Susanne Krege

An Individual Patient Data Meta-Analysis of the Long-Term Outcome of Randomised Studies Comparing Intravesical Mitomycin C versus Bacillus Calmette-Guérin for Non–Muscle-Invasive Bladder Cancer

BACKGROUND Patients with non-muscle-invasive bladder cancer with an intermediate or high risk need adjuvant intravesical therapy after surgery. Based largely on meta-analyses of previously published results, guidelines recommend using either bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) in these patients. Individual patient data (IPD) meta-analyses, however, are the gold standard. OBJECTIVE To compare the efficacy of BCG and MMC based on an IPD meta-analysis of randomised trials. DESIGN, SETTING, AND PARTICIPANTS Trials were searched through Medline and review articles. The relevant trial investigators were contacted to provide IPD. MEASUREMENTS The drugs were compared with respect to time to recurrence, progression, and overall and cancer-specific death. RESULTS AND LIMITATIONS Nine trials that included 2820 patients were identified, and IPD were obtained from all of them. Patient characteristics were 71% primary, 54% Ta, 43% T1, 25% G1, 58% G2, and 16% G3, and 7% had prior intravesical chemotherapy. Based on a median follow-up of 4.4 yr, 43% recurred. Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), while there was a 28% risk increase (p=0.006) for BCG in the trials without maintenance. BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy. In the subset of 1880 patients for whom data on progression, survival, and cause of death were available, 12% progressed and 24% died, and, of those, 30% of the deaths were due to bladder cancer. No statistically significant differences were found for these long-term end points. CONCLUSIONS For prophylaxis of recurrence, maintenance BCG is required to demonstrate superiority to MMC. Prior intravesical chemotherapy was not a confounder. There were no statistically significant differences regarding progression, overall survival, and cancer-specific survival between the two treatments.

Risk Factors for Relapse in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors: Results of the German Testicular Cancer Study Group Trial

PURPOSE To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

M3 muscarinic receptors mediate contraction of human urinary bladder

Since muscarinic receptors appear to be the physiologically most important control system for urinary bladder contraction, we have characterized the receptor subtype mediating contraction in response to the muscarinic agonist carbachol in the human bladder. Experiments were based on four antagonists, the non‐selective atropine, the M1‐selective pirenzepine, the M2‐selective methoctramine and the M3‐selective darifenacin. All antagonists yielded Schild‐plots with a slope close to unity. The order of potency (atropinedarifenacin>pirenzepine>methoctramine) as well as the estimated antagonist affinities suggested that contraction of the human bladder occurs predominantly if not exclusively via the M3 receptor.

[18F]Fluorodeoxyglucose Positron Emission Tomography in Nonseminomatous Germ Cell Tumors After Chemotherapy: The German Multicenter Positron Emission Tomography Study Group

PURPOSE In patients with metastatic nonseminomatous germ cell cancer (NSGCT), residual masses after chemotherapy (CTX) can consist of vital carcinoma, mature teratoma, or necrosis. This prospective trial has evaluated the accuracy of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the prediction of histology compared with computed tomography (CT) and serum tumor markers (STM). PATIENTS AND METHODS A total of 121 patients with stage IIC or III NSGCT scheduled for secondary resection after cisplatin-based CTX were included. FDG-PET was performed after completion of CTX. All results were confirmed by histopathology and correlated to STM and CT. RESULTS Prediction of tumor viability with FDG-PET was correct in 56%, which did not reach the expected clinically relevant level of 70%, and was not better than the accuracy of CT (55%) or STM (56%). Sensitivity and specificity of FDG-PET were 70% and 48%. The positive predictive values were not significantly different (55%, 61%, and 59% for CT, STM, and PET, respectively). Judging only vital carcinoma as a true malignant finding, the negative predictive value increased to 83% for FDG-PET. CONCLUSION The presence of vital carcinoma and mature teratoma is common (55%) in residual masses in patients with NSGCT, and CT and STM cannot reliably predict absence of disease. In contrast to prior studies, this prospective trial, which is the only with histologic confirmation in all patients, demonstrated that FDG-PET is unable to give a clear additional clinical benefit to the standard diagnostic procedures, CT and STM, in the prediction of tumor viability in residual masses.

Surgery for Metastatic Urothelial Carcinoma with Curative Intent: The German Experience (AUO AB 30/05)

BACKGROUND Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany. DESIGN, SETTING, AND PARTICIPANTS Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008. INTERVENTION Resected metastatic sites were the following: retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery. MEASUREMENTS Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM. RESULTS AND LIMITATIONS Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number. CONCLUSIONS Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.

