Timing of androgen deprivation monotherapy and combined treatments in castration-sensitive and castration-resistant prostate cancer: a narrative review.

PURPOSE: Standard androgen deprivation therapy (ADT) can be initiated early at the time of diagnosis in asymptomatic castration-sensitive advanced prostate cancer. This definition has recently been expanded to also include an early combined treatment with standard ADT and new antihormonal drugs. We aimed to present the best available evidence for the timing of initiation of ADT monotherapy and combined treatments in castration-sensitive/-resistant prostate cancer. METHODS: For this narrative review, we searched Cochrane reviews in the Cochrane Library, systematic reviews and randomized controlled trials in MEDLINE, phase III and ongoing trials in ClinicalTrials.gov and screened the reference lists to extract articles of interest. One author screened the references which were finally included after assessing their relevance through discussion with other experts in the field. RESULTS: The identified references were grouped by medication (standard ADT, androgen biosynthesis inhibitor, androgen receptor antagonists or combined therapies) and tumor stage (castration sensitive or resistant). The evidence was narratively summarized and discussed in the context of the current therapeutic landscape. CONCLUSIONS: Early standard ADT can reduce symptoms of disease progression and may extend progression-free and overall survival. The patient should be well informed about the higher rates of treatment-related side effects. Deferring standard ADT might be indicated only for well-informed or unfit patients. Early standard ADT is increasingly combined with new antihormonal drugs in castration-sensitive metastatic prostate cancer to gain additional survival and quality of life benefits. Combined treatment at the time of development of castration-resistant disease is well established.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

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.

[Sectoral interface-an opportunity for health services research?] / Intersektorale Schnittstelle ­ eine Chance für Studien zur Versorgungsforschung?

The request for increased outpatient care is currently widely discussed in healthcare debates. With that, the sectoral interface (outpatient/hospital) is receiving greater attention, which provides an incentive for better cooperation and coordination of all healthcare providers. This also marks an opportunity to establish new cross-sectoral structures-also for research. The definitions of cross-sectoral care and the research content need to be in a standardized and consolidated manner. The provision of treatment data along the entire patent's path remains essential for health services research. In this context, the cross-sectoral interface could be regarded as fragile in that it is particularly sensitive to disruptions. The current increasing digitalization can also be seen as an opportunity to minimize the loss of information through the further development of cross-sectoral structures and to improve patient care, while simultaneously making a contribution to research across sectoral borders.

[Radium-223 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) : The androgen receptor-independent active agent in the therapeutic sequence]. / Radium-223 zur Therapie des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) : Der androgenrezeptorunabhängige Wirkstoff in der therapeutischen Sequenz.

BACKGROUND: Radium-223 improves overall survival and preserves quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases and no known visceral metastases. Radium-223 can be used in combination with a luteinizing hormone releasing hormone (LHRH) analogue and as part of a sequential treatment scheme if disease progresses after at least two prior lines of systemic mCRPC therapies or if no other available systemic treatment is eligible. OBJECTIVES: Today physicians are faced with a previously unknown multitude and complexity of options for the treatment of mCRPC. An increasing number of clinical trials contribute to the dynamics of the therapeutic landscape. Radium-223 was approved for mCRPC treatment in 2013. Up to now the recommendations of use have been adjusted several times. Highlighting recent clinical trials and practice, this paper explores the position of radium-223 within the therapeutic sequence and outlines key elements for the interdisciplinary cooperation between uro-oncologists and nuclear medicine specialists. RESULTS: The mode of action of radium-223 does not depend on the androgen receptor (AR) pathway. Thus, it is an option in the therapeutic sequence when the efficacy of other agents is reduced by resistance. Furthermore, the efficacy of prior or subsequent medications are neither reduced nor enhanced by radium-223. The opportunity of an AR-independent and survival-prolonging medication should be taken as soon as the indication criteria are met because the incidence of visceral metastases increases during disease progression. According to current mCRPC guidelines, the osteoprotective use of bisphosphonates or denosumab is recommended, before treatment with radium-223 is started or resumed.

Outcomes and response to therapy in bladder cancer. Are biomarkers of any help?

