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Vergleich der Effektivität der Langzeitinstillation mit Mitomycin C gegen Kurzzeitprophylaxen mit MMC oder Bacillus Calmette-Guerin

Untersuchung bei Patienten mit nicht muskelinvasivem Urothelkarzinom der Harnblase

Comparison of the effectiveness between long-term instillation of mitomycin C and short-term prophylaxis with MMC or bacille Calmette-Guérin

Study of patients with non-muscle-invasive urothelial cancer of the urinary bladder

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Zusammenfassung

Hintergrund

Die adjuvante Instillationstherapie mit Chemo- bzw. Immuntherapeutika ist integraler Bestandteil in der Behandlung nicht muskelinvasiver Blasenkarzinome. In der Auswahl des Medikaments sowie in der optimalen Therapiedauer der Anwendung besteht allerdings kein genereller Konsens. Inhalt dieser multizentrischen Studie war der Vergleich einer Langzeittherapie mit Mitomycin C (MMC) mit 2 Kurzzeittherapien mit MMC oder Bacillus Calmette-Guerin (BCG) beim intermediären/Hochrisiko- (Intermediate-/High-risk-)Blasentumor nach transurethraler Resektion (TUR-B). Bei Patienten mit Niedrigrisiko- (Low-risk-)Blasentumoren wurde die Effektivität 6-wöchentlicher MMC-Instillationen ermittelt, sowie mit den jeweiligen Ergebnissen bei Patienten ohne adjuvante Behandlung verglichen.

Material und Methoden

Bei 495 Patienten mit Intermediate-/High-risk-Blasentumoren (Rezidiv und/oder multifokales pTaG1, pTaG2-3 oder pT1G1-3) wurde randomisiert entweder BCG RIVM 2x108 CFU 6-mal wöchentlich, MMC 20 mg 6-mal wöchentlich oder MMC 20 mg 6-mal wöchentlich mit anschließenden monatlichen Instillationen über 3 Jahre verabreicht. 132 Low-risk-Patienten (Erstdiagnose eines unifokalen pTaG1-Blasentumors) wurden in 2 Arme randomisiert. Im 1. Arm wurden 20 mg MMC 6-mal wöchentlich instilliert. Im Kontrollarm erhielten die Patienten keine adjuvante Therapie.

Ergebnisse

Bei den Patienten der Intermediate-/High-risk-Gruppe betrug die 3-Jahres-Rezidivfreiheit im BCG-Arm 65,5% (95%-KI=55,9–73,5%) und im MMC-Kurzzeitarm 68,6% (95%-KI=59,9–75,7%). Im MMC-Langzeitarm war die 3-Jahres-Rezidivfreiheit mit 86,1% (95%-KI=77,9–91,4%) signifikant erhöht (Log-Rank-Test, p=0,001). Bei der MMC-Langzeitgabe trat keine erhöhte Toxizität auf. In der Low-risk-Gruppe betrug die 3-Jahres-Rezidivfreiheit nach adjuvanter Therapie 74% (95%-KI=60,0–83,8%), bei den Patienten ohne Adjuvans 63% (95%-KI=46,6–75,5%), entsprechend einer Hazard-Ratio von 0,58 (95%-KI=0,28–1,18%). Der Unterschied in den Behandlungsarmen war nicht signifikant.

Schlussfolgerung

Die Langzeitprophylaxe mit MMC führt bei Intermediate-/High-risk-Blasenkarzinomen zu einer signifikant verringerten Rezidivrate bei vergleichbarem Toxizitätsprofil im Vergleich zu Kurzzeit-MMC- bzw. Kurzzeit-BCG. Bei Low-risk-Tumoren zeigte sich in unserer Studie keine signifikante Senkung der Rezidivrate durch 6 adjuvante MMC-Instillationen. Diese Behandlung stellt somit keine Alternative zur Frühinstillation dar.

Abstract

Background

Adjuvant instillation therapy with chemo- or immunotherapeutic agents is an integral component in the treatment of non-muscle-invasive bladder cancer. There is, however, no general consensus on the choice of medication and the optimal duration of therapy. This multicenter trial compared a long-term treatment regimen with mitomycin C (MMC) with two short-term treatment approaches with MMC or bacille Calmette-Guérin (BCG) for intermediate-/high-risk bladder tumor after transurethral resection. In patients with low-risk bladder tumors, the effectiveness of six weekly MMC instillations was determined and compared with the results of patients not receiving adjuvant treatment.

Material and methods

A total of 495 patients with intermediate-/high-risk bladder tumor (recurrent and/or multifocal pTaG1, pTaG2-3, or pT1G1-3) were randomly administered either BCG-RIVM 2×108 CFU in six weekly instillations, MMC 20 mg in six weekly instillations, or MMC 20 mg in six weekly instillations with subsequent monthly instillations for 3 years. A total of 132 low-risk patients (first diagnosis of a unifocal pTaG1 bladder tumor) were randomly allocated to two treatment arms. In the first arm, 20 mg MMC were instilled weekly six times. In the control arm, the patients received no adjuvant therapy.

Results

The 3-year recurrence-free rate in the patients of the intermediate-/high-risk group was 65.5% (95% CI: 55.9–73.5%) in the BCG arm and 68.6% (95% CI: 59.9–75.7%) in the MMC short-term arm. In the MMC long-term arm, the 3-year recurrence-free rate was significantly higher at 86.1% (95% CI: 77.9–91.4%, log-rank test: p=0.001). There was no increased toxicity observed with long-term administration of MMC. In the low-risk group, the 3-year recurrence-free rate after adjuvant therapy was 74% (95% CI: 60.0–83.8%) and in the patients receiving no adjuvant treatment 63% (95% CI: 46.6–75.5%, corresponding to a hazard ratio of 0.58 (95% CI: 0.28–1.18%). The difference between the treatment arms was not significant.

Conclusion

Long-term prophylaxis with MMC results in a significantly reduced recurrence rate in intermediate-/high-risk bladder cancer with a comparable toxicity profile in comparison to short-term MMC or short-term BCG. Our study showed no significant decrease of the recurrence rate in low-risk tumors with six adjuvant MMC instillations. This treatment approach thus does not represent an alternative to early instillation.

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Authors and Affiliations

  1. Abteilung für Urologie, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland

    H. Isbarn, L. Budäus, S. Conrad, H. Huland & M.G. Friedrich

  2. Medac GmbH, Wedel, Deutschland

    U. Pichlmeier

  3. Abteilung für Urologie, Friederikenstift, Hannover, Deutschland

    S. Conrad

  4. Klinik für Urologie und Kinderurologie, Klinikum, Krefeld, Deutschland

    M.G. Friedrich

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  1. H. Isbarn
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Isbarn, H., Budäus, L., Pichlmeier, U. et al. Vergleich der Effektivität der Langzeitinstillation mit Mitomycin C gegen Kurzzeitprophylaxen mit MMC oder Bacillus Calmette-Guerin. Urologe 47, 608–615 (2008). https://doi.org/10.1007/s00120-008-1671-z

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