Thorsten H. Ecke

Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma

Targeted agents sunitinib and temsirolimus are effective in advanced renal cell carcinoma. Treatment algorithms for single-agent use have been proposed in order to optimize timing and type of therapy. The aim of this study was to investigate the tolerability and adverse event profile of patients who received sunitinib and temsirolimus in sequence. We performed a retrospective analysis of patients with advanced renal cell carcinoma who received temsirolimus after disease progression under sunitinib therapy. Dosages of both drugs were in accordance with the recommendations given by the respective manufacturers. Temsirolimus was provided before its official approval within a compassionate use program. Adverse event assessment followed the National Cancer Institute Common Toxicity Criteria. Thirteen patients receiving temsirolimus after progression under sunitinib were identified. Overall treatment time with targeted drugs (sunitinib/temsirolimus) was 34.8 (17–78) weeks, treatment with sunitinib was 28.6 (12–72), and with temsirolimus 6.2 (2–16) weeks, respectively, whereas mean therapy interruption time between both approaches was 4.4 (2–12) weeks. Under sunitinib, we observed 52 transient adverse events, 49 (94.2%) were of grade I/II, whereas 3 (5.8%) were of grade III. Under temsirolimus 36 adverse events, only grade I/II in nature were remarked. Sequential use of temsirolimus after progression under sunitinib seems to be feasible and results in a predictable, medically manageable side effect profile. Further evaluation is necessary to define the oncological validity of this sequencing approach.

Combined treatment with pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory after first-line therapy.

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m2 for the first dose and 320 mg/m2 every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in &ggr;-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m2) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

Long-term response in advanced bladder cancer involving the use of temsirolimus and vinflunine after platin resistance.

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

Vinflunine as second-line treatment in platin-resistant metastatic urothelial carcinoma: a review.

The novel third-generation bifluorinated semisynthetic vinca alkaloid, vinflunine, is a microtubule inhibitor that shows superior antitumor activity and a favorable safety profile compared with other vinca alkaloids. The main antineoplastic effects of vinflunine arise from its interaction with tubulin, the major component of microtubules in mitotic spindles. Vinflunine is known to have low affinity for tubulin, high intracellular accumulation, and important effects on microtubule dynamics. It has been shown to have activity against transitional cell carcinoma of the urothelial tract. Vinflunine was investigated in a randomized phase III clinical trial comparing vinflunine and best supportive care versus best supportive care alone in patients with advanced transitional cell carcinoma of the urothelial tract, who were progressive after first-line platinum-containing therapy. At an acceptable safety profile without cumulative toxicity, second-line treatment with vinflunine has shown a survival advantage and has therefore been approved in 2009 for this indication. This review gives a brief outline on vinflunine as a second-line treatment for platin-resistant advanced urothelial carcinoma; it describes pharmacology, efficacy studies, tolerance, and side effects and briefly discusses future clinical perspectives.

Targeted agents in second-line bladder cancer therapy.

The treatment of metastasized urothelial cancer has been evolving in recent years. In particular, in the second-line setting after the failure of platinum-containing therapy, options are few and besides vinflunine, the recently approved standard in Europe, well-designed highly selective clinical trials may be possible alternatives for patients in this palliative situation. However, targeted therapy approaches have not achieved the same results in urothelial cancer as for instance in renal cell carcinoma. Many of the new targeted drugs have been investigated as single agents in phase II clinical trials without convincing oncologic outcome. This review aims to highlight the most relevant clinical studies examining targeted agents in the second-line setting of metastasized transitional carcinoma of the urothelium.

Body mass index (BMI) and mutations of tumor suppressor gene p53 (TP53) in patients with urinary bladder cancer

OBJECTIVE Obesity is estimated to account for up to 20% of all cancer deaths. Mutations of TP53 are frequently correlated with tumor development and progression. We evaluated the effect of body mass index (BMI) and mutation status of tumor suppressor gene p53 (TP53) on patients with urinary bladder cancer. MATERIALS AND METHODS Clinical samples were used from 75 patients with tumors of the urinary bladder. Mutation status in TP53 exons 5, 6, 7, and 8 was analyzed by temperature gradient gel electrophoresis of exon-specific PCR products and by sequence analysis. Statistical analysis included Pearsons correlation. RESULTS For noninvasive bladder cancer, the mutation frequency in TP53 was 44.6%, while for invasive bladder cancer the mutation frequency in TP53 was 84.2%. Normal weight, overweight, and patients with obesity had a TP53 mutation frequency of 68.4%, 44.8%, and 25%, respectively (P < 0.05). CONCLUSIONS TP53 mutation frequently occurs in higher stages of bladder tumors. Body mass index is not associated with a higher TP53 mutation frequency in our study, but BMI should be included for collecting data of bladder cancer risk profile.