In oncology patients and clinicians are confronted with the search for measures which could help to elicit the individual patient's risk of future outcome, such as recurrence of disease after primary treatment, response to chemo-therapy or a general outline on the aggressiveness of a given lesion. In patient counselling, the emerging role of evidence based treatment choices reveals with cumulative certainty that the available information is inconclusive. This review will focus on current investigations of determinants to predict response to chemotherapy in advanced bladder cancer or to define prognosis of patients prior to any definite treatment. It will discuss the current evidence for the current systemic treatment options and highlight the many promising approaches of implementing markers either as a basis for a clinical decision in combination with other prognosticators (to better detect individuals at risk or to avoid unnecessary invasive procedures) or as a possible part of relevant pathways to be targeted. It will also discuss the role of biological markers with regards to the relevant clinical question and provide the current evidence to each field. It will highlight the need to further harmonize terminology, approaches and circumstances under which markers are evaluated and will provide suggestions for general methodological principles and guidelines for design, conduct, analysis and reporting of marker studies. The exploration of the current aspects of marker research may outline why collaborative, multicentre, and multidisciplinary efforts should be an integral part of future studies.

[Presurgical assessments]. / Assessments vor Operationen.

For the estimation of perioperative risks and mortality in the context of radical urological tumor surgery in elderly patients, the guidelines meanwhile require the use of geriatric assessments. The aim of this work is therefore to explain frequently used geriatric assessments and to give an overview of their predictive significance in radical urological tumor surgery. Comprehensive geriatric assessments provide a good description of the patient's state of health, but are hardly feasible in clinical routine due to their complexity. It is more reasonable to use screening tools with subsequent targeted examination of high-risk patients. Special tools allow the standardized assessment of functional status, mobility, cognition, mood, nutrition, frailty, comorbidities and polypharmacy and have different prognostic significance. Evidence on the predictive value of assessments prior to radical urological tumor surgery is mainly described for the systematic classification of comorbidities. In cystectomy, the Charlson Comorbidity Index (CCI) and the American Society of Anesthesiologists (ASA) score allow an estimation of the risk of complications and mortality. The focus of assessments prior to prostatectomy is to identify patients with sufficient life expectancy to benefit from radical surgery. CCI and ASA scores as well as the Eastern Co-operative Oncology Group (ECOG) score can help to assess the risk of perioperative complications in kidney tumor surgery.

[Molecular tumor board-renal cell carcinoma]. / Molekulares Tumorboard ­ Nierenzellkarzinom.

The introduction of molecular targeted agents has fundamentally changed the treatment of metastatic renal cell carcinoma. A first wave of development was based on the improved understanding of tumor biology since the discovery of the importance of the von Hippel-Lindau gene as the key driver of the disease and paved the way for antiangiogenic agents. Of relevance is the overexpression of proangiogenic and proliferation-promoting factors (VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor) as well as an overactivation of the PI3K-Akt signaling pathway: the target structure is the "mammalian target of rapamycin" (mTOR) molecule, which is involved in the regulation of cell proliferative processes. VEGF-, PDGF-, and mTOR-signals and signaling pathways are central targets of current targeted substances. A second wave is certainly to be seen in the development of therapeutic approaches with the targeted activation and modulation of the immune system, which has brought "immunotherapy" back into the focus of interest. Central development is the application of immune-checkpoint inhibitors, with the help of which (re-)activation of the cellular defense, especially of T cells, takes place, which per se holds the potential of a cytoreductive therapy by killing the tumor cells. Even though the prognosis has improved significantly due to the rapid development of recent years, treatment remains challenging as most patients experience progress, and long-term survival is only achieved in about 20% of cases because some patients are primarily refractory or do not respond. The more intensive interlocking of molecular biology, pathology, clinical research, and interdisciplinary uro-oncology, as is the claim of molecular tumor boards, can contribute to the individual selection of a suitable therapy strategy and, thus, establish the latest findings and developments for the benefit of patients in the clinic.

[Treatment situation in metastastic Castration Naive Prostate Cancer (mCRPC) and the implications on clinical routine]. / Therapiesituation beim metastasierten kastrationsnaiven Prostatakarzinom (mCNPC) und die Auswirkungen im klinischen Alltag.