DOCETAXEL AND IFOSFAMIDE AS SECOND LINE TREATMENT FOR PATIENTS WITH ADVANCED OR METASTATIC UROTHELIAL CANCER AFTER FAILURE OF PLATINUM CHEMOTHERAPY: A PHASE 2 STUDY

PURPOSE This phase 2 trial was designed to assess the efficacy and safety of combination chemotherapy with docetaxel and ifosfamide in previously treated patients with advanced urothelial cancer. MATERIALS AND METHODS Enrolled in our study were 22 patients with advanced urothelial cancer who failed to respond or had relapse after previous platinum based chemotherapy. Treatment consisted of 60 mg./m.2 docetaxel given during 1 hour and 2.5 gm./m.2 ifosfamide given for 24 hours every 3 weeks with 500 mg. mesna administered intravenously at the start of the ifosfamide infusion, and 4 and 8 hours later. Patients also received premedication with oral dexamethasone. RESULTS The objective response rate in 20 evaluable patients was 25%, including 4 complete responses (20%) associated with lymph node only recurrence. Disease was stable in 5 cases. At followup 16 patients had died 1 to 11 months (median 4) after the initiation of treatment, while 6 remained alive at 4 to 14 months, including 3 who were continuously disease-free. Treatment was well tolerated. Grades 3 and 4 leukopenia developed in 17% and 4% of the cycles, respectively. Neutropenic sepsis and grade 4 thrombocytopenia developed in 1 case each. Nausea and vomiting were mild to moderate. Other nonhematological toxicities included a hypersensitivity reaction in 1 patient and paresthesias in 2. CONCLUSIONS The combination of docetaxel and ifosfamide is active in previously treated patients with urothelial cancer, although it appears to be a reasonable treatment option only in those with lymph node dominant recurrence. The mild toxicity underlines the usefulness of the regimen in this setting. Further investigation of the combination in previously untreated patients seems warranted.

Does gender or age affect the efficacy and safety of tolterodine

PURPOSE We compared the importance of patient age and gender relative to the intensity of baseline symptoms of overactive bladder in the therapeutic response to the muscarinic receptor antagonist tolterodine. MATERIALS AND METHODS Data from an open label, observational study of 2,250 patients with overactive bladder treated for 12 weeks with tolterodine were analyzed for alterations in frequency, urgency and urge incontinence, and for global efficacy and tolerability using logistic regression analysis, stratifying for gender, age, baseline symptom intensity and tolterodine dose. RESULTS Gender or tolterodine dose were not consistently associated with altered treatment efficacy. Greater age was associated with a slight but statistically significant decrease in treatment efficacy. Patients with great baseline symptom intensity had greater treatment associated improvement but a lesser chance to become symptom-free. Even with a large number of patients no statistically significant gender or age associated alterations in the tolerability of tolterodine treatment were detected. CONCLUSIONS The extent of the therapeutic response to tolterodine is largely determined by the extent of baseline symptoms. While gender does not affect the efficacy or tolerability of tolterodine in a clinically relevant manner, advanced age is associated with a slight decrease in efficacy but not in tolerability.

Saw palmetto extracts potently and noncompetitively inhibit human α1-adrenoceptors in vitro

We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have α1‐adrenoceptor antagonistic properties in vitro.

The Role of Positron Emission Tomography in the Evaluation of Residual Masses After Chemotherapy for Advanced Stage Seminoma

PURPOSE Treatment in patients with seminoma who have residual or recurrent masses following chemotherapy is still a matter of debate. Surgical resection is currently the most common recommendation for masses greater than 3 cm, resulting in overtreatment in up to 70% of those affected. We analyzed the accuracy of preoperative positron emission tomography for predicting viable tumor residuals in patients with seminoma. MATERIALS AND METHODS In a prospective, multicenter trial computerized tomography and FDG (2-(F-18)-fluoro-2-deoxy-D-glucose) positron emission tomography were performed before surgical resection for residual or recurrent masses in 20 patients who had undergone chemotherapy for stage IIb, IIc or III seminoma. Histopathological findings were directly correlated with positron emission tomography results. RESULTS Of the patients 18 presented with residual masses and 2 had recurrent masses following chemotherapy. Histopathological assessment revealed viable tumor in 3 patients and benign lesions in 17. All patients with viable tumor were identified correctly by positron emission tomography. No false-negative results were observed but 9 patients had false-positive positron emission tomography results. This resulted in a negative predictive value of 1 (95% CI 0.63-1) and a positive predictive value of 0.25 (95% CI 0.05-0.57) for FDG-positron emission tomography in our patient cohort. CONCLUSIONS Our data indicate that FDG-positron emission tomography is capable of excluding viable disease in residual masses, even those exceeding 3 cm. Therefore, it may be considered an additional tool to improve patient counseling. However, the decision to perform surgical resection of the residual mass should not be based exclusively on a positive positron emission tomography image since false-positive results appear to be common.

Phase II study : Adjuvant single-agent carboplatin Therapy for clinical stage I seminoma

OBJECTIVE Though para-aortal and ipsilateral iliacal radiation is the established adjuvant treatment for clinical stage I seminoma, promising results have been reported on adjuvant single-agent carboplatin therapy. PATIENTS AND METHODS We treated 43 patients with clinical stage I seminoma according to this option. They received 2 courses of single-agent carboplatin (400 mg/m2) at an intervall of 3 weeks. Therapy could be performed on an outpatient basis within 2 h. RESULTS Therapy was well tolerated. Apart from minor gastrointestinal disorders and mild myelosuppression, no adverse reactions were observed. The median follow-up is 28 months. Up to now no recurrences have been noted. CONCLUSIONS If the recurrence rate remains as low as after adjuvant radiotherapy, which should be proved in a phase III study, single-agent carboplatin therapy will be an alternative adjuvant approach for clinical stage I seminoma.