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Aktuelle Urol 2019; 50(S 01): s1-s10
DOI: 10.1055/a-0972-0914
Übersicht

Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms

Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma
Kurt Miller
1   Charité – Universitätsmedizin Berlin, Urologie, Berlin
,
Lothar Bergmann
2   Ambulantes Krebszentrum Schaubstraße (AKS), Frankfurt
,
Christian Doehn
3   Urologikum Lübeck
,
Jürgen E. Gschwend
4   Klinikum rechts der Isar, Technische Universität München, Urologische Klinik und Poliklinik, München
,
Markus A. Kuczyk
5   Medizinische Hochschule Hannover, Klinik für Urologie und Urologische Onkologie, Hannover
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Zusammenfassung

Die Prognose von Patienten mit metastasiertem Nierenzellkarzinom (mRCC) hat sich dank neuer Therapien deutlich verbessert. Überlebenszeiten von mehr als zwei Jahren sind realistisch. Immuntherapien mit Checkpoint-Inhibitoren haben das Therapiespektrum in der Erst- und Zweitlinientherapie erweitert.

Sunitinib, Pazopanib, Tivozanib und die Kombination Bevacizumab + Interferon-alpha sind unabhängig vom Risikoscore für die Erstlinientherapie beim mRCC zugelassen. Für die Kombination Nivolumab + Ipilimumab sowie für Cabozantinib ist die Zulassung jeweils auf Patienten mit intermediärem und hohem Progressionsrisiko beschränkt. Die Immuntherapie war bez. des Gesamtüberlebens in dieser Subgruppe signifikant wirksamer als Sunitinib. Temsirolimus ist nur für Hochrisikopatienten zugelassen.

Sunitinib und Pazopanib haben eine Zulassung auch für die Zweitlinientherapie – bei Pazopanib gilt diese für den Einsatz nach Zytokinen. Für Nivolumab und Cabozantinib wurde in der Zweitlinientherapie ein signifikanter Überlebensvorteil gegenüber Everolimus gezeigt. Die Kombination Lenvatinib + Everolimus sowie Axitinib sind weitere für die Zweitlinie zugelassene Substanzen. Everolimus als Monotherapie ist durch die neuen Optionen in der Zweitlinie abgelöst worden.

Bei zunehmender Anzahl verfügbarer Therapien ist die Frage nach der optimalen Sequenztherapie weiterhin offen.

Ziel eines interdisziplinären RCC-Expertengesprächs war es, gemeinsame Therapieempfehlungen auf Basis der aktuell publizierten Daten und der eigenen klinischen Erfahrung für den Praxisalltag abzuleiten. Die Ergebnisse werden in dieser Publikation vorgestellt.

Abstract

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma has improved significantly. A median overall survival of more than two years is a realistic goal. Immunotherapies with checkpoint inhibitors are new first-line and second-line options.

Sunitinib, Pazopanib, Tivozanib and the combination of Bevacizumab + interferon alpha are approved for first-line therapy, regardless of the progression risk score. The use of both the combination Nivolumab + Ipilimumab and Cabozantinib is limited to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with Sunitinib. Temsirolimus is only approved for high-risk patients.

Sunitinib and Pazopanib can also be used as second-line options, with the use of Pazopanib being limited to the event of cytokine failure. Nivolumab and Cabozantinib demonstrated superior overall survival compared to Everolimus. Furthermore, the combination of Lenvatinib + Everolimus and Axitinib are approved treatment options in second-line and further settings. Everolimus monotherapy has been replaced by the new options.

The question regarding the optimal sequence of treatments is still unanswered.

An interdisciplinary expert meeting aimed to discuss the criteria that should be used for therapy. The members discussed several aspects of treating patients with RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented here.

