Predicting Limited Survival Following Inguinal Lymph Node Dissection in Penile Cancer: Should We Revisit the Goals of Care?

OBJECTIVE: Patients with advanced penile squamous cell cancer have a poor prognosis and can benefit from early palliative care consultation. We built a model to identify those patients most likely to benefit. METHODS: Patients with penile squamous cell cancer undergoing inguinal lymph node dissection were identified from the National Cancer Database (NCDB) and a multi-institutional international dataset (INT). A multivariable Cox proportional hazards model for overall survival (OS) was developed using the NCDB and applied to the INT dataset. Parameters were used to make receiver operating characteristic (ROC) curves. ROC-related criteria were optimized to identify a predictive probability cut point and dichotomize patients from INT into risk groups for limited OS of <6 and <12 months. RESULTS: NCDB had 860 deaths; 105 (5%) at 6 months and 296 (15%) at 12 months. INT had 257 deaths; 56 (8%) at 6 months and 124 (18%) at 12 months. Limited OS was associated with older age, greater T and N stage, and fewer lymph nodes removed. Optimized ROC criteria using the OS <6 months curve best dichotomized INT patients into high-risk group with median OS of 24 months (95% CI 18-34) and low-risk group with median OS of 174 months (95% CI 120-NE). CONCLUSION: We developed a simple model that could be used as a screening tool for early palliative care referral.

Concomitant vs Staged Therapeutic Inguinal Lymphadenectomy in Clinically Node Positive Penile Squamous Cell Carcinoma: Does It Make a Difference?

PURPOSE: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. MATERIALS AND METHODS: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. RESULTS: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. CONCLUSIONS: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection.

Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours.

BACKGROUND: Testicular germ cell tumours (TGCTs) have a high metastasis rate. However, the mechanisms related to their invasion, progression and metastasis are unclear. Therefore, we investigated gene expression changes that might be linked to metastasis in seminomatous testicular germ cell tumour (STGCT) patients. METHODS: Defined areas [invasive tumour front (TF) and tumour centre (TC)] of non-metastatic (with surveillance and recurrence-free follow-up >2 years) and metastatic STGCTs were collected separately using laser capture microdissection. The expression of 760 genes related to tumour progression and metastasis was analysed using nCounter technology and validated with quantitative real-time PCR and enzyme-linked immunosorbent assay. RESULTS: Distinct gene expression patterns were observed in metastatic and non-metastatic seminomas with respect to both the TF and TC. Comprehensive pathway analysis showed enrichment of genes related to tumour functions such as inflammation, angiogenesis and metabolism at the TF compared to the TC. Remarkably, prominent inflammatory and cancer-related pathways, such as interleukin-6 (IL-6) signalling, integrin signalling and nuclear factor-κB signalling, were significantly upregulated in the TF of metastatic vs non-metastatic tumours. CONCLUSIONS: IL-6 signalling was the most significantly upregulated pathway in metastatic vs non-metastatic tumours and therefore could constitute a therapeutic target for future personalised therapy. In addition, this is the first study showing intra- and inter-tumour heterogeneity in STGCT.

Feasibility and Oncologic Outcome of Salvage Surgery in Isolated Seminal Vesicle Remnants after Radical Prostatectomy.

BACKGROUND: To demonstrate the feasibility of resecting isolated locally relapsing seminal vesicle remnants after primary radical prostatectomy and radiotherapy. Early oncologic outcomes and prognostic risk factors for relapse are demonstrated. OBJECTIVES AND METHODS: A total of 32 patients underwent open resection of locoregional prostate cancer recurrence in seminal vesicles, as documented on either MRI, 11C-choline, or 68Ga-PSMA PET/CT scans. Age, PSA-DT, PSA, and time to recurrence after primary treatment resection status were used in a uni- and multivariate Cox regression analysis for biochemical relapse after surgery. RESULTS: Median patient age at time of salvage surgery was 70 (57-77) years. Median PSA and PSA-DT was 2.79 (0.4-61.54) ng/mL and 5.4 (1.6-20.1) months, respectively. Median surgical time and hospital stay was 132 (75-313) min and 5.5 (4-13) days, respectively. After a mean follow-up of 29 (2-92) months, 3 patients died at 8, 14, and 40 months after salvage surgery, and 6 (18.75%) patients remain without biochemical relapse and further treatment. Median progression-free survival was 12 (1-81) months. In the univariable Cox regression analysis, age at time of surgery, preoperative PSA, and the time from primary treatment to salvage surgery were identified as significant parameters for biochemical relapse. Only the interval from primary to salvage surgery was significant in the multivariate analysis with a hazard ratio of 1.008 (95% CI: 1.001-1.015, p = 0.018). In the entire cohort, 4 adjunctive surgeries (3 ureteroneocystostomies and 1 nephrectomy) were needed due to local progressive disease. CONCLUSION: Seminal vesicle resection is feasible with no significant intra- or postoperative complications. Almost all patients progressed to biochemical or systemic relapse. Salvage surgery must be seen as a preventive for local symptoms, in our experience most often postrenal ipsilateral obstruction.

