Insights into the management of penile squamous cell carcinoma: from conventional approaches to emerging novel therapies.

INTRODUCTION: Penile squamous cell carcinoma (PSCC), a rare genitourinary cancer, is associated with poor outcomes due to limited treatment effectiveness, especially in advanced stages. AREAS COVERED: While chemotherapy and/or surgery remain the standard of care, emerging therapies like immunotherapy, targeted therapy, and human papillomavirus (HPV) directed therapies show promise. Key to advancing treatment is understanding the immune microenvironment to gain insights into tumor resistance mechanisms and potential therapeutic targets. The scarcity of data on PSCC is a major obstacle in advancing research for this rare cancer. EXPERT OPINION: Future research should prioritize collaborative efforts across various research centers and countries. Enhancing data sharing and pooling resources can lead to a more comprehensive understanding of PSCC, ultimately supporting the development of precision medicine strategies tailored to this specific cancer type. This collaborative approach is essential for making significant strides in PSCC treatment and care.

Diagnostically Challenging Multifocal Penile Epithelioid Hemangioma Successfully Treated With Doxorubicin Hydrochloride.

ABSTRACT: Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, is an unusual vascular proliferation that tends to manifest in the head and neck region. Its occurrence on the penis is rare, with only scarce reported cases in the literature. The histopathological examination of this condition poses a challenge because it shares similarities with other entities, such as epithelioid hemangioendothelioma, epithelioid angiosarcoma, cutaneous epithelioid angiomatous nodule, or Kaposi sarcoma (KS). The infrequency of EH in penile locations underscores the need for accurate diagnostic differentiation and tailored treatment strategies for this atypical presentation. This case report highlights a rare instance of multifocal penile EH. The patient's lesions exhibited distinctive histopathologic features, with extensive eosinophilic infiltration, presence of necrosis, and infiltration to subcutaneous fat. The patient was treated with doxorubicin, a chemotherapy drug, with a very good response. This successful therapeutic outcome underscores the potential efficacy of doxorubicin in the management of multifocal penile EH. The comprehensive analysis of this case contributes to our understanding of the clinical presentation, histopathologic features, and treatment modalities for this rare penile tumor, providing valuable insights for future clinical considerations.

Comparison of Early Inguinal Lymph Node Dissection and Neoadjuvant Chemotherapy in Penile Cancer Patient with Bulky Nodal Metastasis: A Cohort Study.

PURPOSE: Penile cancer is a rare malignancy, where extranodal extension in inguinal or pelvic lymph nodes is associated with decreased 5-year cancer-survival rate in this study, we try to assess survival and quality of life in a penile cancer patient with bulky lymph node. METHODS: We retrospectively reviewed data from penile cancer patients with bulky lymph nodes who underwent treatment between July 2016 and July 2021 at tertiary referral hospital care. The inclusion criteria (age >18 yr, histologically proven penile cancer, and completion of last treatment 6 months prior to this study) yielded a cohort of 20 eligible penile cancer patients with bulky lymph nodes (> 4 cm/bilateral mobile/unilateral fixed). Only patients who had completed therapy at least 6 months prior to the study were included. After obtaining consent, they were asked to complete the EORTC QLQ-C30 questionnaire to evaluate the patient's quality of life. RESULTS: Out of 20 patients, 5 patients underwent direct ILND and 15 patients underwent chemotherapy. Median follow-up after primary diagnosis was 114+32 months in patients with early ILND and 52+11 months in patients who underwent delayed lymph node dissection. Out of 5 patients who underwent early ILND, all of them survived during follow-up, and achieved cancer-free status without residual tumor and with excellent functional outcomes (Karnofsky 90). There was no significant difference in social function (p-value = 0.551), physical function (p-value = 0.272), role function (p-value = 0.546), emotional function (p-value = 0.551), cognitive function (p-value = 0.453), and global health status (p-value = 0.893) between patient which treated with early ILND and Neoadjuvant Chemotherapy. However, patients who underwent early ILND showed a relatively better clinical outcome. CONCLUSION: Early ILND followed by adjuvant chemotherapy for penile cancer with palpable lymph nodes is more favourable than neoadjuvant TIP chemotherapy.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Metastatic Penile Squamous Cell Carcinoma Responsive to Enfortumab Vedotin.