Schlüsselwörter

Nierenzellkarzinom - Nephrektomie - Metastasen - Medikamentöse Therapie - Immuntherapie

Keywords

renal cell cancer - metastases - medical treatment - immunotherapy


Publication History

Article published online:
04 September 2019

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • Literatur

  • 1 Robert Koch-Institut. Krebs in Deutschland für 2013/2014. Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg.). 11. Ausgabe, Berlin 2017
    PubMedGoogle Scholar
  • 2 Corgna E. et al. Renal cancer. Crit Rev Oncol Hemat 2007; 64: 247-262
    CrossrefPubMedGoogle Scholar
  • 3 Motzer RJ. et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590
    CrossrefPubMedGoogle Scholar
  • 4 Sternberg CN. et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update. Eur J Cancer 2013; 49: 1287-1296
    CrossrefPubMedGoogle Scholar
  • 5 Escudier B. et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010; 28: 2144-2150
    CrossrefPubMedGoogle Scholar
  • 6 Motzer RJ. et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378: 1277-1290
    CrossrefPubMedGoogle Scholar
  • 7 Motzer RJ. et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1803-1813
    CrossrefPubMedGoogle Scholar
  • 8 Choueiri TK. et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial. J Clin Oncol 2017; 35: 591-597
    PubMedGoogle Scholar
  • 9 Motzer RJ. et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 2013; 31: 3791-3799
    CrossrefPubMedGoogle Scholar
  • 10 Choueiri TK. et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1814-1823
    CrossrefPubMedGoogle Scholar
  • 11 Motzer R. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; 16: 1473-1482
    CrossrefPubMedGoogle Scholar
  • 12 Ljungberg B. et al. EAU Guideline Renal Cell Carcinoma. 2018 http://uroweb.org/guideline/renal-cell-carcinoma (Abruf: 4.2.2019)
    PubMedGoogle Scholar
  • 13 Escudier B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019; DOI: 10.1093/annonc/mdz056. [Epub ahead of print]
    CrossrefPubMedGoogle Scholar
  • 14 NCCN Guidelines® . Version 2.2019 – September 17, 2018; https://www.nccn.org/professionals/physician_gls/default.aspx#site (Abruf: 4.2.2019)
    PubMedGoogle Scholar
  • 15 Bergman L. et al. Onkipedia-Leitlinie Nierenzellkarzinom (Hypernephrom). Stand: Januar 2018
    PubMedGoogle Scholar
  • 16 Heng DY. et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27: 5794-5799
    CrossrefPubMedGoogle Scholar
  • 17 Moch H. et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol 2016; 70: 93-105
    CrossrefPubMedGoogle Scholar
  • 18 Motzer RJ. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma (mRCC): updated efficacy and safety results and further analysis of prognostic factors. New Engl J Med 2007; 356: 115-124
    CrossrefPubMedGoogle Scholar
  • 19 Hudes G. et al. Temsirolimus, Interferon alfa, or both for advanced renal-cell carcinoma. New Engl J Med 2007; 356: 2271-2281
    CrossrefPubMedGoogle Scholar
  • 20 Sternberg CN. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28: 061061-061068
    CrossrefPubMedGoogle Scholar
  • 21 Bergmann L. et al. A Prospective Randomized Phase-II Trial with Temsirolimus vs. Sunitinib in non-clear Renal Cell Carcinoma. A Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and Interdisciplinary Renal Cell Carcinoma Group of the German Cancer Society (IAGN). ECCO. 2015 abstract #2617
    PubMedGoogle Scholar
  • 22 Escudier B. et al. Open-label, phase II raptor study of everolimus (EVE) for papillary mRCC: Efficacy in type 1 and type 2 histology. Eur J Cancer 2016; 69: 226-235
    PubMedGoogle Scholar
  • 23 Armstrong AJ. et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016; 17: 378-388
    CrossrefPubMedGoogle Scholar
  • 24 Tannir NM. et al. Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. Eur Urol 2016; 69: 866-874
    CrossrefPubMedGoogle Scholar
