Management of Lymph Node-positive Penile Cancer: A Systematic Review.

CONTEXT: Lymph node (LN) involvement in penile cancer is associated with poor survival. Early diagnosis and management significantly impact survival, with multimodal treatment approaches often considered in advanced disease. OBJECTIVE: To assess the clinical effectiveness of treatment options available for the management of inguinal and pelvic lymphadenopathy in men with penile cancer. EVIDENCE ACQUISITION: EMBASE, MEDLINE, the Cochrane Database of Systematic Reviews, and other databases were searched from 1990 to July 2022. Randomised controlled trials (RCTs), nonrandomised comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: We identified 107 studies, involving 9582 patients from two RCTs, 28 NRCSs, and 77 CSs. The quality of evidence is considered poor. Surgery is the mainstay of LN disease management, with early inguinal LN dissection (ILND) associated with better outcomes. Videoendoscopic ILND may offer comparable survival outcomes to open ILND with lower wound-related morbidity. Ipsilateral pelvic LN dissection (PLND) in N2-3 cases improves overall survival in comparison to no pelvic surgery. Neoadjuvant chemotherapy in N2-3 disease showed a pathological complete response rate of 13% and an objective response rate of 51%. Adjuvant radiotherapy may benefit pN2-3 but not pN1 disease. Adjuvant chemoradiotherapy may provide a small survival benefit in N3 disease. Adjuvant radiotherapy and chemotherapy improve outcomes after PLND for pelvic LN metastases. CONCLUSIONS: Early LND improves survival in nodal disease in penile cancer. Multimodal treatments may provide additional benefit in pN2-3 cases; however, data are limited. Therefore, individualised management of patients with nodal disease should be discussed in a multidisciplinary team setting. PATIENT SUMMARY: Spread of penile cancer to the lymph nodes is best managed with surgery, which improves survival and has curative potential. Supplementary treatment, including the use of chemotherapy and/or radiotherapy, may further improve survival in advanced disease. Patients with penile cancer with lymph node involvement should be treated by a multidisciplinary team.

Prognostic Markers and Trials in Penile Cancer.

New tumor biomarkers open the potential for designing personalized therapy for penile squamous cell carcinoma. Despite the initial promising results of some biomarkers, controversy remains due to contradictory studies. Further robust research work is required before incorporating biomarkers in the personalized management of penile cancer. This narrative review aims to highlight some of the most commonly and recently investigated biomarkers of penile cancer and to summarize the ongoing registered clinical trials for the management of penile cancer patients.

Pelvic lymph node dissection alone versus adjuvant radiotherapy in node positive penile cancer: A systematic review.

Introduction: The management options for regional lymph nodes (LNs) in men with penile cancer include surveillance, surgery, and chemotherapy. The use of radiotherapy (RT) for nodal disease follows tradition and single-institution policies. We aimed to analyse the existing evidence regarding the management of penile cancer patients with suspected or known metastatic pelvic LNs using pelvic LN dissection (PLND) with RT versus PLND or RT alone. Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with no filters for language or time. The search was conducted in EMBASE, MEDLINE/PubMed, and Cochrane Library. Inclusion criteria were adult men with penile cancer and suspected metastatic pelvic LNs, undergoing PLND with or without RT or RT alone. Primary outcomes included disease-specific survival and locoregional recurrence. Secondary outcomes included overall survival and complications of therapy. Results: A total of 552 articles were identified. Only eight retrospective studies were eligible for inclusion (including 406 patients). All studies had a high risk of bias. None of the studies reported the use of neoadjuvant RT. Indications for PLND varied but were usually two or more clinically positive inguinal nodes with or without extracapsular extension. Adjuvant RT was mainly used in positive pelvic LNs or pN2/pN3 stages. The rate of locoregional recurrence following adjuvant RT was 70%. Complications of treatment were reported in two studies only. Conclusions: There is insufficient evidence to recommend the use of adjuvant RT following PLND in penile cancer patients. The quality of evidence is low due to the retrospective design and high risk of bias. Randomized clinical trials are required to assess the efficacy and safety of adjuvant RT and PLND.

Management of penile cancer patients during the COVID-19 pandemic: An eUROGEN accelerated Delphi consensus study.

OBJECTIVES: To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. MATERIALS AND METHODS: A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. RESULTS: Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. CONCLUSIONS: The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

Penile cancer treatment costs in England.