Penile squamous cell carcinoma is a rare disease with very limited data to guide treatment decisions. In particular, there is minimal evidence for effective therapies in the metastatic setting. Here, we present a case of metastatic penile squamous cell carcinoma with response to the Nectin-4 inhibitor enfortumab-vedotin-ejfv (EV). EV was selected due to the evidence of the high expression of Nectin-4 in squamous cell carcinomas, including penile carcinoma. The patient had both radiographic and symptomatic improvement after two cycles of treatment, despite having been treated with multiple prior lines of traditional chemotherapy. This case provides support for the use of antibody-drug conjugates (ADC), including EV, in this disease with few other options in the advanced setting. Further studies examining Nectin-4 and ADCs in penile squamous cell carcinoma should be completed, as high-quality evidence is needed to guide treatment after initial progression for these patients.

Dyspnea Secondary to Mediastinal Mass: A Rare Presentation of Metastatic Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma is a rare diagnosis in the United States; however, the incidence is significantly higher in developing countries. This cancer is categorized into human papilloma virus (HPV)-associated and independent disease. In this article, we present a rare case of HPV-independent penile squamous cell carcinoma. Our patient was a 75-year-old Caucasian male who initially presented with a penile ulcer which was managed with partial penectomy and adjuvant chemotherapy. The patient was monitored on surveillance and did not pursue lymph node dissection. He was noted to have recurrence with metastatic disease 5 years after his initial presentation. Due to the aggressive nature of his disease, the patient was admitted to the hospital and treated with chemotherapy and immunotherapy.

The role of Her-2 in penile squamous cell carcinoma progression and cisplatin chemoresistance and potential for antibody-drug conjugate-based therapy.

BACKGROUND: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. There is no standard second-line therapy for advanced PSCC. Human epidermal growth factor receptor 2 (Her-2)-targeted antibody-drug conjugates (ADCs) are novel low-toxicity agents which have greatly improved clinical outcomes for several advanced cancers. We aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of Her-2-targeted ADCs in PSCC. METHODS: Her-2 immunohistochemistry was performed for the largest single-centre PSCC cohort to date (367 patients). PSCC cell lines, cisplatin-resistant cell lines, subcutaneous xenograft, and footpad metastatic models were used to investigate the biological roles of Her-2 in PSCC progression. Cytotoxicity, apoptosis assays, and western blotting investigated the mechanism of Her-2 induced cisplatin-chemoresistance. The efficacy of Disitamab Vedotin (RC48), a Her-2-targeted ADC, was evaluated in PSCC. RESULTS: Her-2 was identified as an adverse prognostic indicator associated with advanced Tumor-Node-Metastasis (TNM) stages and poor survival with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 promotes cell proliferation, migration, invasion, tumour progression, and cisplatin resistance in PSCC. Mechanistically, Her-2 inhibits cisplatin-induced cell apoptosis by the activation of Akt phosphorylation at Ser473 and disrupts the balance between proapoptotic and antiapoptotic proteins. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, RC48 displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumours. CONCLUSION: Our study suggests that Her-2 is an available therapeutic biomarker for PSCC. Her-2-targeted ADC might have the potential to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and provide precious second-line clinical choice for appropriate cisplatin-based chemoresistance patients.

Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors.

BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

[Systemic treatment of penile cancer: New concepts? New achievements?] / Systemtherapie des Peniskarzinoms ­ neue Konzepte? Neue Erfolge?

Systemic chemotherapy has been in use for metastatic penile carcinoma for years, but its success is limited. Its significance is largely associated with its role in multimodal treatment for lymphatic metastasis in the context of radical lymph node surgery. In cases of limited lymph node involvement, the combination of surgical treatment plus cisplatin- and taxane-based triple combinations may be curative. Advances in the understanding of molecular changes in penile cancer and the search for potential therapy targets have led to numerous studies. Although there is evidence of efficacy of immunotherapeutics, no significant therapeutic improvements have been seen in the clinical routine.

Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial.

