PMID- 29784193 OWN - NLM STAT- MEDLINE DCOM- 20190528 LR - 20240329 IS - 1873-7560 (Electronic) IS - 0302-2838 (Print) IS - 0302-2838 (Linking) VI - 74 IP - 5 DP - 2018 Nov TI - Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. PG - 611-620 LID - S0302-2838(18)30349-X [pii] LID - 10.1016/j.eururo.2018.05.002 [doi] AB - CONTEXT: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC). OBJECTIVE: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC. EVIDENCE ACQUISITION: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated. EVIDENCE SYNTHESIS: The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR(random)]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HR(random): 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (OR(random): 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR(random): 0.83, 95% CI: 0.73-0.95, p=0.005). CONCLUSIONS: This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs. PATIENT SUMMARY: Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects. CI - Copyright (c) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. FAU - Sun, Maxine AU - Sun M AD - Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Marconi, Lorenzo AU - Marconi L AD - Department of Urology, Coimbra University Hospital, Coimbra, Portugal. FAU - Eisen, Tim AU - Eisen T AD - Department of Oncology, Addenbrooke's Hospital, Cambridge Biomedical Research Centre, UK. FAU - Escudier, Bernard AU - Escudier B AD - Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. FAU - Giles, Rachel H AU - Giles RH AD - Patient Advocate, International Kidney Cancer Coalition, Duivendrecht, The Netherlands; Department Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, University of Utrecht, The Netherlands. FAU - Haas, Naomi B AU - Haas NB AD - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. FAU - Harshman, Lauren C AU - Harshman LC AD - Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Quinn, David I AU - Quinn DI AD - Section of Genitourinary Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. FAU - Larkin, James AU - Larkin J AD - Royal Marsden NHS Trust Foundation Trust, London, UK. FAU - Pal, Sumanta K AU - Pal SK AD - Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. FAU - Powles, Thomas AU - Powles T AD - The Royal Free NHS Trust and Barts Cancer Institute, Queen Mary University of London, London, UK. FAU - Ryan, Christopher W AU - Ryan CW AD - Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. FAU - Sternberg, Cora N AU - Sternberg CN AD - Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy. FAU - Uzzo, Robert AU - Uzzo R AD - Department of Surgery, Fox Chase Cancer Center - Temple University Health System, Philadelphia, PA, USA. FAU - Choueiri, Toni K AU - Choueiri TK AD - Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: Toni_Choueiri@dfci.harvard.edu. FAU - Bex, Axel AU - Bex A AD - Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: a.bex@nki.nl. LA - eng GR - 6858/CRUK_/Cancer Research UK/United Kingdom GR - P30 CA014089/CA/NCI NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20180518 PL - Switzerland TA - Eur Urol JT - European urology JID - 7512719 RN - 0 (Angiogenesis Inhibitors) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) SB - IM CIN - Eur Urol. 2018 Nov;74(5):621-622. PMID: 30072208 CIN - Eur Urol. 2019 Mar;75(3):e67-e68. PMID: 30466889 CIN - J Urol. 2019 Jun;201(6):1050-1051. PMID: 30865845 MH - Angiogenesis Inhibitors/adverse effects/*therapeutic use MH - Carcinoma, Renal Cell/*drug therapy/metabolism/mortality/pathology MH - Chemotherapy, Adjuvant MH - Clinical Trials, Phase III as Topic MH - Disease Progression MH - Disease-Free Survival MH - Humans MH - Kidney Neoplasms/*drug therapy/metabolism/mortality/pathology MH - Neoplasm Recurrence, Local MH - *Neovascularization, Pathologic MH - Nephrectomy MH - Progression-Free Survival MH - Randomized Controlled Trials as Topic MH - Receptors, Vascular Endothelial Growth Factor/*antagonists & inhibitors/metabolism MH - Risk Factors MH - Signal Transduction/drug effects MH - Time Factors MH - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/metabolism PMC - PMC7515772 MID - NIHMS1628293 OTO - NOTNLM OT - Adjuvant therapy OT - Meta-analysis OT - Metastatic renal cell carcinoma OT - Systemic therapy OT - Targeted therapy EDAT- 2018/05/23 06:00 MHDA- 2019/05/29 06:00 PMCR- 2020/09/25 CRDT- 2018/05/23 06:00 PHST- 2018/02/22 00:00 [received] PHST- 2018/05/03 00:00 [accepted] PHST- 2018/05/23 06:00 [pubmed] PHST- 2019/05/29 06:00 [medline] PHST- 2018/05/23 06:00 [entrez] PHST- 2020/09/25 00:00 [pmc-release] AID - S0302-2838(18)30349-X [pii] AID - 10.1016/j.eururo.2018.05.002 [doi] PST - ppublish SO - Eur Urol. 2018 Nov;74(5):611-620. doi: 10.1016/j.eururo.2018.05.002. Epub 2018 May 18.