Nierenzellkarzinom 2009 Eine Auswahl M.Staehler Urologische Klinik der LMU Direktor: Prof. Dr. C.G. SFef
Themen Nierenzellkarzinom 2009 Bevacizumab+Interferon: Phase III Daten SuniFnib: Overall- Survival Daten Pazopanib 1st +2nd line Daten Neoadjuvanz Wachstumsrate Nierentumore Langzeitdaten ParFelle Nephrektomie >4cm
Study schema Eligibility criteria Confirmed metastas4c RCC with a component of clear cell histology Karnofsky PS 70% Measurable or evaluable disease (by RECIST) No prior systemic treatment Adequate end- organ func4on No CNS metastases BP <160/90 with meds No DVT within 1 year or arterial thrombo4c event within 6 months Prior nephrectomy not requireda S T R A T I F Y R A N D O M I Z E IFNA 9 MU TIW IFNA 9 MU TIW + Bevacizumab 10 mg/kg IV q d1 and d15 PaFents straffied for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1 2 risk factors vs. 3 or more risk factors)* *Motzer R, et al. J Clin Oncol 2002;20:289 Rini, et al. Bevacizumab plus interferon- alpha versus interferon- alpha monotherapy in pafents with metastafc renal cell carcinoma: Results of overall survival for CALGB 90206. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA5019)
Kaplan- Meier overall survival by treatment arm Overall survival (probability) 1.0 0.8 0.6 0.4 0.2 IFN: Median OS 17.4 months BEV/IFN: Median OS 18.3 months Stra4fied log- rank p=0.069 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Number of pa4ents at risk IFN 363 286 221 177 148 118 98 64 37 10 1 BEV/IFN 369 314 242 190 160 139 116 94 42 17 2 Rini, et al. Bevacizumab plus interferon- alpha versus interferon- alpha monotherapy in pafents with metastafc renal cell carcinoma: Results of overall survival for CALGB 90206. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA5019)
AVOREN study design Nephrectomised pa4ents with advanced RCC (n=649) Stra4fica4on: Country MSKCC risk group IFNα + bevacizumab (n=327) IFNα + placebo (n=327) PD PD Endpoints Primary:* OS Secondary: PFS, TTP, TTF, RR, safety Treatment Bevacizumab/placebo 10 mg/kg IV q2w IFN 9 MIU sc TIW (maximum 52 weeks) Escudier, et al. Final results of the phase III, randomized, double- blind AVOREN trial of first- line bevacizumab (BEV) + interferon- α2a (IFN) in metastafc renal cell carcinoma (mrcc). J Clin Oncol 27:15s, 2009 (suppl; abstr 5020)
Probability of survival 1.0 0.8 0.6 0.4 0.2 Final Overall Survival IFN + Bevacizumab (n=327) IFN + placebo (n=322) HR=0.86 (95% CI: 0.72 1.04) p=0.1291 (stratified*) 0 21.3 23.3 0 6 12 18 24 30 36 42 Time (months) Patients at risk (n) IFN + Bevacizumab327 278 237 194 157 124 84 27 IFN + placebo 322 262 216 177 141 113 78 22 *Stratified by Motzer score and region 1 Escudier, et al. Final results of the phase III, randomized, double- blind AVOREN trial of first- line bevacizumab (BEV) + interferon- α2a (IFN) in metastafc renal cell carcinoma (mrcc). J Clin Oncol 27:15s, 2009 (suppl; abstr 5020)
OS by post-protocol therapies Median OS IFN + Bevacizumab vs IFN + Placebo (n) IFN + Bevacizumab (months) IFN + Placebo (months) HR (95% CI) Subsequent TKI* 113 vs 120 38.6 33.6 0.80 (0.56 1.13) Subsequent sunitinib 83 vs 92 43.6 39.7 0.88 (0.58 1.35) Subsequent sorafenib 60 vs 50 38.6 30.7 0.73 (0.44 1.20) *Subsequent therapy defined as any post-protocol therapy, any line (before or after PD) TKIs include sunitinib, sorafenib, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib and unspecified protein TKI Escudier, et al. Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon- 2a (IFN) in metastatic renal cell carcinoma (mrcc). J Clin Oncol 27:15s, 2009 (suppl; abstr 5020)
Bevacizumab + IFN Phase III CALGB n=732 AVOREN n=649 IFN+Bev IFN IFN+Bev IFN+Placebo ORR 25.5% 13.1% 31% 13% PFS months 8.4 4.9 10.4 5.5 OS months 18.3 17.4 23.3 21.3 / 19.8 MSKCC low 26% 26% 29% 27% MSKCC interm. 64% 64% 56% 56% MSKCC high 10% 10% 8% 9% Median Age (a) 61 62 60 61 2nd line TKI 37% 46% 34% 37% Nx 85% 85% 100% 100%
Bevacizumab + IFN Phase III CALGB Primary Endpoint OS, HR 0.76, 86% 13 17mo Secondary Endpoint PFS, ORR, Safety AVOREN OS, HR 0.76, 80% 13 17mo PFS, ORR, Safety OS p=0.069 p=0.129 PFS p<0.001 p<0.001 ORR p<0.001 p<0.001
Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA.
