Steffen F. Krause

Quadrimodal treatment of high-risk T1 and T2 bladder cancer: Transurethral tumor resection followed by concurrent radiochemotherapy and regional deep hyperthermia

BACKGROUND AND PURPOSE To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT). MATERIAL AND METHODS Between 2003 and 2007, 45 patients were enrolled. After TUR-BT patients received radiotherapy (RT) of the bladder and regional lymph nodes with 50.4 Gy, and a boost to the bladder of 5.4-9 Gy. RCT was applied to 43/45 patients. RHT was administered once weekly. Response was re-evaluated 6 weeks after RT by restaging-TUR. Toxicity was graded with the CTCAE, version 3.0. QoL was evaluated by a dedicated questionnaire. RESULTS The median follow-up was 34 months (range 12-60). The median number of hyperthermia treatments was 5 (range 1-7). Acute toxicity grades 3 and 4 occurred in 20% (9/45) and 9% (4/45), respectively. Late toxicity grades 3/4 were seen in 24% (11/45). Complete response rate was 96% (43/45). Local recurrence-free survival was 85%, overall survival was 80%, disease-specific survival was 88%, metastasis-free survival was 89%, and the bladder-preserving rate was 96% (43/45) at 3 years. Eighty percent (24/30) were at least mostly satisfied with their bladder function. CONCLUSIONS The quadrimodal treatment was feasible and well tolerated. Local control and bladder-preserving rates were encouraging.

SURVIVIN EXPRESSION AS A PREDICTIVE MARKER FOR LOCAL CONTROL IN PATIENTS WITH HIGH-RISK T1 BLADDER CANCER TREATED WITH TRANSURETHRAL RESECTION AND RADIOCHEMOTHERAPY

PURPOSE The objectives of this study were to investigate the expression of survivin in tumor samples from patients with high-risk T1 bladder cancer and to correlate its expression with clinicopathologic features as well as clinical outcomes after initial transurethral resection (TURBT) followed by radiotherapy (RT) or radiochemotherapy (RCT). METHODS AND MATERIALS Survivin protein expression was evaluated by immunohistochemistry on tumor specimen (n = 48) from the initial TURBT, and was correlated with clinical and histopathologic characteristics as well as with 5-year rates of local failure, tumor progression, and death from urothelial cancer after primary bladder sparring treatment with RT/RCT. RESULTS Survivin was not expressed in normal bladder urothelium but was overexpressed in 67% of T1 tumors. No association between survivin expression and clinicopathologic factors (age, gender, grading, multifocality, associated carcinoma in situ) could be shown. With a median follow-up of 27 months (range, 3-140 months), elevated survivin expression was significantly associated with an increased probability of local failure after TURBT and RCT/RT (p = 0.003). There was also a clear trend toward a higher risk of tumor progression (p = 0.07) and lower disease-specific survival (p = 0.10). CONCLUSIONS High survivin expression is a marker of tumor aggressiveness and may help to identify a subgroup of patients with T1 bladder cancer at a high risk for recurrence when treated with primary organ-sparing approaches such as TURBT and RCT.

Examination of Tumorigenesis of Precursor Lesions in Bladder Cancer by in situ Hybridization

Through examinations using fluorescence in situ hybridization (FISH) of chromosomes 1 and 9, we tried to obtain more information on dysplasia and carcinoma in situ (Cis) in relation to the oncogenesis of bladder cancer. 63 paraffin sections (dysplasia grades I–III and Cis) were evaluated, and 8 negative sections functioned as a control group. For FISH, DNA samples of CEP 1 and 9 (α satellites) were chosen. Gains (aneuploidy) or losses (monosomy) of chromosomal material were determined microscopically. Dysplasia grades I–III showed a 5–18% aberration in chromosome 1 aneuploidy and a 19–29% aberration in monosomy 9. Cis revealed 27% aneuploidy of chromosomes 1 and 9. Although at present dysplasia grade III and Cis of the bladder are viewed as histopathologically identical, we examined both molecular genetic differences in chromosome 9. As referred to in the literature we found the same genetic aberrations for dysplasias (grades I–III) and noninvasive papillary bladder tumors as well as for Cis and solid invasive bladder cancer.

Bladder cancer - the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register clinicaltrials.gov

BackgroundUro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade.MethodsWe searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95% confidence intervals, and a p value <0.05 was considered statistically significant.ResultsThe number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85% of these studies are focusing on prostatic (45%) and kidney neoplasms (40%), whereas only 11% were registered for bladder cancers.ConclusionsWhile the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported.

Treatment Options for High-Risk T1 Bladder Cancer

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.

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.

Treatment options for high-risk T1 bladder cancer: status quo and future perspectives of radiochemotherapy.

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.

Multimodal therapy for bladder sparing with high grade bladder tumors

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.

Treatment Options for High-Risk T1 Bladder Cancer@@@Behandlungsoptionen für T1-Harnblasenkarzinome mit hohem Risiko. Aktueller Stand und Zukunftsperspektiven der Radiochemotherapie: Status Quo and Future Perspectives of Radiochemotherapy

Purpose:To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT).Material and Methods:A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed.Results:First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guérin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series.Conclusion:Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.Ziel:Dieser Artikel gibt eine Übersicht über die Standards und neuen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms mit Schwerpunkt auf der Rolle der Radiotherapie (RT) bzw. Radiochemotherapie (RCT).Material und Methodik:Es wurde eine systematische Literatursuche hinsichtlich der aktuellen Entwicklungen in der Diagnostik und Therapie des oberflächlichen „high-risk“-Harnblasenkarzinoms durchgeführt.Ergebnisse:Die Einführung der fluoreszenzgestützten transurethralen Resektion (TUR) und eine anschließende zweite TUR erhöhen die Diagnosesicherheit und verbessern die Ergebnisse. Zusätzlich kann eine postoperative Chemoinstillation nach der ersten TUR die Rezidivrate um 40% senken. Als Adjuvans zeigt die Bacillus-Calmette-Guérin-(BCG-)Instillation die besten Resultate. Die sofortige Zystektomie soll daher ausgewählten Patienten vorbehalten bleiben. Eine Phase-III-Studie für T1G3-Tumoren, welche die RT mit konservativen Behandlungsstrategien verglich, erbrachte keinen Vorteil für die RT. Daten einer Studie aus Erlangen, in der 80% der Patienten mit „high-risk“-T1-Tumoren eine RCT erhielten, sind mit den besten BCG-Serien vergleichbar.Schlussfolgerung:Die Entscheidung zwischen einem primär organerhaltenden Therapieansatz und einer frühzeitigen Zystektomie bleibt schwierig. Die alleinige RT zeigt sich im randomisierten Vergleich den Instillationstherapien nicht überlegen. Die Daten zur RCT sind vielversprechend und rechtfertigen diese Therapie als Alternative zur intravesikalen Therapie bzw. frühen Zystektomie.