  • 25 Bex A. et al. Comparing Everolimus to Sunitinib in Non-clear-cell Renal Cell Carcinoma. Eur Urol 2016; 69: 875-876
    CrossrefPubMedGoogle Scholar
  • 26 Ciccarese C. et al. Addressing the best treatment for non-clear cell renal cell carcinoma: A meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies. Eur J Cancer 2017; 83: 237-246
    CrossrefPubMedGoogle Scholar
  • 27 Rimar KJ. et al. Anti-programmed Death Receptor 1 Blockade Induces Clinical Response in a Patient With Metastatic Collecting Duct Carcinoma. Clin Genitourin Cancer 2016; 14: e431-434
    CrossrefPubMedGoogle Scholar
  • 28 Rouvinov K. et al. Rapid Response to Nivolumab in a Patient With Sarcomatoid Transformation of Chromophobe Renal Cell Carcinoma. Clin Genitourin Cancer 2017; DOI: 10.1016/j.clgc.2017.05.028.
    CrossrefPubMedGoogle Scholar
  • 29 Adrianzen Herrera DA. et al. Impressive and durable response to nivolumab in a patient with metastatic type 2 papillary renal cell carcinoma: On-label but without evidence. Invest New Drugs 2017; 35: 665-668
    CrossrefPubMedGoogle Scholar
  • 30 Rexer H. et al. Nivolumab combined with ipilimumab versus sunitinib monotherapy-SUNNIFORECAST AN 41/16 of the AUO: A phase 2, randomized, open-label study in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma. Urologe A 2017; 56: 802-803
    PubMedGoogle Scholar
  • 31 Vera-Badillo FE. et al. Systemic Therapy for Non-clear Cell Renal Cell Carcinomas: A Systematic Review and Meta-analysis. Eur Urol 2015; 67: 740-749
    CrossrefPubMedGoogle Scholar
  • 32 Haas NB. et al. ECOG 1808: Randomized phase II trial of sunitinib with or without gemcitabine in advanced kidney cancer with sarcomatoid features. J Clin Oncol 2016; 34: 4511 (suppl; abstr)
    CrossrefPubMedGoogle Scholar
  • 33 Motzer RJ. et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology 2018; 36: 578 , ASCO GU Abstract 578
    PubMedGoogle Scholar
  • 34 Ahrens M. et al. Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options. Oncol Res Treat 2019; DOI: 10.1159/000495366. [Epub ahead of print]
    CrossrefPubMedGoogle Scholar
  • 35 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF). Diagnostik, Therapie und Nachsorge des Nierenzellkarzinoms. , Langversion 1.2,2017, AWMF Registernummer: 043/017OL, http://leitlinienprogramm-onkologie.de/Nierenzellkarzinom.85.0.html (abgerufen am: 6.2.2019)
    PubMedGoogle Scholar
  • 36 Escudier B. et al. Treatment selection in metastatic renal cell carcinoma: expert consensus. Nat Rev Clin Oncol 2012; 9: 327-337
    CrossrefPubMedGoogle Scholar
  • 37 Bergmann L. et al. Treatment algorithm for metastatic renal cell carcinoma--recommendations based on evidence and clinical practice. In Oncol Res Treat, Edition Netherlands 2014; 136-141
    CrossrefPubMedGoogle Scholar
  • 38 Fachinformation Opdivo® . Stand: Januar 2019
    PubMedGoogle Scholar
  • 39 Choueiri TK. et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial. J Clin Oncol 2017; 35: 591-597
    CrossrefPubMedGoogle Scholar
  • 40 Lee JL. et al. Randomized phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type Renal cell carcinoma: RESTORE trial. Ann. Oncol 2015; 26: 2300-2305
    CrossrefPubMedGoogle Scholar
  • 41 Motzer R. et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722-731
    CrossrefPubMedGoogle Scholar
  • 42 Motzer RJ. et al. Overall Survival in Renal-Cell Carcinoma with Pazopanib versus Sunitinib. N Engl J Med 2014; 370: 1769-1770
    CrossrefPubMedGoogle Scholar
  • 43 Larkin J. et al. First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis. Expert Opin Pharmacother 2015; 16: 1915-1927
    CrossrefPubMedGoogle Scholar
  • 44 Fachinformation Torisel®. ; Stand: Januar 2019
    PubMedGoogle Scholar
  • 45 Rini BI. et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380: 1116-1127
    CrossrefPubMedGoogle Scholar
  • 46 Motzer RJ. et al. JAVELIN Renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). ESMO. 2018 abstr. LBA6_PR
