Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

[Rational follow-up of non-muscle invasive bladder cancer]. / Rationale Nachsorge des nicht-muskelinvasiven Harnblasenkarzinoms.

BACKGROUND: Follow-up for non-muscle invasive bladder cancer (NMIBC) is a challenge for urologists that has not been finally resolved. The intensity of follow-up is based on the recurrence and progression behavior of the tumor as well as the patient's individual situation. MATERIALS AND METHODS: The following article focuses on the current data situation, the valid German S3 guideline and the available instruments for the detection of relapses and progression, taking into account tumor stages and degree of malignancy. RESULTS: Urethrocystoscopy, imaging and urine cytology are generally recommended, but the recommendations appear to be too extensive in the case of so-called intermediate risk profiles. Depending on the situation, urine markers could optimize follow-up, although results from prospective randomized studies are still pending. CONCLUSIONS: The current follow-up of NMIBC is invasive, carries the risk of side effects and increases costs. In the absence of scientific evidence, recommendations for follow-up for NMIBC are naturally based on expert opinion. In the opinion of the authors, overdiagnosis is currently taking place particularly in patients with an intermediate risk profile. The first prospective, marker-based studies are ongoing and will be helpful in the near future to improve the data situation relevant to urological practice.

[Nutritional prevention of urological tumours]. / Alimentäre Prävention urologischer Tumoren.

Through the last decade considerations on the role of vitamins and antioxidants in the primary prevention of genitourinary tumors have changed dramatically. In spite of all efforts, the efficacy of a specific compound has not been proven so far. In consequence, recommendations to use vitamins or other supplements for the primary prevention of urological tumors should be avoided. However, there is some evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet may not only prevent prostate cancer (PCA) but also harbour additional beneficial effects on general health. Although quantification of these findings may be difficult, it becomes evident that these measures will have additional synergistic effects on cardiovascular diseases. Considering the large number of PCA patients dying not cancer-related but from concomitant diseases, primary prevention in particular of PCA should always also consider the general health of the target population. More recent studies suggest a potential effect of nutritional compounds on biochemical tumour recurrence in PCA patients after definite therapy. These observations may serve as a starting point for validation within controlled clinical trials.

[Metabolic syndrome and prostate cancer]. / Metabolisches Syndrom und Prostatakarzinom.

The relationship between metabolic syndrome (MS) and prostate cancer (PCA) is highly complex and harbors multiple facets not least because MS is not a single entity but represents a poorly defined inhomogeneous mixture of different diseases and conditions. Although numerous studies suggest a correlation between MS or components of MS and the development of prostate cancer, current evidence cannot be considered convincing. While diabetes appears to be inversely related to PCA, increased serum levels of triglycerides, cholesterol and insulin-like growth factor 1 (IGF-1) may be predictive for high grade disease. Further studies suggested that MS and high serum insulin levels are independent predictors of an unfavorable prognosis in patients with metastatic PCA. Early detection and improved therapeutic options have dramatically prolonged the course of the disease in advanced PCA through the last decades. As a consequence, development of MS in patients undergoing hormone therapy along with the cardiovascular risks has gained increasing relevance. Based on this evolution prevention, early detection and sustainable therapy represent an important clinical challenge to modern urologists active in urooncology.

[Phytotherapy of benign prostate syndrome and prostate cancer: better than placebo]. / Phytotherapie bei benignem Prostatasyndrom und Prostatakarzinom : Besser als Placebo?

In some countries plant extracts have belonged to the most popular drugs for the treatment of the benign prostatic syndrome (BPS) for decades; however, only few of the large number of published studies meet the criteria of the WHO benign prostatic hyperplasia (BPH) consensus conference. The few placebo-controlled long-term (study period >6 months) studies suggest a positive effect of some extracts (saw palmetto fruit, ß-sitosterol, urtica, rye grass and a saw palmetto/urtica combination) on lower urinary tract symptoms (LUTS), urinary flow rate, post-void residual volume but effects on prostate volume or prostate-specific antigen (PSA) were only inconsistently demonstrable. To date no study has proven an effect on disease progression, such as acute urinary retention or need for surgical interventions. Due to the controversial data various extraction techniques and compositions of various products, neither American, European, British nor German BPH guidelines recommend plant extracts for the indication BPS although some placebo-controlled trials provided encouraging data. Further prospective studies according to WHO standards are required to determine the role of plant extracts for the management of BPS. For the indication of prostate cancer (PCa) plant extracts have been evaluated for disease prevention and management of several tumor stages but none of these studies have provided convincing evidence that plant extracts are superior to placebo and none of the Pica guidelines have recommended their use.Based on current knowledge plant extracts can never supplement evidence-based PCa management and should be used only in addition to the standard treatment. There is no scientific evidence for the use of dietary supplementation with high doses of vitamins or selenium-containing products.

