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.

Patterns of Recurrence and Survival After Pelvic Treatment for Locally Advanced Penile Cancer.

Background: Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies. Objective: To describe the disease course after pelvic lymph node (LN) treatment for PeCa. Design setting and participants: We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection. Outcome measurements and statistical analysis: In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS). Results and limitations: The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature. Conclusions: The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies. Patient summary: In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary.

Lymphovascular and perineural invasion are risk factors for inguinal lymph node metastases in men with T1G2 penile cancer.

PURPOSE: To analyse the risk of inguinal lymph node (ILN) metastases in T1G2 penile cancer stratified by lymphovascular invasion (LVI), perineural invasion (PNI) and tumour size. METHODS: Retrospective study of men with localised T1G2 penile cancer with non-palpable lymph nodes and no local recurrence during follow-up at six European institutional high-volume centres was performed. ILN involvement was defined as cancer detected during ultrasound-guided fine-needle aspiration cytology, core needle biopsy, dynamic sentinel lymph node biopsy, ILN dissection or inguinal recurrence during follow-up. Uni- and multivariable logistic regression analyses were performed. RESULTS: In the cohort of 554 men with T1G2 penile cancer, from 6 European institutions, ILN metastases were observed in 46/554 men (8%, 95% confidence interval (CI) 6-11%). Men with both, LVI- and PNI- primary cancers had the lowest risk of ILN involvement (6%) whereas men with LVI + or PNI + showed ILN metastases in 22% and 30%. In multivariable regression, men with LVI + or PNI + had higher odds for ILN metastases compared to men with LVI- and PNI- (OR 3.9, 95% CI 1.6-9.0, p value < 0.01) Tumour size was not associated with ILN risk (OR 1.01 95% CI 0.99-1.04, p = 0.17). CONCLUSION: Approximately, one out of ten men with T1G2 overall and one out of four men with either LVI + or PNI + still have ILN metastases despite being clinically node negative. Therefore, invasive ILN staging should strongly be recommended in T1G2 with LVI + or PNI + but importantly, must be discussed in patients with T1G2 with LVI- or PNI-.

Incidence and risk factor analysis of complications after sentinel node biopsy for penile cancer.

OBJECTIVE: To determine the incidence and types of complications after dynamic sentinel node biopsy (DSNB) in patients with penile cancer (PeCa) and identify risk factors for the occurrence of postoperative complications. PATIENTS AND METHODS: We evaluated 644 patients with PeCa (1284 DSNB procedures) with at least one clinically node negative (cN0) groin who underwent DSNB between 2011 and 2020 at a single high-volume centre. The 30- and 30-90-day postoperative complications were collected according to the modified Clavien-Dindo classification and the standardised methodology proposed by the European Association of Urology panel. Uni- and multivariable generalised linear mixed models were used to identify risk factors for the occurrence of complications per groin. RESULTS: A 30-day postoperative complication occurred in 14% of groins (n = 186), of which 94% were mild to moderate. Wound infection and lymphocele formation were most common. A 30-90-day postoperative complication occurred in 3.4% of the groins, all of which were mild or moderate (Grade I-II). The number of removed lymph nodes (LNs) per groin was the main independent predictor for any 30-day complications and Grade ≥II complications (odds ratio 1.40; P < 0.001). There was an increase in the probability of postoperative complications with the number of LNs removed after accounting for all confounders. CONCLUSIONS: Despite being less morbid than (modified) inguinal LN dissection, DSNB is still associated with a considerable risk of postoperative mild-to-moderate complications. This risk increases with increasing number of LNs removed. Further procedural refinement aimed at removing the true sentinel node(s) only, may help further reduce the morbidity of surgical staging in PeCa.

Clinicopathological predictors of finding additional inguinal lymph node metastases in penile cancer patients after positive dynamic sentinel node biopsy: a European multicentre evaluation.