Risk factors and survival outcomes for upstaging after inguinal lymph node dissection for cN1 penile squamous cell carcinoma.

OBJECTIVES: To identify incidence and risk factors for upstaging from cN1 to pN2/N3 at inguinal lymphadenectomy (ILND) for penile cancer (pSCC). Our secondary objective is to assess survival outcomes and associations for cN1 patients undergoing ILND. SUBJECTS/PATIENTS AND METHODS: Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND and had complete data were identified in a multi-institutional international cohort from 8 referral centers in 7 countries diagnosed from 1980 to 2017. Upstaging was defined as pN2/N3 at ILND. Multivariable logistic regression analysis was used to determine associations with upstaging, and Cox multivariable logistic regression analysis to determine associations with overall survival (OS). RESULTS: Of 144 patients were included in the final study population. 84 patients (58%) were upstaged from cN1 to pN2/N3, and 25 (17%) were down staged to pN0. Upstaging was associated with pT3/T4 (OR 4.1, 95%CI 1.5-11.7, P < 0.01) and pTX (OR 7.1, 95CI 1.6-51.1, P = 0.02). Age, smoking status, HPV status, and LVI were not associated with upstaging. Age (HR 1.03/y, 95%CI 1.01-1.06, P < 0.01) and upstaging (HR 2.8, 95%CI 1.3-5.9, P < 0.01) were associated with worse OS. Upstaged patients had a 5-year OS of 49%, compared with 86% for patients who were not upstaged. CONCLUSION: The majority of cN1 pSCC patients harbor a higher-risk disease state than their clinical staging suggests, especially those with higher pT stages. More intensive pre-operative workup may be warranted for these patients to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials.

Patterns of Recurrence following Inguinal Lymph Node Dissection for Penile Cancer: Optimizing Surveillance Strategies.

PURPOSE: Our primary objective is to detail the incidence, site, and timing of penile squamous cell carcinoma (pSCC) recurrence after inguinal lymph node dissection (ILND). MATERIALS AND METHODS: We performed a retrospective analysis of 551 patients who underwent ILND for pSCC from 2000 to 2017. The primary outcome was pSCC recurrence after ILND. Recurrences were identified and stratified by site. Timing of recurrence was determined. Multivariable logistic regression analysis determined associations with recurrence. Multivariable Cox regression analysis determined associations with overall survival (OS). Sub-group analysis of the distant recurrences analyzed timing and OS by site of distant recurrence. RESULTS: After ILND pSCC recurred in 176 (31.9%) patients. Median time to recurrence was 10 months for distant recurrences, 12 for inguinal, 10.5 for pelvic, and 44.5 for local. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months of ILND, versus 127 months for local recurrences. Post-ILND recurrence was associated with pN2 (OR 1.99, 95% CI 1.0-4.1), and pN3 (OR 7.2, 95% CI 4.0-13.7). Patients who had local recurrence had similar OS to those without (HR 1.5, 95% CI 0.6-3.8), and worse OS was identified in patients with inguinal (HR 4.5, 95% CI 2.8-7.1), pelvic (HR 2.6, 95% CI 1.5-4.5), or distant (HR 4.0, 95% CI 2.7-5.8) recurrences. Patients with lung recurrences had worse OS than other sites (HR 2.2, 95% CI 1.1-4.3). CONCLUSIONS: Of the patients 31.9% had post-ILND recurrence associated with high pN staging. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months, suggesting surveillance beyond this is low yield. Local recurrences occurred over a longer timeline, emphasizing necessity of long-term surveillance of the primary site.

Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma.

BACKGROUND: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking. OBJECTIVE: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status. DESIGN, SETTING, AND PARTICIPANTS: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information. INTERVENTION: ILND, with or without chemotherapy or RT for involved lymph nodes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV+ and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV+ PSCC. RESULTS AND LIMITATIONS: Patients with HPV+ PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV+ patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV+ patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV+ status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV+ PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data. CONCLUSIONS: Perioperative RT was more effective in the HPV+ PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations. PATIENT SUMMARY: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients.

A risk calculator predicting recurrence in lymph node metastatic penile cancer.

OBJECTIVES: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM. PATIENTS AND METHODS: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts. RESULTS: Positive surgical margins, pN3 , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1). CONCLUSION: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.

[Prostate cancer: surgical complications]. / Prostatakarzinom ­ chirurgische Komplikationen.

