[Value of immunotherapy in the perioperative treatment of localized muscle invasive bladder cancer]. / Stellenwert der Immuntherapie in der perioperativen Behandlung des lokalisierten muskelinvasiven Harnblasenkarzinoms.

Immune checkpoint inhibitors are standard of care in the treatment of metastatic and locally advanced urothelial cancer. Their use in perioperative treatment is currently under investigation as monotherapy as well as in combination with chemotherapy or radiation regimens. This article provides an overview of recent trials, current data as well as an outlook on future developments in the perioperative management of urothelial cancer.

["Surgery only" is not enough: potential of multimodal therapy in urothelial bladder carcinoma]. / "Surgery only" reicht nicht aus: Potenziale einer multimodalen Therapie beim Urothelkarzinom der Harnblase.

Radical cystectomy is the standard treatment for muscle invasive bladder cancer. Using perioperative cisplatin-based chemotherapy, 5­year overall survival rates are 5% higher with neoadjuvant chemotherapy compared to local therapy alone. New multimodal concepts have been developed to improve oncologic efficacy and to reduce treatment-related morbidity. Perioperative use of checkpoint inhibitors aims at improving efficacy, while bladder-preserving concepts try to avoid cystectomy in good responders. This article reviews new developments in radioimmunotherapy and perioperative combination therapies as well as bladder-preserving concepts like trimodal bladder therapy.

[Quality assurance for the treatment of muscle-invasive and metastasized bladder carcinoma in Germany : An initiative of the Working Groups Urological Oncology (AUO) and Internal Oncology (AIO) in the German Cancer Society (DKG)]. / Qualitätssicherung zur Therapie des muskelinvasiven und metastasierten Harnblasenkarzinoms in Deutschland : Eine Initiative der Arbeitsgemeinschaften Urologische Onkologie (AUO) und Internistische Onkologie (AIO) in der Deutschen Krebsgesellschaft (DKG).

BACKGROUND: The S3-guideline on bladder cancer recommends radical cystectomy and cisplatin-based perioperative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC). Recommendation for metastatic urothelial cancer (mUC) is cisplatin-based or immuno-oncological (IO) treatment in platinum-ineligible patients (pts) or as 2nd-line therapy. OBJECTIVES: Aim of the study was to obtain representative data on clinical routine treatment of MIBC and mUC in Germany. MATERIALS AND METHODS: A nationwide survey was performed to obtain data on stage-related patient volume in hospitals and office-based physicians. Based on these results, a representative sample of treatment data was collected retrospectively from pts with MIBC and mUC. RESULTS: Data from 956 pts (MIBC 576; mUC: 380) were collected. Of the MIBC pts, 49.8% received a systemic therapy (80.4% of them received cisplatin/gemcitabine) and 50.2% were treated with a cystectomy without POC. Significant factors for cystectomy without POC were higher age > 75 years (odds ratio [OR] 4.91, 95% confidence interval [CI] 3.01-8.11, p < 0.001) and platinum-ineligible pts (OR 2.15, 95% CI 1.30-3.59; p = 0.003). Treatment decision without interdisciplinary tumor board was also correlated with no POC (OR 2.43, 95% CI 1.65-3.61, p < 0.001). In mUC platinum-pretreated pts generally receive IO therapy (OR 12.07, 95% CI 6.94-21.82, p < 0.001). Other significant factors are positive PD-L1 status (OR 3.72, 95% CI 1.30-5.71, p < 0.001), higher age > 75 years (OR 2.83, 95% CI 1.43-5.73, p = 0.003) and platinum-ineligible pts (OR 2.57, 95% CI 1.30-5.71, p = 0.007). CONCLUSIONS: The "gold standard" cisplatin/gemcitabine is established in Germany if pts are treated with POC. Nonetheless half of the MIBC pts did not receive a POC, especially if the treatment decision is not discussed in a tumor board. In mUC IO therapy is established as 2nd-line therapy after a platinum-based treatment. Although the guideline recommendations are largely implemented, there is potential for optimization, especially in the establishment of interdisciplinary tumor boards.

[Advanced bladder cancer : From chemo- to immunotherapy]. / Fortgeschrittenes Urothelkarzinom : Von der Chemotherapie zur Immuntherapie.

In November 2016, the results of a phase III clinical trial with the protein cell death (PD)-1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published and showed an overall survival benefit in comparison with conventional chemotherapy with vinflunine, docetaxel, or paclitaxel. In a similar trial the PD-L1 antibody atezolizumab showed no significant benefit in comparison to chemotherapy in the subgroup of PD-L1-positive patients and, thus, missed its primary endpoint. For other PD-1/PD-L1 directed substances, large phase I/II trials reported data concerning response rates and overall survival. This substance class will most likely become the new treatment standard in second-line treatment of metastatic urothelial cancer. Currently, PD-1/PD-L1 inhibitors are also being tested within randomized phase III trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or cytotoxic T­lymphocyte-associated protein (CTLA)-4 inhibitors. Whereas data from single-arm phase II clinical trials have already been published, preliminary phase III data are expected in 2018.

[Chemotherapy-induced nausea and vomiting : Current recommendations for prophylaxis]. / Chemotherapieinduzierte Nausea und Emesis : Aktuelle Empfehlungen zur Prophylaxe.

The chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent side effects in cytostatic therapy and a profound challenge during the therapy of cancer patients. Therefore, standardized guideline-orientated prophylaxis is essential and a fundamental contribution for the success of treatment. This review summarizes the current recommendations for CINV of the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN) and the S3-guideline Supportive Therapie of the Leitlinienprogramm Onkologie and shall facilitate its use in the daily routine.

[Efficacy of a ketogenic diet in urological cancers patients : A systematic review]. / Wirksamkeit der ketogenen Diät bei urologischen Tumorerkrankungen : Ein systematischer Review.

BACKGROUND: Beside the classical anticancer treatment tumor patients try to find proactive alternative therapies to fight their disease. Lifestyle changes such as introducing a ketogenic diet is one of the most popular among them. The German Association of Urological Oncology (AUO, Arbeitsgemeinschaft Urologische Onkologie) presents a systematic review investigating the evidence of ketogenic diet in cancer patients. MATERIALS AND METHODS: A systematic literature research was conducted in the databases Medline, Livivo, and the Cochrane Library. Only clinical studies of tumor patients receiving chemotherapy while on a ketogenic diet were included. The assessment of the results was performed according to the predefined primary endpoints overall survival and progression-free survival and secondary endpoints quality of life and reduction of adverse effects induced by cytostatics. RESULTS: Nine studies met the inclusion criteria: eight prospective and one retrospective study case series respectively cohort-studies, with a total of 107 patients. Currently there is no evidence of a therapeutic effect of a ketogenic diet in patients with malignant tumors regarding the clinical outcome or quality of life. CONCLUSION: Based on the current data, a ketogenic diet can not be recommended to cancer patients because prospective, randomized trials are missing.

Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.

BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.

[Side effects of chemotherapy]. / Nebenwirkungen der Chemotherapie.

Urologic tumors are frequently treated by multimodal therapeutic strategies with the consequence of an increasing number of adverse events. The most common chemotherapy-induced side effects are neutropenia, stomatitis, mucositis, diarrhea, and emesis. The efficacy of tumor therapy can be improved by good prophylaxis and standardized management of side effects.

[PSMA-targeted radioligand therapy in prostate cancer]. / Radionuklidtherapie des Prostatakarzinoms mittels PSMA-Lutetium.

Radioligand therapy (RLT) directed against prostate-specific membrane antigen (PSMA) enables tumor-specific treatment directed against PSMA-overexpressing prostate cancer cells. Several PSMA ligands such as PSMA-617 or PSMA-I&T have been developed that can be labeled with ß­radiating lutetium-177. These are currently applied in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC). PSMA-directed RLT is currently being offered in several nuclear medicine departments throughout Germany. Several retrospective case series demonstrate its activity with a prostate-specific antigen (PSA) decrease >50% in 30-60% of mCRPC patients. The toxicity seems to be low. Hematologic grade 4 toxicity has not been observed and grade 3 toxicities rarely occur. The main nonhematologic adverse events are intermittent dry mouth because of unspecific PSMA expression in the salivary glands as well as fatigue and nausea. Currently there are no prospective studies available for evaluation of PSMA-targeted RLT and a survival benefit over approved standard therapies such as abiraterone, enzalutamide, radium-223-dichloride, docetaxel or cabazitaxel has not been shown. PSMA-targeted RLT should therefore currently only be offered after critical evaluation in patients who exhausted the approved standard therapies.

The Role of PD-L1 Expression and Intratumoral Lymphocytes in Response to Perioperative Chemotherapy for Urothelial Carcinoma.

Introduction: Immunological pathways are relevant for the effectiveness of conventional cytotoxic chemotherapy. Recently, checkpoint inhibition of the PD-1/PD-L1 axis has been shown to be therapeutically relevant in urothelial carcinoma. Objective: To monitor PD-L1 expression on tumor cells and intratumoral infiltration with CD8 positive lymphocytes during perioperative chemotherapy for urothelial cancer and to evaluate their use as potential predictive markers for chemotherapy. Patients and Methods: Sixty-four patients with muscle-invasive urothelial cancer were included in the analysis. Twenty-two patients received preoperative chemotherapy and 42 were treated in an adjuvant setting for locally advanced disease or lymph node metastases. PD-L1 status and the density of infiltration with CD8-positive cells were assessed by immunohistochemistry and analysed for their association with survival (adjuvant group) and response to chemotherapy (preoperative group). For PD-L1 positivity we used a cutoff of 10% positive tumor cells. Results: In the adjuvant group, 11 of 42 patients (26.2%) had PD-L1 positive tumor cells. Twenty-six of 42 (61.9%) patients were highly infiltrated with CD8 + lymphocytes. There was no significant evidence of an association with overall survival for PD-L1 status nor for CD8 infiltration density (p = 0.63 and 0.71). In the preoperative group, eight of the 22 (36.4%) patients were PD-L1 positive and 13 (59%) were highly infiltrated with CD8 + lymphocytes before chemotherapy. There was no evidence of associations with response or survival. Eight patients showed a pathological response to preoperative treatment. These had a significantly longer overall survival than non-responders (p = 0.01). In the preoperative group the pre-treatment expression of the immunologic markers could be compared to the post-treatment status. Only one patient showed a changed PD-L1 status and three patients a changed CD8 status. Conclusions: The tumoral expression of PD-L1 in urothelial carcinoma does not seem to be largely influenced by chemotherapy. Our data do not provide evidence that tumoral expression of PD-L1 and CD8 are useful as prognostic or predictive markers. Small sample size is the major limitation of our study.