BACKGROUND: Penile cancer is a rare malignancy in Western countries, with an incidence rate of around 1 per 100,000. Due to its rarity, most treatment recommendations are based on small trials and case series reports. Furthermore, data on the resource implications are scarce. The objective of this study was to estimate the annual economic burden of treating penile cancer in England between 2006 and 2011 and the cost of treating a single case based on a modified version of the European Association of Urology penile cancer treatment guidelines. METHODS: A retrospective (non-comparative) case series was performed using data extracted from Hospital Episode Statistics. Patient admission data for invasive penile cancer or carcinoma in situ of the penis was extracted by ICD-10 code and matched to data from the 2010/11 National Tariff to calculate the mean number of patients and associated annual cost. A mathematical model was simultaneously developed to estimate mean treatment costs per patient based on interventions and their associated outcomes, advised under a modified version of the European Association of Urologists Treatment Guidelines. RESULTS: Approximately 640 patients per year received some form of inpatient care between 2006 and 2011, amounting to an average of 1,292 spells of care; with an average of 48 patients being treated in an outpatient setting. Mean annual costs per invasive penile cancer inpatient and outpatient were £3,737 and £1,051 respectively, with total mean annual costs amounting to £2,442,020 (excluding high cost drugs). The mean cost per case, including follow-up, was estimated to be £7,421 to £8,063. Results were sensitive to the setting in which care was delivered. CONCLUSIONS: The treatment of penile cancer consumes similar levels of resource to other urological cancers. This should be factored in to decisions concerning new treatment modalities as well as choices around resource allocation in specialist treatment centres and the value of preventative measures.

The treatment of penile carcinoma in situ (CIS) within a UK supra-regional network.

OBJECTIVES: To review outcomes of the treatment of carcinoma in situ (CIS) of the penis at a large supra-regional penile cancer network, where centralisation has permitted greater experience with treatment outcomes, and suggest treatment strategies. PATIENTS AND METHODS: The network penile cancer database, which details presentation, treatment and complications was analysed from 2003 to 2010, identifying patients with CIS, with a minimum follow-up of 2 years, looking at treatments administered and outcomes. RESULTS: In all, 57 patients with mean (range) age of 61 (34-91) years were identified. In all, 18 were treated by circumcision only, 20 by circumcision and local excision (LE) and 19 by circumcision and 5-flurouracil (5-FU). The mean (range) follow-up was 3.5 (2-8) years. Of those treated by circumcision none subsequently developed CIS on the glans. For those who underwent circumcision + LE, five of 20 (25%) developed recurrence requiring further treatment. Of those treated by circumcision + 5-FU, 14/19 (73.7%) completely responded. Of the five incomplete responders, two had focal invasive malignancy at repeat biopsy. One incomplete responder underwent glansectomy and four grafting. No complete responders relapsed. Complications of 5-FU included significant inflammatory response in seven (36.8%), with two requiring hospital admission and one neo-phimosis (5.3%). CONCLUSION: This study suggests that patients undergoing circumcision for isolated CIS and complete responders to 5-FU may require only short-term follow-up, as recurrence is unlikely, whereas longer follow up is required for all other patients. However, numbers in this study are small and larger studies are needed to support this. An incomplete response to 5-FU dictates immediate re-biopsy, as it carries a significant chance of previously undetected invasive disease.

Should centralized histopathological review in penile cancer be the global standard?

OBJECTIVE: To assess the role of centralized pathological review in penile cancer management. MATERIALS AND METHODS: Newly diagnosed squamous cell carcinomas (SCC) of the penis, including squamous cell carcinoma in situ (CIS), from biopsy specimens were referred from 15 centres to the regional supra-network multidisciplinary team (Sn-MDT) between 1 January 2008 and 30 March 2011. Biopsy histology reports and slides from the respective referring hospitals were reviewed by the Sn-MDT pathologists. The biopsy specimens' histological type, grade and stage reported by the Sn-MDT pathologist were compared with those given in the referring hospital pathology report, as well as with definitive surgery histology. Any changes in histological diagnosis were sub-divided into critical changes (i.e. those that could alter management) and non-critical changes (i.e. those that would not affect management). RESULTS: A total of 155 cases of squamous cell carcinoma or CIS of the penis were referred from 15 different centres in North-West England. After review by the Sn-MDT, the histological diagnosis was changed in 31% of cases and this difference was statistically significant. A total of 60.4% of the changes were deemed to be critical changes that resulted in a significant change in management. When comparing the biopsy histology reported by the Sn-MDT with the final histology from the definitive surgical specimens, a good correlation was generally found. CONCLUSIONS: In the present study a significant proportion of penile cancer histology reports were revised after review by the Sn-MDT. Many of these changes altered patient management. The present study shows that accurate pathological diagnosis plays a crucial role in determining the correct treatment and maximizing the potential for good clinical outcomes in penile cancer. In the case of histopathology, centralization has increased exposure to penile cancer and thereby increased diagnostic accuracy, and should therefore be considered the 'gold standard'.

Identifying the needs of penile cancer sufferers: a systematic review of the quality of life, psychosexual and psychosocial literature in penile cancer.