There is an ongoing change of paradigm in the treatment of metastatic prostate cancer (mPC). Taxan-based chemotherapy demonstrated a prolonged survival of patients in several randomized phase III trials. This is true in the situation of metastatic castration-resistent prostate cancer (mCRPC) as well as in the hormone-naïve stage (metastatic castration-naive PC [mCNPC]). In patients with mCNPC, treatment with docetaxel in combination with androgen deprivation therapy (ADT) prolonged the median total survival time by 15 months in comparison to ADT alone. Comparable results were obtained by the endocrine combination treatment with ADT/abiraterone. With the current data in mind it seems to be useful to discuss the value of early combination therapy with ADT/docetaxel or ADT/abiraterone as well as the impact on further treatment options in the mCRPC setting and to define criteria for treatment decisions in clinical practice.

Plasmacytoid urothelial carcinoma of the bladder: histological and clinical features of 5 cases.

PURPOSE: Urothelial carcinoma with plasmacytoid morphology is a rare and only recently described histological variant. To date only 22 cases have been published. We present clinical and histopathological features of 5 cases of plasmacytoid urothelial carcinoma at our institutions. MATERIALS AND METHODS: From a consecutive series of 130 muscle invasive urothelial carcinoma cases 3 of plasmacytoid urothelial carcinoma (2.3%) were identified. Two additional plasmacytoid urothelial carcinoma cases, including 1 that was noninvasive, were also studied. Data were collected from clinical charts, histological review and followup. RESULTS: Four patients had a muscle invasive tumor at first presentation. The nonmuscle invasive plasmacytoid urothelial carcinoma represents the second published case in the literature. Conventionally differentiated urothelial carcinoma was focally present in every case. Plasmacytoid urothelial carcinoma cells were dyshesive and showed abundant eosinophilic cytoplasm, leading to a plasmacytoid appearance. Positive staining for epithelial markers confirmed the epithelial nature of the tumor. All tumors showed negative E-cadherin expression. Adjuvant or neoadjuvant chemotherapy seemed to have a beneficial effect on survival in patients with advanced tumors since they experienced prolonged survival. CONCLUSIONS: Plasmacytoid urothelial carcinoma is a rare variant of urothelial carcinoma with defined clinical and pathological characteristics. Diagnostic pitfalls are missing hematuria and no grossly identifiable tumor despite muscle invasive tumor stage. Cases only show mucosal induration and thickened bladder walls. Our data raise the possibility that the loss of E-cadherin expression is a prerequisite for plasmacytoid urothelial carcinoma. Awareness of these aspects should lead to earlier diagnosis and improved long-time survival in patients with plasmacytoid urothelial carcinoma.

[Plasmacytoid carcinoma. Five case reports of a rare variant of urothelial carcinoma]. / Das plasmazytoide Urothelkarzinom. 5 Fallberichte einer seltenen Variante des konventionellen Urothelkarzinoms.

Plasmacytoid carcinoma is a rare variant of urothelial carcinoma and is characterised by distinct histopathological and clinical characteristics. The incidence varies between 2.7% and 3.1% of all muscle-invasive urothelial carcinoma. It is an aggressive, high-grade tumor with poor prognosis. Negative E-cadherin expression seems to be important for exact diagnosis. Systemic chemotherapy of plasmacytoid carcinoma could lead to prolonged patient survival.

[Multimodal therapy for bladder sparing with high grade bladder tumors]. / Multimodale Therapien zum Blasenerhalt bei High-grade-Blasentumoren.

The demographic changes of our society, with an increasing number of elderly patients and higher comorbidity, leads to the fact that managing transitional cell carcinoma (TCC) in the elderly is becoming increasingly more important. Thus, the value and indication of conservative or less invasive treatment approaches have to be continuously re-evaluated. The gold standard of treatment for invasive high grade TCC is radical cystectomy with curative intent. However, not each and every patient is suitable for this procedure or the operation is rejected. Thus, alternative treatment options (curative or palliative) including bladder sparing approaches should be offered to this group of patients. These include transurethral resection (TUR-B), open partial cystectomy, chemotherapy (intravesical or systemic), local radiation and minimally invasive interventional therapies alone or in combination. A lower physical and mental burden and, more important, a faster convalescence and the maintenance of the quality of life, are the major aims of these strategies. From an oncologic point of view these concepts have to be viewed with caution, since they may only lead to a temporarily stable disease or the elimination of symptoms. However, long-term follow-up demonstrates that with the correct indication for a multi-modal treatment, a subset of patients with high grade TCC of the bladder may be cured when implementing a bladder sparing approach.