PURPOSE: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT). PATIENTS AND METHODS: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens. RESULTS: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors (P = .003) and those with high infiltration of intratumoral CD3+CD8+ T cells (P = .037). CONCLUSION: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3+CD8+ T-cell infiltration, may help to better select responders.

A successful treatment with ALA-PDT: A case-report on erythroplasia of Queyrat misdiagnosed as urethritis.

Queyrat erythroplasia is an intraepidermal squamous cell carcinoma localized on the glans penis or the inner side of the foreskin. It accounts for about 10% of all penile malignancies and up to 33% cases may lead to invasive squamous cell carcinoma and the intraurethral erythroplasia of Queyrat is relatively rare. Treatment of Queyrat erythroplasia present a challenge especially if the proximal urethra is involved. Here, we report a case of intractable Queyrat erythroplasia involving the urethral meatus. This case suggested that 5-aminolaevulinic acid photodynamic therapy is effective and safe in the treatment of Queyrat erythroplasia, which provides a new choice for the patients with Queyrat erythroplasia with poor therapeutic effect.

Selinexor demonstrates anti-tumor efficacy in paired patient-derived xenograft models and hydrogel-embedded histoculture drug sensitivity test of penile cancer.

BACKGROUND: Penile cancer is a rare malignancy with a poor prognosis, even with various treatment options. Considering the little progress in the study of the pathogenesis and treatment of penile cancer because of the lack of models that mimic the biological properties of the tumor, we have developed a patient-derived xenograft (PDX) model and paired hydrogel-embedded histoculture drug sensitivity test (HDST) to screen for drugs that can inhibit tumors. The increased expression of XPO1, as a key nuclear export protein involved in the transport of various tumor suppressors and cell cycle regulatory proteins, is associated with the prognosis of a variety of tumors [World J Uroly 27(2):141-150, 2009]. Selinexor is an inhibitor of XPO1, which can treat cancers, such as multiple myeloma, gastric cancer, triple-negative breast cancer, and non-small cell carcinoma [Transl Androl Urol 6(5):785-790, 2017; OncoTargets Therapy 13:6405-6416, 2020]. However, whether XPO1 inhibition has a role in penile cancer remains unknown. Therefore, this article used the PDX and HDST models to investigate whether the inhibition of XPO1 has an effect on penile cancer and its underlying mechanism. METHODS: We used penile cancer tumor tissues to construct a PDX model of penile cancer and paired PDXE model and confirmed the consistency of PDX tumor tissues in source patients. Then, we assessed the ability of Selinexor to inhibit penile cancer tissues in vivo using a PDX model and in vitro by HDST. We also examined the potential mechanism of XPO1 action on penile cancer by IHC and TUNEL. Finally, we assessed the safety of the drug treatment by H&E and biochemical blood analysis. RESULTS: Result showed that the penile cancer PDX model and patient penile cancer tissues were clinically consistent in morphological characteristics and protein expression. In addition, Selinexor could inhibit tumor growth in PDX models and HDST. We found that P53, P21 expression was upregulated; Cyclin D1 expression was downregulated, and apoptosis of tumor cells was increased in the Selinexor-treated PDX model. Moreover, it had no significant effect on liver, kidney, and cardiac function. CONCLUSION: The PDX model of penile cancer was a powerful tool for penile cancer research and new drug development. It showed that Selinexor can effectively inhibit penile cancer in vitro and in vivo. In addition, XPO1 may affect P53, P21, and Cyclin D1 expression to regulate the growth and apoptosis of penile carcinoma.

Prediction of Treatment Response and Survival with Chemotherapy for Metastatic Penile Cancer by the Modified Glasgow Prognostic Score.