Radical prostatectomy (RP), performed as an open, laparoscopic or robotic procedure, remains the "gold standard" for patients with localised prostate cancer who can be cured with surgery and have a life expectancy of at least 10 years. Today, RP is also used as a first-line treatment for locally advanced prostate cancer, possibly in a multimodal setting with adjuvant radiation/hormonal therapy. The increasing experience of surgeons, better knowledge of anatomy and refinements of surgical techniques have greatly improved oncological and functional outcomes. In our article we would like to give an overview of the complications associated with this surgical procedure.

68 Ga-PSMA-PET/CT helps to select patients for salvage radical prostatectomy with local recurrence after primary radiotherapy for prostate cancer.

OBJECTIVE: To investigate the diagnostic performance of gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) in patients with recurrent prostate cancer with regard to the presence of lymph node metastases (LNM) and local recurrences after primary radiotherapy. PATIENTS AND METHODS: We retrospectively reviewed 142 patients following salvage radical prostatectomy (sRP), 50 of which had a 68 Ga-PSMA PET/CT performed as a preoperative staging module. Predictive clinical parameters were analysed in a multivariate Cox regression analysis. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) and the accuracy of 68 Ga-PSMA PET/CT were analysed with regard to LNM and local recurrence. RESULTS: In all, 613 lymph nodes were resected in 40 patients and 23 lymph nodes had metastatic deposits in 14 patients. In all patients local recurrence could have been found with 68 Ga-PSMA PET/CT. Sensitivity, specificity, PPV and NPV and accuracy on a per lymph node basis were 34.78% (16.38-57.2%), 100% (99.38-100%), 100%, 97.52% (96.69-98.15%) and 97.55% (96.00-98.62%). For detecting local recurrence, the sensitivity and PPV were both 100% with an accuracy of 100% (92.89-100%). CONCLUSION: 68 Ga-PSMA PET/CT should be the standard imaging in biochemical recurrent prostate cancer. With this imaging module one detects first local recurrence and can detect locoregional and distant metastases more precisely than standard CT and bone scan.

Optimising the selection of candidates for neoadjuvant chemotherapy amongst patients with node-positive penile squamous cell carcinoma.

OBJECTIVES: To identify predictors of poor overall survival (OS) amongst patients with penile squamous cell carcinoma (pSCC) with clinical inguinal lymphadenopathy (cN+), in order to define the best candidates for neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Using an international, multicentre database of 924 patients with pSCC, we identified 334 men who harboured cN+ with available clinical and follow-up data. Lymph node involvement was defined either by the presence of palpable inguinal node disease or by preoperative computed tomography (CT) assessment. Fluorine-18 fluorodeoxyglucose positron-emission tomography (18 F-FDG-PET)/CT scan was performed based on clinical judgment of the treating physician. Regression-tree analysis generated a risk stratification tool for prediction of 24-month overall mortality (OM). Kaplan-Meier explored the OS benefit related to the use of NAC according to the regression-tree-stratified subgroups. RESULTS: Overall, 120 (35.9%), 152 (45.5%), and 62 (18.6%) patients harboured cN1, cN2, and cN3 disease. 18 F-FDG-PET/CT was performed in 48 (14.4%) patients, and 16 (4.8%) had inguinal and pelvic nodal PET detection. The median OS was 107 months, with a 24-month OS of 66%. At regression-tree analysis (area under the curve = 70%), patients with cN3 and cN2 with PET/CT-detected inguinal and pelvic nodal activity had a higher risk of 24-month OM (>50%). NAC was associated with improved 24-month OS rates (54% vs 33%) only in this subgroup of patients (P = 0.002), which was also confirmed after multivariable adjustment (hazard ratio 0.28, 95% confidence interval 0.13-0.62; P = 0.002). CONCLUSION: Patients with pSCC with cN3 or cN2 and inguinal and pelvic 18F-FDG-PET/CT scan detected disease had higher 24-month OM rates according to our regression-tree model. NAC was associated with improved OS only in these subgroups of patients. Our novel decision model may help to stratify cN+ patients, and identify those who most likely will benefit from NAC prior to radical surgical resection.

[Personalised medicine in prostate cancer]. / Personalisierte Medizin beim Prostatakarzinom.

Prostate cancer is the most common cancer in men. Its incidence increases with age. New treatment options have been introduced and there is a clear trend to more aggressive treatment in newly diagnosed metastatic disease. While prolonged survival of patients has been achieved, the new expensive drugs are associated with an increased burden on the healthcare system. Meanwhile, similarly to other tumour entities, there is a pool of different drugs available with comparable oncologic efficacy, but different side-effects. Effective diagnostic investigation and treatment decisions require additional factors, above and beyond clinical parameters, for a more individual treatment approach. In castration-resistant prostate cancer (CRPCA), there are promising molecular markers for treatment decisions. In metastatic disease, liquid biopsies and next generation sequencing of metastatic biopsies allow for genetic analysis. These will provide more insight into tumour dynamics and allow for patient selection. This review concentrates on molecular markers in CRPCA.