[Follow-up of bladder cancer : The right examinations at the right time]. / Tumornachsorge des Harnblasenkarzinoms : Die richtigen Untersuchungen zum richtigen Zeitpunkt.

Schedules for the follow-up (FU) of bladder cancer patients are predominantly based on studies with low level of evidence and the resulting guidelines' recommendations that are often founded on expert consensus. FU of non-muscle invasive bladder cancer (NMIBC) includes cystoscopy and cytology as standard, and imaging modalities to a lower extent. FU of muscle-invasive bladder cancer (MIBC) depends primarily on the therapeutic modality chosen and on the stage of disease. In this scenario, FU is complemented by functional and quality of life related aspects. These apply even more for FU in palliative situations. Here, the individual focus is on examinations that might have a consequence in terms of survival and/or symptom relief.

[Metastatic castration-resistant prostate cancer : Use of cabazitaxel taking into consideration current data]. / Metastasiertes kastrationsresistentes Prostatakarzinom : Neues zu Cabazitaxel unter Berücksichtigung der aktuellen Datenlage.

BACKGROUND: At the 2016 ASCO annual meeting, new data from two randomized phase III studies concerning taxane-based chemotherapy as a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) were presented. OBJECTIVES: The focus is on the clinical impact of these data. MATERIALS AND METHODS: A group of German experts in the field of urogenital-oncologic expertise discussed the clinical impact with respect to the current data. RESULTS: The study results support the current clinical data. They confirm the efficacy and safety of cabazitaxel beyond first-line therapy with docetaxel for patients with mCRPC. CONCLUSIONS: Cabazitaxel is an important treatment option after docetaxel progression. With respect to the performance status of a patient, it is adequate to reduce the dosage to 20 mg/m2 cabazitaxel.

[Advanced Prostate Cancer Consensus Conference 2017 : Discussion of the recommendations for diagnosis and treatment of metastatic prostate cancer by a German panel of experts]. / Advanced Prostate Cancer Consensus Conference 2017 : Diskussion der Empfehlungen zur Diagnostik und Therapie des metastasierten Prostatakarzinoms durch ein deutsches Expertengremium.

In March 2017 the 'Advanced Prostate Cancer Consensus Conference' (APCCC) took place in St. Gallen (Switzerland). The APCCC-panelists are internationally well known experts. With the actual data in mind they discussed treatment options for patients with advanced prostate cancer in order to update the international APCCC-recommendations from the previous meeting in 2015. Recently these consensus recommendations have been published in "European Urology".A group of German experts discussed this year APCCC-votes during the meeting and the recommendations that were concluded from the votes from the German perspective. Reasons for an additional German discussion are country-specific variations that may have influenced the APCCC-votes und recommendations. Due to the concept of the APCCC-meeting the wording of the questions could not always be as necessary.One focus of this year consensus discussion was the treatment of metastatic castration-naive prostate cancer (mCNPC). There are new data which may also influence the therapeutic situation of patients with metastatic castration-resistant prostate cancer (mCRPC). Further points of discussion were the impact of new imaging procedures in the clinical setting as well as the treatment of oligometastatic prostate cancer.

[Transurethral resection of bladder tumors and prostate enlargement in physiological saline solution (TURIS). A prospective study]. / Transurethrale Resektion von Blasentumoren und Prostataadenomen in physiologischer Kochsalzlösung (TURIS). Eine prospektive Studie.