PURPOSE: There is increasing evidence that a persistent systemic inflammatory response predicts lower survival in patients with malignant disease. The modified Glasgow Prognostic Score (mGPS) is defined by a combination of elevated C-reactive protein (CRP) (>10 mg/L) and hypoalbuminemia (<35 g/L). It is considered as an independent prognostic marker in several organ malignancies. The aim of this study was to investigate the value of mGPS in metastatic penile carcinoma in predicting treatment response and survival. METHODS: One hundred and fifty-six patients with penile carcinoma treated with chemotherapy were included in this retrospective study. The mGPS before chemotherapy was classified into 3 groups (mGPS 0 [CRP <10, any albumin], mGPS 1 [CRP >10 mg/L, albumin >35 g/L], and mGPS 2 [CRP >10 mg/L, albumin <35 g/L]). Overall survival and disease-free survival were calculated by Kaplan-Meier analysis and chemotherapy toxicity by CTC criteria. Univariate Cox proportional hazards models were calculated to estimate the effect of each predictor on OS and DFS. RESULTS: Survival was significantly different in the 3 mGPS classes, with mGPS 0 patients showing the best treatment response and survival. Univariate analysis showed that mGPS (p < 0.0001), tumor stage (p = 0.004), and venous and lymphatic invasion (p = 0.011) were factors independently associated with prognosis. The response to chemotherapy differed significantly between mGPS groups (mGPS 0, 36/51 [71%]; mGPS 1, 24/70 [34%]; mGPS 2, 9/35 [26%], p = 0.03 and p = 0.37, respectively). mGPS was significantly associated with chemotherapy-associated toxicity, with treatment adaptation (p < 0.01) and toxicity-related deaths (p = 0.028). CONCLUSIONS: Systemic inflammatory response and nutritional status as expressed by the mGPS are independent predictors of treatment response, chemotherapy-associated toxicity, and survival in metastatic penile carcinoma. In addition to other known pathological markers of tumor aggressiveness, the mGPS can be used as a clinical predictor of prognosis.

First-line programmed death receptor-1 (PD-1) inhibitor and epidermal growth factor receptor (EGFR) blockade, combined with platinum-based chemotherapy, for stage IV penile cancer.

OBJECTIVES: To evaluate the anti-tumour activity and safety of anti-programmed death receptor-1 (PD-1) antibody plus epidermal growth factor receptor blockade combined with platinum-based chemotherapy (PEP) as first-line therapy for stage IV penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: We conducted a retrospective review of 17 patients with stage IV PSCC undergoing first-line PEP at Sun Yat-sen University Cancer Center between January 2018 and September 2021. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of 17 patients who received first-line PEP, 13 were observed to have partial responses. Twelve patients subsequently received consolidated surgery. Nine of these achieved pN0 status, of whom six with locally advanced PSCC achieved pathological complete response. The median (range) follow-up time was 24.87 (3.63-29.40) months. Median PFS and median OS were not reached, with 2-year PFS and OS rates being 68.4% (95% confidence interval [CI] 48.7-96.1) and 62.9% (95% CI 41.6-95), respectively. Eight patients experienced Grade 3 or 4 treatment-related AEs. No Grade 5 AEs or death associated with treatment was observed. CONCLUSIONS: Anti-PD-1 antibody plus epidermal growth factor receptor blockade and platinum-based chemotherapy showed promising anti-tumour activity, acceptable toxicity, and satisfying long-term survival for stage IV PSCC. Larger clinical trials are needed to validate our findings.

Increased HRD score in cisplatin resistant penile cancer cells.

BACKGROUND/INTRODUCTION: Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP) in patients with metastatic penile cancer mostly results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance against standard therapy could help to understand molecular mechanisms underlying chemotherapy resistance and to identify candidate treatments for an efficient second line therapy. METHODS: We generated a cell line from a humanpapilloma virus (HPV) negative penile squamous cell carcinoma (UKF-PEC-1). This cell line was subject to chronic exposure to chemotherapy with CDDP and / or 5-FU to induce acquired resistance in the newly established chemo-resistant sublines (PEC-1rCDDP2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1r5-FU500, adapted to 500 ng/ml 5- FU; UKF-PEC1rCDDP2500/r5-FU500, adapted to 2500 ng/ml CDDP and 500 ng/ml 5 -FU). Afterwards cell line pellets were formalin-fixed, paraffin embedded and subject to sequencing as well as testing for homologous recombination deficiency (HRD). Additionally, exemplary immunohistochemical stainings for p53 and gammaH2AX were applied for verification purposes. Finally, UKF-PEC-1rCDDP2500, UKF-PEC-1r5-FU500, UKF-PEC1rCDDP2500/r5-FU500, and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib. RESULTS AND CONCLUSIONS: The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1rCDDP2500 was characterized by an increased HRD score, which is supposed to be associated with increased PARP inhibitor and immune checkpoint inhibitor sensitivity in cancer. However, UKF-PEC-1rCDDP2500 did not display sensitivity to PARP inhibitors.