    PubMedGoogle Scholar
  • 47 Motzer RJ. et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol 2018; 36: 578 , no. 6_suppl
    CrossrefPubMedGoogle Scholar
  • 48 Escudier B. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370: 2103-2111
    CrossrefPubMedGoogle Scholar
  • 49 Rini BI. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378: 1931-1939
    CrossrefPubMedGoogle Scholar
  • 50 Motzer RJ. et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14: 552-562
    CrossrefPubMedGoogle Scholar
  • 51 Wolchok JD. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412-7420
    CrossrefPubMedGoogle Scholar
  • 52 Escudier B. et al. Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. Eur Urol 2017; 72: 368-376
    CrossrefPubMedGoogle Scholar
  • 53 George S. et al. Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial. JAMA Oncol 2016; 2: 1179-1186
    CrossrefPubMedGoogle Scholar
  • 54 Foller S. et al. [Adverse events of immune checkpoint inhibitors]. Urologe A 2017; 56: 486-491
    CrossrefPubMedGoogle Scholar
  • 55 Kumar V. et al. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol 2017; DOI: 10.3389/fphar.2017.00049.
    CrossrefPubMedGoogle Scholar
  • 56 Johannsen M. et al. Can tyrosine kinase inhibitors be discontinued in patients with metastatic renal cell carcinoma and a complete response to treatment? A multicentre, retrospective analysis. Eur Urol 2009; 55: 1430-1438
    CrossrefPubMedGoogle Scholar
  • 57 McDermott DF. et al. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol 2015; 33: 2013-2020
    CrossrefPubMedGoogle Scholar
  • 58 Méjean A. et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med 2018; 379: 417-427
    CrossrefPubMedGoogle Scholar
  • 59 Bex A. et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol 2018; DOI: 10.1001/jamaoncol.2018.5543. [Epub ahead of print]
    CrossrefPubMedGoogle Scholar
  • 60 Yuki H. et al. Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report. In Onco Targets Ther, Edition New Zealand 2014; 289-295
    PubMedGoogle Scholar
  • 61 Sassa N. et al. Efficacy of pre-surgical axitinib for shrinkage of inferior vena cava thrombus in a patient with advanced renal cell carcinoma. In Jpn J Clin Oncol, Edition England 2014; 370-373
    CrossrefPubMedGoogle Scholar
  • 62 Karam JA. et al. Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma. Eur Urol 2014; 66: 874-880
    CrossrefPubMedGoogle Scholar
  • 63 Kats-Ugurlu G. et al. Neoadjuvant sorafenib treatment of clear cell renal cell carcinoma and release of circulating tumor fragments. Neoplasia 2014; 16: 221-228
    CrossrefPubMedGoogle Scholar
  • 64 Bex A. et al. Integrating surgery with targeted therapies for renal cell carcinoma: current evidence and ongoing trials. Eur Urol 2010; 58: 819-828
    CrossrefPubMedGoogle Scholar
  • 65 Jonasch E. et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 4076-4081
    CrossrefPubMedGoogle Scholar
  • 66 Thomas AA. et al. Surgical resection of renal cell carcinoma after targeted therapy. J Urol 2009; 182: 881-886
    CrossrefPubMedGoogle Scholar
  • 67 Cowey CL. et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol 2010; 28: 1502-1507
    CrossrefPubMedGoogle Scholar
  • 68 Ravaud A. et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016; 375: 2246-2254
    CrossrefPubMedGoogle Scholar
  • 69 Ristau BT. et al. Retroperitoneal Lymphadenectomy in High Risk, Nonmetastatic Renal Cell Carcinoma: An Analysis of the ASSURE (ECOG-ACRIN 2805) Adjuvant Trial. J Urol 2018; 199: 53-59
    CrossrefPubMedGoogle Scholar
  • 70 Motzer RJ. et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol 2017; 35: 3916-3923
    CrossrefPubMedGoogle Scholar
  • 71 Gross-Goupil M. et al. Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the Phase III, Randomized ATLAS Trial. Ann Oncol 2018; 29: 2371-2378
    CrossrefPubMedGoogle Scholar