[Intraoperative frozen section diagnosis of the genitourinary tract]. / Intraoperative Schnellschnittdiagnostik des Urogenitaltrakts.

Up to now intraoperative frozen section, diagnosis has been of limited utility in urologic oncology. In the future, it may become more important due to a significant increase in the number of nerve-sparing operations performed for prostate cancer. Accuracy and benefit of intraoperative frozen sections depend both on a good communication between surgeons and pathologists as well as on a strict assessment of the need for surgery in the individual patient. In order to optimize cost-efficiency and to reduce the associated risks the indications for intraoperative frozen sections must be rigorously appraised. This report outlines clinically relevant indications for intraoperative frozen section diagnosis in tumors of the urinary tract, kidneys, prostate, testis and penis according to the most recent guidelines. The diagnostic scope and problems of this method are also discussed.

[Chemoprevention of prostate cancer - a plea]. / Chemoprävention des Prostatakarzinoms - Ein Plädoyer.

The high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make the diagnosis of and therapy for prostate cancer a special challenge for urologists. Effective prevention of the disease may help to improve some of the problems mentioned above. Two randomised, controlled studies have proved that effective chemoprevention of prostate cancer is viable using 5α-reductase inhibitors (finasteride, dutasteride). Furthermore, there is increasing evidence that other compounds, e. g., selective oestrogen receptor modulators (SERMs), NSAIDs and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economical aspects. The authors conclude that the options of chemoprevention should be investigated in an open and unbiased way.

[Supportive options in the treatment of urological tumours]. / Supportion in der urologischen Tumortherapie.

An ageing society with a consecutive increase of genitourinary malignancies along with remarkable changes in systemic cancer therapy provide the basis for an increasing role of supportive measures. While surgical treatment, radiation or chemotherapy are undergoing subsequent standardisation, supportive measures are still widely used on the basis of personal experience alone. However, effective support is the prerequisite for a successful systemic treatment. Within this review the most relevant side effects of systemic therapy for urological tumors are summarised and the respective therapeutic options are presented in a brief but practice-oriented way. The authors have aimed at the consideration of evidence-based measures, wherever possible.

[Prevention of uro-oncological diseases]. / Prävention uroonkologischer Erkrankungen.

During the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has changed dramatically. Despite all efforts the efficacy of a specific compound has not yet been proven and as a consequence recommendations for the use of vitamins or other supplements for tumor prevention should no longer be given. In contrast life style modification might be helpful as recent investigations suggested that smoking not only promotes the development of bladder cancer but is also involved in prostate and renal cell carcinogenesis. In addition there is some evidence that moderate food consumption, reduction of dairy product consumption and an Asian or Mediterranean diet can prevent prostate cancer and also harbor additional beneficial effects for general health. These observations should be the starting point of future epidemiological research. This may be considered as a change of paradigm in prostate cancer prevention. In contrast there is clear evidence of the efficacy of chemoprevention using 5α-reductase inhibitors as the use of finasteride and dutasteride significantly reduces the detection of prostate cancer. However, translation of these findings into urological practice remains a matter of controversial discussion.

[What can medicine expect from health economics?]. / Was erwartet die Medizin von der Gesundheitsökonomie?

Medicine has changed dramatically in the past ten decades thanks to the introduction of innovative diagnostic and therapeutic procedures. However, besides the unmistakable advances achieved in medicine, the costs of all health care systems have risen dramatically. In contrast to the escalation in expenditures, only moderate gains in proceeds have been accomplished. This situation requires that future financial resources be judiciously expended. The field of health economics has set as its goal the analysis of medical measures in terms of costs and benefits to be able to provide information on these parameters to those involved in the public health sector. The emerging problems are diverse and extend from assessment of effects and side effects to difficulties in standardizing analytical procedures and comparing results between different health care systems.In the context of this manuscript an attempt has been made to illustrate the methodological approaches to health economics based on current issues in the diagnosis and treatment of prostate cancer. This contribution intends to motivate stakeholders to view health economics as a tool to promote improvements in medical care and not as a means to regulating and rationing medical measures.

Prevention strategies for prostate cancer.

Through the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has dramatically changed. Despite all efforts efficacy of a specific compound has not been proven, so far. In consequence, recommendations for a use of vitamins or other supplements with the intention of prostate cancer prevention should be avoided today. In contrast, there is some evidence that life style modification might be helpful: recent investigations suggest that smoking may be involved in prostate cancer carcinogenesis. In addition, there is evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet might not only prevent prostate cancer but also harbors additional beneficial effects on general health. This move from single compounds to more complex diets can be considered as a change of paradigm in prostate cancer prevention and could be the starting point of future epidemiological research. Disappointing findings with regards to nutritional cancer prevention contrast with a solid evidence concerning the efficacy of chemoprevention using 5a-reductase inhibitors: Long-term use of Finasteride and Dutasteride significantly reduces prostate cancer detection. Further candidate drugs are under investigation. However, translation of these findings into urological practice remains a matter of controversial discussion.