Sintilimab-Induced Diabetic Ketoacidosis in a Patient with Radiation and Multichemorefractory Penile Cancer: A Case Report and Literature Review.

Penile squamous cell carcinoma (PSCC) is a rare disease. The treatment options for advanced penile cancer are often limited, and the prognosis remains poor. We reported a 52-year-old male recurrent and metastatic PSCC patient with high PD-L1 expression (90%) and TMB (14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection, and excision of the abdominal wall mass. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin then being carried out, the carcinoma still progressed. The patient then obtained progression-free survival with continuous sintilimab, although he experienced the new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He had negative type 1 diabetes-associated autoantibodies and the susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory PSCC who has obtained the remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab and anlotinib treatment.

PD-1 inhibitor treatment in a penile cancer patient with MMR/MSI status heterogeneity: A case report.

Penile cancer is a rare malignant disease. Paclitaxel combined with platinum is often used as a first-line chemotherapeutic regimen for late-stage penile cancer, and there is no standard second-line treatment. Clinical trials of immunotherapy for penile cancer are ongoing. There are no reports on PD1 inhibitor treatment in metastatic penile carcinoma patients with MMR/MSI status heterogeneity. A 68-year-old patient was hospitalized with bilateral inguinal lymph node metastasis and local penile recurrence after penile cancer surgery. The lesion of the right inguinal lymph node showed a mismatch-repair-deficient (dMMR)/microsatellite instability-low (MSI-L) status. After 3 cycles of sintilimab (a PD1 inhibitor) combined with paclitaxel and cisplatin, the partial response of the tumor was evaluated. Subsequently, sintilimab monotherapy was used as maintenance treatment for 2 months. However, The lesion of local penile recurrence showed mismatch repair proficient (pMMR)/microsatellite stability (MSS) status by secondary biopsy when progressed rapidly. Interestingly, after continued treatment with sintilimab combined with gemcitabine, the patient achieved a partial response again. We should be aware of the importance of secondary biopsy for different lesions to confirm the heterogeneity of MMR/MSI status. For penile cancer patients with MMR/MSI status heterogeneity, PD1 inhibitors combined with chemotherapy are safe and effective. Due to oligometastatic lesion progression caused only by the heterogeneity of MMR/MSI status, PD1 inhibitor cross-line therapy can also be considered an appropriate treatment.

Effectiveness and safety of adjuvant chemotherapy compared to neoadjuvant chemotherapy in patients with penile cancer and positive lymph nodes regarding overall survival and free disease survival: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness of adjuvant chemotherapy compared with neoadjuvant chemotherapy in patients with node-positive penile cancer in terms of overall and disease-free survival. METHODS: We conducted a search strategy in MEDLINE, Embase, and Central databases. We complemented the search with unpublished literature through manual search, conferences, thesis databases, Open Grey, Google Scholar, and Clinicaltrials.gov. There were no restrictions in language. We used the MINORS tool to assess the risk of bias. Furthermore, we performed a random-effects meta-analysis according to the expected heterogeneity. The outcomes were overall survival, progression-free survival, and adverse effects. The Effect measure was hazard ratio (HR) with a confidence interval of 95%. RESULTS: We included 1,197 patients. Seven articles reported overall survival; while 3 reported progression-free survival. The pooled overall survival HR was 1.41 (0.99-2.02), while the progression-free survival HR was 1.63 (1.09-2.44) for adjuvant vs neoadjuvant therapy. An analysis of adverse effects was not possible. CONCLUSIONS: There were no differences when comparing adjuvant vs. neoadjuvant chemotherapy or adjuvant vs. no intervention chemotherapy. We conclude that progression-free survival had a better response with adjuvant chemotherapy when compared with neoadjuvant therapy. We suggest more studies with adequate design to offer a stronger recommendation.