BACKGROUND: Penile cancer is an uncommon malignancy with an incidence of 1 per 100,000. Conservative and radical treatments can be disfiguring and may have an impact on sexual function, quality of life (QOL), social interactions, self-image and self-esteem. Knowledge of how this disease affects patients is paramount to developing a global, multi-disciplinary approach to treatment. METHODS: A Medline/PubMed literature search was conducted using the terms "sexual function penis cancer"; "quality of life penis cancer" and "psychological effects penis cancer" from 1985 to 2008. Articles containing quantitative data on QOL, sexual function or psychological well-being were included. RESULTS: 128 patients from 6 studies were included. 5 studies contained retrospective data whilst 1 study collected prospective data on erectile function. In the 6 studies 13 different quantitative tools were used to assess psychological well-being, QOL and sexual function. The General Health Questionnaire (GHQ) showed impaired well-being in up to 40% in 2 studies. Patients undergoing more mutilating treatments were more likely to have impaired well-being. The Hospital Anxiety and Depression Score (HADS) demonstrated pathological anxiety up to 31% in 2 studies. 1 study used the Diagnostic and Statistical Manual of Mental Disorders of psychiatric illness (DSM III-R) with 53% exhibiting mental illness, 25% avoidance behaviour and 40% impaired well-being. 12/30 suffered from post-traumatic stress disorder. The IIEF-15 was the commonest tool used to assess sexual function. The results varied from 36% in 1 study with no sexual function to 67% in another reporting reduced sexual satisfaction to 78% in another reporting high confidence with erections. CONCLUSION: The treatment of penile cancer results in negative effects on well-being in up to 40% with psychiatric symptoms in approximately 50%. Up to two-thirds of patients report a reduction in sexual function. This study demonstrates that penile cancer sufferers can exhibit significant psychological dysfunction, yet no standardised tools or interventional pathways are available. Therefore, there is a need to identify and assess adequate tools to measure psychological and sexual dysfunction in this group of patients.

Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer.

PURPOSE: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m(2) in increments of 50 mg/m(2) per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. RESULTS: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m(2). Dose-limiting toxicity was observed at 150 mg/m(2) with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m(2) with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. CONCLUSION: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m(2), with a maximal recommended dose of 100 mg/m(2). This dose regimen has now entered Phase II clinical trials.

Is DRE essential for the follow up of prostate cancer patients? A prospective audit of 194 patients.

BACKGROUND: Prostate cancer follow up forms a substantial part of the urology outpatient workload. Nurse led prostate cancer follow up clinics are becoming more common. Routine follow-up may involve performing DRE, which may require training. OBJECTIVES: The aim of this audit was to assess the factors that influenced the change in the management of prostate cancer patients during follow up. This would allow us to pave the way towards a protocol driven follow up clinic led by nurse specialists without formal training in DRE. RESULTS: 194 prostate cancer patients were seen over a period of two months and all the patients had DRE performed on at least one occasion. The management was changed in 47 patients. The most common factor influencing this change was PSA trend. A change in DRE findings influenced advancement of the clinic visit in 2 patients. CONCLUSIONS: PSA is the most common factor influencing change in the management of these patients. Nurse specialists can run prostate cancer follow-up clinics in parallel to existing consultant clinics and reserve DRE only for those patients who have a PSA change or have onset of new symptoms. However larger studies are required involving all the subgroups of patients to identify the subgroups of patients who will require DRE routinely.

The economic consequences of prostate and bladder cancer in the UK.

OBJECTIVE: To compare the costs of managing prostate and bladder cancer and relate them to current expenditure on research, as the increasing prevalence of both necessitates the adequate direction of resources. METHODS: All new prostate and bladder cancers diagnosed in 2001-2002 were identified from British Association of Urological Surgeons Section of Oncology database (national and local). The total cost of diagnosing, treating and following patients for 5 years was estimated as the sum of direct costs (National Health Service) and indirect costs (loss of earnings). Annual research fund allocation (RFA) for each cancer were obtained from the National Cancer Research Institute UK. RESULTS: There were 15 099 and 7703 patients with newly diagnosed prostate (mean age 72.3 years) and bladder cancers (mean age 71.3 years). The total cost for prostate cancer was estimated at 92.74 million UK pounds, with hormonal therapy alone costing 63.1 million UK pounds. The total cost for bladder cancer was 55.39 million UK pounds, of which superficial disease cost 35.25 million. The mean cost per patient was more for bladder than for prostate cancer (8349 UK pounds vs. 7294). The RFA allocation during this period was 20.56 million UK pounds and 4.62 million UK pounds for prostate and bladder cancer, respectively, and the respective RFA allotment per pound spent on the mean cost of disease management per patient was 2818 UK pounds and 553 UK pounds. CONCLUSION: Individual patient management is more costly for bladder cancer but less is invested in research than for prostate cancer. This study suggests a need to re-evaluate future strategies.