OBJECTIVE: To develop a predictive model for additional inguinal lymph node metastases (LNM) at inguinal lymph node dissection (ILND) after positive dynamic sentinel node biopsy (DSNB) using DSNB characteristics to identify a patient group in which ILND might be omitted. PATIENTS AND METHODS: We conducted a retrospective study of 407 inguinal basins with a positive DSNB in penile cancer patients who underwent subsequent ILND from seven European centres. From the histopathology reports, the number of positive and negative lymph nodes, presence of extranodal extension and size of the metastasis were recorded. Using bootstrapped logistic regression, variables were selected for the clinical prediction model based on the optimization of Akaike's information criterion. The area under the curve (AUC) of the receiver-operating characteristic curve was calculated for the resulting model. Decision curve analysis (DCA) was used to evaluate the clinical utility of the model. RESULTS: Of the positive DSNBs, 64 (16%) harboured additional LNM at ILND. Number of positive nodes at positive DSNB (odds ratio [OR] 2.19, 95% confidence interval (CI) 1.17-4.00; P = 0.01) and largest metastasis size in mm (OR 1.06, 95% CI 1.03-1.10; P = 0.001) were selected for the clinical prediction model. The AUC was 0.67 (95% CI 0.60-0.74). The DCA showed no clinical benefit of using the clinical prediction model. CONCLUSION: A small but clinically important group of basins harbour additional LNM at completion ILND after positive DSNB. While DSNB characteristics were associated with additional LNM, they did not improve the selection of basins in which ILND could be omitted. Thus, completion ILND remains necessary in all basins with a positive DSNB.

Impact of radiation therapy on perineal urethrostomy for penile cancer.

OBJECTIVE: A lack of demonstrated clinical benefit precludes radiotherapy (RT) from being recommended for pN1/pN2 penile cancer (PeCa) lesions; but it may be recommended in case of extranodal (pN3) disease or for positive resection margins. Perineal urethrostomy (PU) is a technique of urinary diversion in patients with PeCa requiring total or subtotal penectomy as primary therapy. Prior studies suggest PU failure rates of up to 30%, without specific mention of the potential role of RT. When RT is delivered for PeCa it is usually to the pre-pubic fat, groin and lateral pelvis, and not to the region of the PU. Here we describe the role of perioperative RT in a large, multi-institutional registry of PU for PeCa. METHODS: In our cohort, 299 patients from seven international, high-volume centers in Belgium, Brazil, China, Netherlands, United Kingdom and the United States underwent PU as urinary diversion for PeCa between 2000 and 2020. Demographic and clinicopathologic characteristics were reviewed. RESULTS: Median patient age was 67 years and median follow-up was 19 months. Seven patients (2.3%) received pre-operative RT; six of them with chemotherapy. 37 received RT post-operatively, 21 (57%) with chemotherapy. Stenosis of the PU occurred in 35 (12%) of the total population. The majority of these patients (74%) required surgical revision at a median of 6.1 months post-operatively. RT delivery was neither significantly related to PU stenosis (p = 0.16) or to subsequent revision (p = 0.75). CONCLUSION: Receipt of RT was not significantly associated with increased stenosis risk in PeCa patients who underwent PU.

Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor.

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV- tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV- cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.

Outcomes of perineal urethrostomy for penile cancer: A 20-year international multicenter experience.

PURPOSE: Perineal urethrostomy (PU) is often the definitive form of urinary diversion in patients with locally-advanced or anatomically unfavorable penile cancer (PC) requiring total penectomy. Here, we report post-operative PU-related complications and PU stenosis rates after total penectomy with PU in a large multicenter cohort of PC patients. METHODS: We retrospectively reviewed the medical records of 299 patients who underwent PU as a means of urinary diversion for primary PC across seven international centers from 2000 to 2020. The Clavien-Dindo grading system was used to record 30-day post-operative complications. Cumulative incidence of stenosis was evaluated using the Kaplan-Meier method. RESULTS: Median patient age was 67 years (interquartile range (IQR) 58-74), and median follow-up was 19 months (IQR 7.2-57). A total of 58 patients (19%) developed a 30-day post-operative complication, of which 45 (79%) were deemed minor (CD Grade I and II). Wound infection (11%; CD grade I-III) and dehiscence (4.0%; CD grade I-III) were the more common complications. The overall incidence of stenosis was 12% (35/299 patients), of which 26 (74%) needed surgical revision (probability of stenosis revision at one year of 9.3%, median time until the revision: 6.1 months (IQR 3.0-13)). Only two stenoses were seen after two years of follow-up. CONCLUSION: We present the most extensive series of PU in the management of PC to date. Wound infections of the primary surgical site were the most common complication. Stenosis occurred mostly within one and a half years after treatment.