB) with patent blue dye and radioisotope is associated with high false-negative rates, indocyanine green might offer an alternative adjunct to improve detection rates.5 Indeed, DSLNB using indocyanine green (ICG)-99mTc-nanocolloid, a hybrid fluorescent-radioactive tracer, was evaluated in a cohort of 404 consecutive PeCa patients and demonstrated outstanding results with an acceptable safety profile.6 This technique appears to outperform versions of DSLNB by maximizing the detection rate, decreasing the false-negative rate, and sparing prophylactic inguinal lymph node dissection, a substantially more morbid procedure. However, the results are unlikely to be generalizable outside of expert care in a high-volume center, as the procedures and protocols are highly technical and highly specialized, requiring a multidisciplinary training program (including the surgeon, nuclear medicine physician, pathologist, and operating room staff). Thus, the feasibility of this innovative technique remains challenging in daily practice.

More recently, genomic analyses have provided transformative knowledge on the genomic and molecular landscape and tumor microenvironment of PeCa. Indeed, around one-quarter of patients with metastatic PeCa display a wide range of clinically actionable genomic alterations in mechanistic target of rapamycin, DNA repair, and receptor tyrosine kinase pathways, pointing to a potential benefit from combined or sequential targeted therapies for treatment-resistant advanced PeCa.7 Additionally, particular subsets of patients with PeCa might benefit from immunotherapy as some PeCa tumors harbor strong PD-L1 expression and a low frequency of mutational signatures suggestive of immunotherapy resistance.7 Consequently, ongoing clinical trials will hopefully elucidate tangible conclusions regarding the role of these novel management strategies.

Despite successful surgical treatment of locoregional PeCa, effective treatment options for advanced disease are limited. Further research to identify the relationship between cellular and molecular components of PeCa, as well as the composition of penile microbiota and its association with HPV infection and PeCa oncogenesis might lead to new cancer prevention and relevant treatment strategies in the near future.

Written by: Florent Peyraud,1,6 Clément Allenet,2 Marine Gross-Goupil,1 Charlotte Domblides,1,6 Félix Lefort,1,6 Amaury Daste,1 Mokrane Yacoub,3 Thibaud Haaser,4 Ludovic Ferretti,5 Grégoire Robert,2,6 Alain Ravaud1,6

  1. Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France
  2. Department of Urology, Bordeaux University Hospital, Bordeaux, France
  3. Department of Pathology, Bordeaux University, Bordeaux, France
  4. Department of Radiotherapy, Bordeaux University Hospital, Bordeaux, France
  5. Department of Urology, HIA Robert-Picqué, Villenave d’Ornon, France
  6. Bordeaux University, Bordeaux, France

1. Pham, Minh N., Allison M. Deal, Jed E. Ferguson III, Yue Wang, Angela B. Smith, Matthew E. Nielsen, Raj S. Pruthi, and Michael E. Woods. "Contemporary survival trends in penile cancer: Results from the National Cancer Database." In Urologic Oncology: Seminars and Original Investigations, vol. 35, no. 12, pp. 674-e1. Elsevier, 2017.
2. Lei, Jiayao, Alexander Ploner, K. Miriam Elfström, Jiangrong Wang, Adam Roth, Fang Fang, Karin Sundström, Joakim Dillner, and Pär Sparén. "HPV vaccination and the risk of invasive cervical cancer." New England Journal of Medicine 383, no. 14 (2020): 1340-1348.
3. Soares, Andrey, Icaro Thiago de Carvalho, Aluízio Gonçalves da Fonseca, Antonio Machado Alencar, Carlos Heli Bezerra Leite, Diogo Assed Bastos, João Paulo Holanda Soares et al. "Penile cancer: a Brazilian consensus statement for low-and middle-income countries." Journal of cancer research and clinical oncology (2020): 1-16.
4. Harder, Thomas, Ole Wichmann, Stefanie J. Klug, Marianne AB van der Sande, and Miriam Wiese-Posselt. "Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review." BMC medicine 16, no. 1 (2018): 110.
5. Aydin, Ahmet Murat, Nicholas H. Chakiryan, and Philippe E. Spiess. "Will Dynamic Sentinel Lymph Node Biopsy Become the New International Standard for Evaluating High-risk Penile Cancer in Patients with Clinically Negative Lymph Nodes?." European Urology (2020).
6. Dell’Oglio, Paolo, Hielke M. de Vries, Elio Mazzone, Gijs H. KleinJan, Maarten L. Donswijk, Henk G. van der Poel, Simon Horenblas, Fijs WB van Leeuwen, and Oscar R. Brouwer. "Hybrid Indocyanine Green–99mTc-nanocolloid for Single-photon Emission Computed Tomography and Combined Radio-and Fluorescence-guided Sentinel Node Biopsy in Penile Cancer: Results of 740 Inguinal Basins Assessed at a Single Institution." European Urology 78, no. 6 (2020): 865-872.
7. Aydin, Ahmet Murat, Jad Chahoud, Jacob J. Adashek, Mounsif Azizi, Anthony Magliocco, Jeffrey S. Ross, Andrea Necchi, and Philippe E. Spiess. "Understanding genomics and the immune environment of penile cancer to improve therapy." Nature Reviews Urology 17, no. 10 (2020): 555-570.

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