Therapeutic options in male genital tract inflammation.

Chronic inflammatory conditions of the genital tract are still unsatisfactorily recognised in the workup of male infertility due to inappropriate definitions and inconsistent diagnostic criteria. The most popular term used for description of both, infections and inflammation in the genital tract is MAGI (male accessory gland infection). In asymptomatic patients, the diagnosis is primarily based on leucocytospermia (i.e., more than 1 million peroxidase-positive leucocytes per ml ejaculate), although ongoing infections should be identified and distinguished from post-infectious or non-infectious inflammatory disease. In addition to alterations of the basic semen parameters, sperm functions -and DNA integrity may be affected by chronic inflammation of the male genital tract. Despite considerable diagnostic drawbacks and a rather limited database concerning evidence-based therapy, adequate management of affected patients appears mandatory. Antibiotic treatment aims at the eradication or reduction of pathogenic bacteria in the ejaculate. Available studies suggest, that NSAID are effective in chronic inflammatory conditions. Moreover, low-dose corticosteroids, mast cell blockers, and other immune-modulatory compounds as well as a sequential adjuvant treatment with antioxidants can be considered as therapeutic options.

[The significance of palliative surgery in castration-resistant prostate cancer]. / Palliative chirurgische Therapieoptionen beim kastrationsresistenten Prostatakarzinom.

If prostate cancer recurs after primary treatment, deprivation therapy with LHRH analogues or antagonists is the treatment of choice in men with metastatic prostate cancer. However, this treatment only achieves palliative results. Median time to progression ranges between 11 and 78 months. After the introduction of Docetaxel as a first-line treatment in castration-resistant prostate cancer (CRPCA) and cabazitaxel as a second-line chemotherapy, several new drugs containing abiraterone, enzalutamide, radium 223 and sipuleucel-T have become available, which can lead to complete or partial remissions in metastasis, but do not have an effect on the prostate itself as has been shown recently. As a result of local progression of CRPCA, local complications of the urinary tract such as subvesical obstruction, recurrent gross haematuria with or without clotting, upper urinary tract dilatation, rectourethral or rectovesical fistulae and rectal obstruction will occur in about one third of all patients. Several surgical treatment options are available to manage the aforementioned complications. In patients with local progressive CRPCA and lower urinary tract symptoms, palliative TUR-P, radical prostatectomy or radical cystoprostatectomy with urinary diversion and even anterior and posterior exenteration can be performed in selected patients, requiring a preoperative multiparametric MRI of the prostate and the pelvic floor along with a laboratory examination to optimise surgical techniques and perioperative outcomes. In case of symptomatic involvement of the upper urinary tract system, the placement of endoluminal DJ stents or percutaneous nephrostomy in men with a poor performance status and a short life expectancy is the treatment of choice. In men with an ECOG performance status of 0 to 1, reconstructive surgery such as ureteral reimplantation, ileal ureteral replacement or placement of a subcutaneous pyelovesical bypass is an appropriate treatment option. To summarise, the aforementioned palliative surgical treatment options should be provided for selected patients and performed by well-experienced urologists.

Testis-Sparing Surgery in Patients with Germ Cell Cancer: Indications and Clinical Outcome.

Testicular cancer affects mainly young men between 20 and 30 years of age. Due to the availability of effective chemotherapy, the majority of patients are cured. Despite an increased risk of metachronous testicular cancer, it should be carefully considered whether immediate orchiectomy is indicated. This mini review gives an account of the available literature on testis-sparing surgery in patients with unilateral or bilateral synchronous or metachronous testicular cancer.

Antiangiogenic therapies in urogenital malignancies: Fiction or fact?

The use of antiangiogenic agents in cancer therapy has become an attractive target in oncological research. However, concerning the uro-oncological field, current guidelines only recommend the use of antiangiogenic agents in metastatic renal cell cancer. Yet in recent years, several approaches for sequential treatment with angiogenesis inhibitors in other urogenital malignancies apart from renal cell cancer are ongoing. Thus, the present review article aims to provide an overview about clinical studies with antiangiogenic agents in prostate-, bladder-, testicular-, as well as penile cancer patients. For this, a literature search was conducted using Medline; moreover we performed a systematic review of data presented at this year's important urooncological meetings. Preliminary data revealed that there are several promising studies ongoing in prostate-, bladder-, testicular-, as well as penile cancer; however, larger studies should be conducted to optimize the use of antiangiogenic agents in clinical practice.