External Validation of an Artificial Neural Network and Two Nomograms for Prostate Cancer Detection

Background. Multivariate models are used to increase prostate cancer (PCa) detection rate and to reduce unnecessary biopsies. An external validation of the artificial neural network (ANN) “ProstataClass” (ANN-Charité) was performed with daily routine data. Materials and Methods. The individual ANN predictions were generated with the use of the ANN application for PSA and free PSA assays, which rely on age, tPSA, %fPSA, prostate volume, and DRE (ANN-Charité). Diagnostic validity of tPSA, %fPSA, and the ANN was evaluated by ROC curve analysis and comparisons of observed versus predicted probabilities. Results. Overall, 101 (35.8%) PCa were detected. The areas under the ROC curve (AUCs) were 0.501 for tPSA, 0.669 for %fPSA, 0.694 for ANN-Charité, 0.713 for nomogram I, and 0.742 for nomogram II, showing a significant advantage for nomogram II (P = 0.009) compared with %fPSA while the other model did not differ from %fPSA (P = 0.15 and P = 0.41). All models overestimated the predicted PCa probability. Conclusions. Beside ROC analysis, calibration is an important tool to determine the true value of using a model in clinical practice. The worth of multivariate models is limited when external validations were performed without knowledge of the circumstances of the models development.

Metastatic penile carcinoma - an update on the current diagnosis and treatment options.

Introduction Penile carcinoma has an incidence of 4,000 cases in Europe. The therapy and prognosis depend decisively on the lymph node status. Lymph node metastases are detected in 23–65% cases depending on the histopathological pattern. Due to improved diagnostic methods an early detection of tumor stage is possible. Multimodal therapeutic concepts can offer curability for a subset of patients, even those suffering from advanced disease. Material and methods Current data on penile cancer based on a selective review of the literature by PubMed and the EAU guidelines 2009. Results Invasive diagnostic tools, such as fine–needle biopsy (FNB) and dynamic sentinel node biopsy (DSNB), improved the diagnosis of lymph node status considerably and reduced the morbidity in specialized centers. The application of 18F–FDG–PET/CT for metastases detection needs further evaluation due to inconsistent results. Inguinal lymphadenectomy is the therapeutic standard in case of metastases proof. It was possible to reduce the complications due to the new modified operation techniques. Patients with extended lymph node and distant metastases have a poor prognosis. Different systemic polychemotherapy regimes are applied currently and are associated with poor outcome (response rates <50%) and high morbidity. Neoadjuvant chemotherapy is recommended in patients with unresectable and relapsing lymph node metastases. Conclusions Currently, inconsistent therapy regimens are applied for metastatic penile cancer. Standardization is urgently needed through the development of high–quality studies and long–term registers in order to lower the morbidity and increase the efficiency of diagnosis and therapy.

Reconstruction of the urethra with a Surgisis® onlay patch in urethral reconstructive surgery: two case reports

IntroductionWe present two case reports of patients with recurrent stricture of the urethra. We used Surgisis® for reconstruction.Case presentationIn these two case reports, we show the positive results of reconstructive surgery with Surgisis® as an alternative surgical approach to common onlay patch surgery of the urethra performed on two Caucasian patients: a 48-year-old man and a 55-year-old man.ConclusionCompared to buccal mucosa flap or foreskin graft surgeries for urethral reconstruction, reconstructive surgery with Surgisis® is considered a relevant therapeutic alternative because of the shorter operation time and the preventable surgery of the buccal cavity or foreskin.

UBC®Rapid Test for detection of carcinoma in situ for bladder cancer

UBC® Rapid Test is a test that detects fragments of cytokeratins 8 and 18 in urine. We present results of a multicentre study measuring UBC® Rapid Test in bladder cancer patients and healthy controls with focus on carcinoma in situ (CIS) and high-grade bladder cancer. From our study with N = 452 patients, we made a stratified sub-analysis for carcinoma in situ of the urinary bladder. Clinical urine samples were used from 87 patients with tumours of the urinary bladder (23 carcinoma in situ, 23 non-muscle-invasive low-grade tumours, 21 non-muscle-invasive high-grade tumours and 20 muscle-invasive high-grade tumours) and from 22 healthy controls. The cut-off value was defined at 10.0 µg/L. Urine samples were analysed by the UBC® Rapid Test point-of-care system (concile Omega 100 POC reader). Pathological levels of UBC Rapid Test in urine are higher in patients with bladder cancer in comparison to the control group (p < 0.001). Sensitivity was calculated at 86.9% for carcinoma in situ, 30.4% for non-muscle-invasive low-grade bladder cancer, 71.4% for nonmuscle-invasive high grade bladder cancer and 60% for muscle-invasive high-grade bladder cancer, and specificity was 90.9%. The area under the curve of the quantitative UBC® Rapid Test using the optimal threshold obtained by receiveroperated curve analysis was 0.75. Pathological values of UBC® Rapid Test in urine are higher in patients with high-grade bladder cancer in comparison to low-grade tumours and the healthy control group. UBC® Rapid Test has potential to be more sensitive and specific urinary protein biomarker for accurate detection of high-grade patients and could be added especially in the diagnostics for carcinoma in situ and non-muscle-invasive high-grade tumours of urinary bladder cancer.