BACKGROUND: Transurethral resection in a conductive irrigant medium is a new procedure in the surgical therapy of bladder tumors and prostate enlargement. In this prospective randomized trial we compared conventional TUR with TUR in saline regarding safety and efficiency. PATIENTS AND METHODS: Between November 2004 and February 2005 a total number of 128 patients were included in this study. After randomization 58 patients were treated by conventional TUR and 70 patients by TURIS (Olympus, SurgMasterSystem). We evaluated resection time, weight of resected tissue, complications, blood loss, changes in serum sodium, and duration of catheterization. RESULTS: Among the tested procedures no statistically significant difference could be observed concerning blood loss, change of serum sodium, and complications. The mean weight of resected tissue of the prostate per time was 0.9 g/min with the TUR procedure and 0.8 g/min with the TURIS procedure. Severe complications like TUR syndrome or perforation of the bladder were not observed at all. In the TURIS group time until catheter removal was longer but also the mean weight of resected tissue of the prostate was higher in the TURIS group (42 g) than in the conventional TUR group (31 g). CONCLUSIONS: Transurethral resection in a conductive irrigant medium (TURIS) can be considered as a safe and effective surgical procedure in the treatment of BPH and superficial urothelial carcinoma. Moreover the risk of TUR syndrome and perforation of the bladder due to nerve stimulation is reduced.

[Metastatic prostate cancer : Update: position paper for the use of chemotherapy]. / Metastasiertes Prostatakarzinom : Update: Positionspapier zum Einsatz der Chemotherapie.

BACKGROUND: Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phase III studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to a significant increase in median overall survival. OBJECTIVE: This position paper aims to provide current data and orientation in the evidence-based treatment of mPC patients in daily clinical practice. MATERIALS AND METHODS: A German group of clinical experts analyzed the current data and developed criteria for the treatment of mPC patients in daily clinical practice. RESULTS: In the current treatment of hormone-naïve mPC, a beneficial effect of chemotherapy in addition to ADT has become evident. Provided patients are in an appropriate condition, those with a high metastatic load should receive chemotherapy in addition to ADT. Especially in high-risk mCRPC patients (PSA >114 ng/ml, visceral metastasis, ADT response <12 months, tumor-associated complaints), first-line chemotherapy is indicated. After docetaxel failure, continuous treatment with cabazitaxel shows superior overall survival compared to sustained antihormonal therapy. CONCLUSION: Chemotherapy is firmly established in treating patients with mCRPC. Long-term, it will be important to identify molecular predictors. The authors suggest the early use of chemotherapy in hormone-naïve mPC, but note that the approval in this indication is currently nonexistent. After disease progression, patients should be treated analogous to mCRPC.

[The causes of urinary bladder cancer and possibilities of prevention]. / Harnblasenkarzinom. Ursachen und Möglichkeiten der Vermeidung.

Bladder cancer is a malignant disease with exogenous and thus avoidable causative factors. Cigarette smoking is by far the most relevant risk factor and a clear dose-response relationship has been documented. That the bladder cancer risk decreases only a few years after the cessation of smoking is noteworthy. Occupational exposure, particularly to aromatic amines such as benzidine and beta-naphthylamine and to certain azo dyes, represents another important risk factor. At high risk are workers involved in the production of these chemicals and, to a lesser extent, those processing them. The currently known environmental factors seem to play a minor role. Treatment-induced risks causing secondary bladder cancer also have to be considered. Currently, the prevention of bladder cancer mainly involves avoiding exposure to known causative factors and early detection of the disease in high risk populations.

[Value of systemic chemotherapy in bladder cancer]. / Stellenwert der systemische Chemotherapie des Harnblasenkarzinoms.

Almost half of the patients with muscle invasive disease already harbor at the time of their first diagnosis occult or distant metastases. Systemic disease has a poor prognosis with a long term survival of less than 10%. The administration of systemic chemotherapy aims to improve the course of locally advanced or metastatic disease.A survival benefit of 5% for patients receiving neoadjuvant and 9-11% using adjuvant chemotherapy is in the first scenario minimal, in the adjuvant setting to be noteworthy. The MVAC-schedule and the Gemcitabine/Cisplatin-combination chemotherapy have to be regarded as standard for induction chemotherapy. However, the 5-year survival rates with 15 or 13% are disappointing.Thus, prognostic factors gain importance since with their consideration significant differences in survival rates can be found. Hope is provided by a novel class of substances, the target-specific drugs, which selectively interfere with the cascade of steps involved in tumorigenesis.