[Primary prevention of urologic tumors: prostate cancer]. / Primärprävention urologischer Tumore: Prostatakarzinom.

Assessment of the role of vitamins and micronutrients in the primary prevention of prostate cancer has changed dramatically in the past 10 years. Efforts to confirm the efficacy of a single substance have not yet succeeded. Therefore, such recommendations should at present no longer be given. Consideration could even be given to discussing whether additional large-scale interventional studies are expedient in this regard. There is still solid evidence that a well-balanced moderate diet, reduced consumption of milk products, and an Asian or Mediterranean diet are not only beneficial for general good health but can also prevent the development of prostate cancer. This should be the focus of further epidemiological studies. Thus, one can certainly speak of a paradigm shift in the prevention of prostate cancer. In contrast, available data on chemoprevention with 5α-reductase inhibitors is unequivocal: intake of finasteride as well as dutasteride correlates with significantly decreased evidence for prostate cancer. Converting this result into urologic practice remains the topic of extensive controversy.

[Secondary and tertiary prevention of urological tumors]. / Sekundär- und Tertiärprävention urologischer Tumore.

The amount and quality of available data on secondary and tertiary prevention of urological tumors are to a large extent unsatisfactory. In the areas of nutrition and supplementary diet the consumption of tomatoes and especially tomato products could have a beneficial effect on the course of the disease for patients with prostate cancer, whereas there is evidence that the consumption of foodstuffs containing calcium (milk and milk products) and linolenic acid as well as a fat-rich diet accelerate tumor progression. Despite as yet unsatisfactory data, men with urothelial tumors or prostate cancer should abstain from smoking and undertake sports activities. For medicinal measures the administration of 5-alpha-reductase inhibitors and bone-promoting substances for patients with prostate cancer are under discussion. The effectiveness of the substances zoledronate and denosumab has been demonstrated in prospective randomized studies. The authors recommend that the scientifically neglected field of tertiary prevention of urological tumors should in future be included as a core factor of scientific investigations.

[Role of immunocytology in the evaluation of patients with painless gross hematuria]. / Rolle der Immunzytologie in der Abklärung von Patienten mit schmerzloser Makrohämaturie.

OBJECTIVE: Gross hematuria is a highly worrisome episode in a patient's history mainly due to the fact that the prevalence of bladder cancer is significant in this group of patients. In this prospective study the role of immunocytology in the evaluation of patients with gross hematuria was investigated. MATERIALS AND METHODS: Ucyt is an immunocytological assay based on microscopic detection of tumor-associated antigens on urothelial cells. The study included 103 consecutive patients with a first episode of painless gross hematuria without prior transitional cell carcinoma. Urine samples were obtained from all patients and examined cytologically and immunocytologically. RESULTS: Clinical assessment by physical examination, laboratory tests, endoscopy, and imaging modalities yielded urothelial cancer in 22 cases (21%). Further diagnoses were BPH (30%), inflammation (10%), urolithiasis (7%), and"further conditions" (16%). In 17 patients the reasons for hematuria were not determined. For cystoscopy, immunocytology, and conventional urine cytology a sensitivity of 89 (excluding UUT), 86, and 45% was observed. Specificity was 94, 82, and 89%, respectively. Two and three bladder tumors were not detected by cystoscopy and immunocytology, respectively. CONCLUSIONS: The combination of cystoscopy and immunocytology yielded 100% sensitivity, while combining cystoscopy and cytology only marginally improved the sensitivity of cystoscopy alone. Since sensitivity appears to be of key relevance in the assessment of patients with gross hematuria, the authors suggest the addition of a sensitive noninvasive test to the diagnostic armamentarium in this situation.

[Risks and prevention of prostate cancer. Commentary on the new S3 guideline]. / Risiken und Prävention des Prostatakarzinoms. Ein Kommentar zur neuen S3-Leitlinie.

Acceptance of prostate cancer as an endemic disease was the basis for the decision reached by the guideline committee to devote a chapter to the topic of risks and prevention of prostate cancer. Analysis of the substantial data regarding these subjects, however, shows that a number of apparently accepted risk factors and recommendations for prevention do not withstand subtle assessment. For this reason, only information concerning the risk factors of age and genetic predisposition is obtained from men. While the role of nutrition in the pathogenesis of prostate cancer remains beyond dispute, data on individual food items are very contradictory. Positive results of interventional studies are not available. Thus, the committee issued general recommendations on nutrition and lifestyle which also include other malignant tumors and the risk for cardiovascular disease. New findings of prospective studies on chemoprevention were incorporated into a statement. Since 5-alpha-reductase inhibitors have not yet been approved for prevention of prostate cancer, no recommendation was given.