Overall Survival Sunitinib vs. IFN Sunitinib IFN-alpha 26.4 Monate 21.8 Monate Unstratified: HR = 0.821 (95% CI, 0.673-1.001) p =.051 Stratified: HR = 0.818 (95% CI, 0.669-0.999) p =.049 PFS Sunitinib 11 Monate PFS IFN-alpha 5 Monate p <.001 ORR Suntinib 47% ORR IFN-alpha 12% p <.001 IFN-alpha Patienten: 33% bekamen Sunitinib, 32% andere VEGF-Signaling Inhibitoren
Gesamtüberleben in Phase III 1st Line Gesamtüberlebenswahrscheinlichkeit 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Sunitinib 1 26,4 Mon. BEV + IFN (AVOREN) 2 23,2 Mon. BEV + IFN (CALGB) 3 18,3 Mon. 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Monate 1. Figlin, ASCO 2008 #5024. 2. Escudier, ASCO 2009 #5020. 3. Rini ASCO 2009 #LBA5019.
Pazopanib
Progressionsfreies Überleben Sternberg, et al. A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol 27:15s, 2009 (suppl; abstr 5021)
Overall Survival 1.0 0.8 48% of placebo patients received pazopanib after PD Proportion surviving 0.6 0.4 0.2 Hazard ratio = 0.73 95% CI (0.47, 1.12) P value = 0.02 (1-sided) Median OS Pazopanib: 21.1 months Placebo: 18.7 months 0.0 0 5 10 15 20 25 Patients at risk Months Pazopanib 290 254 214 115 20 1 Placebo 145 115 93 52 6 O Brien-Fleming boundary for futility / superiority: P=0.201 / 0.004 (1-sided) Sternberg, et al. A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol 27:15s, 2009 (suppl; abstr 5021)
Evidenz Neoadjuvanz Autor n Therapie Indika4on Therapie- dauer Schuch, BJUI 2008 Karakiewicz, Europ Urol 2008 Di Silverio, Urol Int 2008 Thomas, J Urol 2009 Jonasch, JCO 2009 Effekt 4 SuniFnib mrcc 2- x Zyklen Shrinkage n.a. 1 SuniFnib ct3b 6 Zyklen Shrinkage Cavazapen 1 SuniFnib ct3b 4 Zyklen Shrinkage Nekrose 19 SuniFnib mrcc 2- x Zyklen 16% PR 53% PD OS n.a. n.a. n.a. 50 Bevacizumab mrcc 2- x Zyklen 92% OP 24.5 Monate
Wachstum des Nierenzellkarzinoms Bekannte Daten nur bei älteren PaFenten Die natürliche Wachstumsrate unbehandelter kleiner Nierentumore (<4cm) beträgt 0.1-0.7cm/Jahr Die Wachstumsrate großer Nierentumore ist unbekannt. Wir untersuchten im eigenen PaFentengut die Wachstumsrate großer Nierentumoren (>4cm). Staehler et al, BJU Int, 2009
Ergebnisse Result Male/Female 5/4 Median age, years 65.2 (range 29.2 74.2) Median inifal tumor size, cm 2.0 (range 0.0 8.0) Median tumor size at surgery, cm 7.5 (range 5.5 18.0) Median tumor growth rate, cm/year 6.41 (range 2.47 8.66) Median inifal volume, cm³ 4.2 (range 0-270) Median volume at surgery, cm³ 220.9 cm³ (range 87.1 3053.4) Median follow- up months 14.6 (range 6.5 58.4) Staehler et al, BJU Int, 2009
Wachstum ist unabhängig von der initialen Tumorgröße Staehler et al, BJU Int, 2009 p=0.64
Ergebnisse Miulere Größe 56.3 mm (range 41 to 100) Median followup 70.7 months 17 % R1 MulFvariate Analyse: Stage und Fuhrman grade Clinical Progression Free Survival 5- Jahres- Rate 10 Jahres- Rate 92% 88% Overall Survival 82% 77% Cancer Specific Survival 81% 78%
Overall Survival
Outcome of nephron- sparing surgery for T1b renal cell carcinoma Steven Joniau, Kathy Vander Eeckt, Shalom J. Srirangam and Hein Van Poppel Department of Urology, University Hospitals Leuven, Leuven, Belgium Correspondence to Shalom J. Srirangam, Department of Urology, Royal Blackburn Hospital, Blackburn BB2 3HH, UK.
Ergebnisse Medianes Follow- up 40.1 (1-98.3) Monate 6% R1 10% Rezdiv davon 4% Lokalrezidiv 10% entwickelten Niereninsuffizienz Keine Änderung des KreaFninwertes durch OP 5- Jahres- Rate Clinical Progression Free Survival 84% Overall Survival 72% Cancer Specific Survival 99%
Zusammenfassung Bevacizumab+Interferon, SuniFnib Nephrektomie verlängert Überleben PFS signifikant; OS von subsequenter Therapie abhängig Pazopanib 1st +2nd line Daten PFS signifikant, OS n.a., in USA zugelassen, bei uns aktuell in Studien Neoadjuvanz Operable PaFenten operieren, Benefit fraglich Wachstumsrate Nierentumore Bei jüngeren Pat. oder Tumoren > 2cm kein watchful waifng Langzeitdaten ParFelle Nephrektomie >4cm IndikaFon zum Nierenerhalt unabhängig von Tumorgröße
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