Citations

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies.

Abstract Introduction This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. Methods Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan–Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. Results A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. Conclusion Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.

Zusammenfassung Hintergrund Aktuell wurde mit dem Tetrafecta-Score das erste Instrument zur Beurteilung der Behandlungsqualität in der chirurgischen Primärtherapie des Peniskarzinoms (PECa) publiziert. Eine externe wissenschaftliche Auseinandersetzung mit den ihn definierenden Einzelkriterien steht bislang noch aus und bildet das Studienziel. Material und Methode Es wurde eine internationale Arbeitsgruppe bestehend aus 12 Urologen und einem Onkologen mit klinischer und akademisch-wissenschaftlicher Expertise auf dem Gebiet des Peniskarzinoms gegründet. In einem modifizierten vierstufigen Delphi-Prozess wurden unter Einbeziehung der Tetrafecta-Kriterien insgesamt 13 Kriterien für PECa-Patienten in den klinischen AJCC-Stadien 1–4 (T1–3N0–3, aber M0) definiert, von denen in einer geheimen Abstimmung jeder der Experten 5 auswählen musste, um dadurch einen individuellen Pentafecta-Score zu generieren. Anschließend wurde das Rating der Experten aggregiert ausgewertet und dadurch ein finaler Pentafecta-Score gebildet. Ergebnisse Keines der ursprünglichen Tetrafecta-Kriterien wurde in den finalen Pentafecta-Score übernommen, der sich aus den folgenden Kriterien zusammensetzt: 1.) Organerhalt, sofern immer möglich (≤T2), jedoch stets unter Wahrung eines negativen chirurgischen Schnittrandes, 2.) beidseitige inguinale Lymphadenektomie (ILAE) ab pT1G2N0, 3.) perioperative Chemotherapie sollte erfolgen, sofern durch die Leitlinien indiziert, 4.) ILAE sollte, sofern indiziert, in einem zeitlichen Abstand von maximal 3 Monaten zur Primärtumorresektion erfolgen und 5.) die behandelnde Klinik sollte im Minimum 15 chirurgische Primärtherapien bei PECa-Patienten durchführen. Nur 7 der 13 Experten (54%) zeigten eine starke Korrelation ihres individuellen mit dem finalen Pentafecta-Score (rsp >0.60). Schlussfolgerung Auf der Basis eines moderierten Abstimmungsprozesses unter internationalen PECa-Experten wurde ein Pentafecta-Score als Qualitätssicherungs-Instrument für die chirurgische Primärtherapie gebildet, der nun anhand von patientenrelevanten und patientenberichteten Endpunkten zu validieren ist.

We read with great interest the manuscript by Brassetti et al. recently published in your journal and hope it will encourage discussion and debate around the optimization of the surgical management of patients with penile cancer (PECa) [...]

9 Background: The efficacy of neoadjuvant platinum-based chemotherapy (NAPC) in penile squamous cell carcinoma (PSCC) was provided by small clinical trials, leaving clinicians with scant evidence-based guidance. Thus, we aimed to analyze real-world outcomes of patients with PSCC who received NAPC prior to surgical resection. Methods: Patients from 9 tertiary care centers who had undergone NAPC prior surgical resection for PSCC were included with locally advanced (cTany, cN+), non-metastatic (M0) disease. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), Response was determined via best overall response measured with RECIST 1.1 criteria. Results: 167 patients were included, 137 (84%), of which received TIP prior to surgical resection. Ninety-two (55%) patients died during follow up, and the mean follow up for survivors was 57 months. The median OS was 42 months, while the median PFS was 17 months. The table details the response rates to NAPC, the associated survival, and Cox Proportional Hazards Modelling of OS and PFS. Predictors for OS and RFS included lymphovascular invasion, positive number of lymph nodes, extranodal extension, downstaging, best overall response, and ypN status. Figure 1 demonstrates OS outcomes by RECIST best response after chemotherapy, presence of downstaging after NAPC, ypN stage, and presence of extranodal extension. Conclusions: Upfront NAPC is effective in patients with lymph node metastases from penile carcinoma. Unsurprisingly, patients who demonstrated a robust response to therapy had improved survival outcomes compared to those who had not—as measured by RECIST criteria, tumor downstaging, pN staging, and presence of extranodal extension. This study represents the largest conglomeration of multi-institutional penile carcinoma patients treated with NAPC, and provides further supportive data for multimodal therapy for advanced penile cancer patients while prospective clinical trials complete accrual. [Table: see text]

Penile cancer is an extremely rare malignancy that accounts for approximately 1% of cancer deaths in the United States every year. While primary penile cancer can be managed surgically, advanced and metastatic forms of the disease require more aggressive management plans with systemic chemotherapy and/or radiotherapy. Despite the meaningful response to systemic treatments, the 2-year progression-free survival and disease-specific survival have shown disappointing results. Therefore, there is a crucial need for alternative treatment options with more favorable outcomes and a lower toxicity profile. There are currently extensive studies of tumor molecular biology and clinical trials with targeted molecular therapies, such as PD-1, PD-L1, and CTLA-4. In this review, we will describe the penile cancer microenvironment, and summarize the rationale for immunotherapy in penile cancer patients.