Immunocytology in the assessment of patients with asymptomatic hematuria.

Painless hematuria has remained a diagnostic challenge in daily urological practice. Key problem in the assessment of these patients is the discrimination between malignant and non-malignant conditions. In this prospective study the role of immunocytology in the evaluation of patients with hematuria was investigated. Ucyt is a commercially available immunocytological assay based upon microscopical detection of tumor-associated antigens on the membrane of urothelial cells by immunofluorescence. Between October 2000 and July 2007, 301 consecutive patients with a first episode of painless hematuria without prior transitional cell carcinoma were included. Urine samples were obtained from all patients and examined cytologically and immunocytologically. Clinical assessment by physical examination, laboratory tests, endoscopy and imaging in 228 cases with microhematuria and 66 cases with gross hematuria yielded bladder cancer in 10 (4.6%) and 17 (27%) patients, respectively. Clinical workup demonstrated that composition of both groups was entirely different. Sensitivity of cystoscopy and immunocytology was similar in both groups. Furthermore, a negative finding in cystoscopy and immunocytology virtually excluded the presence of urothelial cancer. However, while predictive values of immunocytology were clearly superior to cytology in gross hematuria, cytology performed better in the microhematuria cohort. Combination of cystoscopy and immunocytology yield 100% sensitivity in the assessment of patients with painless hematuria. Based upon performance characteristics the authors recommend to replace urine cytology by a more sensitive marker like immunocytology in gross hematuria. In patients with microhematuria immunocytology could be used to select for patients at risk for urothelial cancer and thus spare negative patients from further examinations.

[Analyses of the role of immunocytology in the differential diagnosis of patients with asymptomatic microhematuria]. / Untersuchungen zur Rolle der Immunzytologie in der Abklärung von Patienten mit asymptomatischer Mikrohämaturie.

INTRODUCTION: Discriminating between malignant and nonmalignant conditions remains a challenge in the evaluation of patients with asymptomatic microhematuria. In this prospective study the role of immunocytology in the assessment microhematuria was studied. MATERIAL AND METHODS: uCyt is a commercially available immunocytological assay based on microscopical detection of tumor-associated antigens in urothelial cells by immunofluorescence. Between September 2000 and December 2006, 222 consecutive patients with newly diagnosed painless microhematuria without prior transitional cell carcinoma were included. All urine samples were examined cytologically and immunocytologically. A total of 211 samples (95%) were assessable. RESULTS: Clinical examination by physical examination, cystoscopy, laboratory tests, and imaging yielded bladder cancer in ten cases (4%). Further diagnoses were BPH (27%), cystitis (including IC) (12%), urolithiasis (9%), urethral or ureteral strictures (6%), papilloma (2%), and"further conditions" (16%). In 52 patients (23%) reasons for hematuria were not identified. Immunocytology was positive in 8 of 10 bladder tumors (80%) and negative in 178 patients with non-tumor-related hematuria (89%). CONCLUSIONS: The high sensitivity and good specificity of immunocytology is comparable with that reported in the literature despite a very low disease prevalence in this population. If assessment of these patients would have only been based on immunocytology, 180 costly and invasive diagnostic procedures would have been saved, with only 29 individuals (14%) undergoing these examinations unnecessarily. The authors conclude that these findings justify further investigation of this issue.

[The Prostate Cancer Prevention Trial (PCPT). Relevance for clinical practice]. / Das "Prostate Cancer Prevention Trial" (PCPT). Die Bedeutung für den klinischen Alltag.

The Prostate Cancer Prevention Trial (PCPT) has been the first interventional trial directly aimed at the prevention of prostate cancer. A total of 18,882 men over 55 years with a PSA serum level less than 3.0 ng/ml were randomized to receive either the 5-alpha-reductase inhibitor finasteride 5 mg/day or placebo for 7 years. Despite a 25% reduction of prostate cancers in the treatment arm the results were discussed controversially. This criticism was mainly due to the observation of significantly more high-grade cancers in the finasteride group. Meanwhile, results of extensive follow-up analyses have been published suggesting that this finding is most likely due to optimized tumor detection in smaller glands. Further work-up demonstrated that PSA diagnosis and the histopathological examination were not compromised by finasteride. Furthermore, in addition to a decrease of prostate cancer the amount of prostatic intraepithelial dysplasia (PIN) was also reduced under finasteride. Future research must now aim at defining high-risk groups specifically profiting from chemoprevention with a 5-alpha-reductase inhibitor.