Skip to main content

Advertisement

Springer Nature Link
Log in

VEGF inhibition in urothelial cancer: the past, present and future

  • Invited Review
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

Purpose

To describe the role of anti-angiogenic agents that have been used as a treatment approach for locally advanced or metastatic urothelial cancers and to propose future directions.

Methods

PubMed/MEDLINE was searched for articles related to VEGF inhibition and locally advanced or metastatic urothelial cancer.

Results

Angiogenesis is a fundamental process for urothelial cancer initiation and progression. First-line therapy for locally advanced or metastatic urothelial cancer includes cisplatin-based chemotherapy combinations; subsequent systemic therapy includes taxanes, nanoparticle albumin-bound (nab) paclitaxel, or pemetrexed. More recently, several anti-PD-L1 and anti-PD-1 antibodies have shown promising activity in the first-line and post-platinum setting; however, immunotherapy remains ineffective in most patients. FGFR inhibitor erdafitinib was recently approved in the third-line setting. Studies on bevacizumab, pazopanib and ramucirumab have shown improved response rates when added to chemotherapy in selected patients, but have not led to overall survival (OS) benefit in randomized controlled studies.

Conclusion

Anti-angiogenic agents have shown promise in recent studies treating locally advanced or metastatic urothelial cancer. However, further work is needed to elucidate ideal treatment combinations in selected patient populations to maximize benefit, with the ultimate goal of being added to the FDA-approved treatment armamentarium for this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References:s

  1. Ferlay J et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386

    CAS  PubMed  Google Scholar 

  2. Dy GW et al (2017) Global burden of urologic cancers, 1990–2013. Eur Urol 71(3):437–446

    PubMed  Google Scholar 

  3. Yee DS et al (2011) Ethnic differences in bladder cancer survival. Urology 78(3):544–549

    PubMed  Google Scholar 

  4. Cumberbatch MG et al (2015) Contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis. JAMA Oncol 1(9):1282–1290

    PubMed  Google Scholar 

  5. Turati F et al (2017) Family history of cancer and the risk of bladder cancer: a case-control study from Italy. Cancer Epidemiol 48:29–35

    PubMed  Google Scholar 

  6. Sternberg CN et al (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European organization for research and treatment of cancer protocol no. 30924. J Clin Oncol 19(10):2638–2646

    CAS  PubMed  Google Scholar 

  7. von der Maase H et al (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18(17):3068–3077

    PubMed  Google Scholar 

  8. Sternberg CN et al (2006) Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42(1):50–54

    CAS  PubMed  Google Scholar 

  9. McCaffrey JA et al (1997) Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 15(5):1853–1857

    CAS  PubMed  Google Scholar 

  10. Ko YJ et al (2013) Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase two study. Lancet Oncol 14(8):769–776

    CAS  PubMed  Google Scholar 

  11. Sweeney CJ et al (2006) Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24(21):3451–3457

    CAS  PubMed  Google Scholar 

  12. Rosenberg JE et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase two trial. Lancet 387(10031):1909–1920

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sharma P et al (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase two trial. Lancet Oncol 18(3):312–322

    CAS  PubMed  Google Scholar 

  14. Bellmunt J et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Apolo AB et al (2017) Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter. J Clin Oncol 35(19):2117–2124

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Powles T et al (2017) Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 3(9):e172411

    PubMed  PubMed Central  Google Scholar 

  17. Patel MR et al (2018) Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN solid tumor): pooled results from two expansion cohorts of an open-label, phase one trial. Lancet Oncol 19(1):51–64

    CAS  PubMed  Google Scholar 

  18. Balar AV et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18(11):1483–1492

    CAS  PubMed  Google Scholar 

  19. Balar AV et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389(10064):67–76

    CAS  PubMed  Google Scholar 

  20. Study of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy alone in urothelial carcinoma (MK-3475-361/KEYNOTE-361). https://ClinicalTrials.gov/show/NCT02853305.

  21. M.S.D.Corp Study of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy alone in urothelial carcinoma (MK-3475-361/KEYNOTE-361). https://ClinicalTrials.gov/show/NCT02853305.

  22. H.-L. Roche Study of atezolizumab as monotherapy and in combination with platinum-based chemotherapy in participants with untreated locally advanced or metastatic urothelial carcinoma. https://ClinicalTrials.gov/show/NCT02807636.

  23. Kim HS, Seo HK (2018) Immune checkpoint inhibitors for urothelial carcinoma. Investig Clin Urol 59(5):285–296

    PubMed  PubMed Central  Google Scholar 

  24. Loriot Y et al (2019) Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 381(4):338–348

    CAS  PubMed  Google Scholar 

  25. M. S. D Corp. 2019 A study of erdafitinib compared with vinflunine or docetaxel or pembrolizumab in participants with advanced urothelial cancer and selected fibroblast growth factor receptor (FGFR). Gene Aberrations https://ClinicalTrials.gov/show/NCT03390504.

  26. Rosenberg JE et al (2019) Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 37(29):2592–2600

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 2019 Astellas pharma global development, I. A study to evaluate enfortumab vedotin versus (vs) chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (EV-301). https://ClinicalTrials.gov/show/NCT03474107.

  28. Narayanan S, Srinivas S (2017) Incorporating VEGF-targeted therapy in advanced urothelial cancer. Ther Adv Med Oncol 9(1):33–45

    CAS  PubMed  Google Scholar 

  29. Fus LP, Gornicka B (2016) Role of angiogenesis in urothelial bladder carcinoma. Cent Eur J Urol 69(3):258–263

    CAS  Google Scholar 

  30. Charlesworth PJ, Harris AL (2006) Mechanisms of disease: angiogenesis in urologic malignancies. Nat Clin Pract Urol 3(3):157–169

    CAS  PubMed  Google Scholar 

  31. Bernardini S et al (2001) Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer. J Urol 166(4):1275–1279

    CAS  PubMed  Google Scholar 

  32. Canoglu A et al (2004) Microvessel density as a prognostic marker in bladder carcinoma: correlation with tumor grade, stage and prognosis. Int Urol Nephrol 36(3):401–405

    PubMed  Google Scholar 

  33. Pignot G et al (2009) Large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker. Eur Urol 56(4):678–688

    CAS  PubMed  Google Scholar 

  34. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989

    CAS  PubMed  Google Scholar 

  35. Ferrara N et al (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discovery 3(5):391–400

    CAS  PubMed  Google Scholar 

  36. Balar AV et al (2013) Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol 31(6):724–730

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hahn NM et al (2011) Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: hoosier oncology group GU 04–75. J Clin Oncol 29(12):1525–1530

    CAS  PubMed  Google Scholar 

  38. Rosenberg JE et al (2019) CALGB 90601 (Alliance): randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma. J Clin Oncol 37:4503–4503

    Google Scholar 

  39. Kumar R et al (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021

    CAS  PubMed  Google Scholar 

  40. Miyamoto S et al (2018) Drug review: pazopanib. Jpn J Clin Oncol 48(6):503–513

    PubMed  Google Scholar 

  41. Necchi A et al (2012) Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol 13(8):810–816

    CAS  PubMed  Google Scholar 

  42. Pili R et al (2013) A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. Clin Genitourin Cancer 11(4):477–483

    PubMed  PubMed Central  Google Scholar 

  43. Narayanan S et al (2016) Phase II study of pazopanib and paclitaxel in patients with refractory urothelial cancer. Clin Genitourin Cancer 14(5):432–437

    PubMed  PubMed Central  Google Scholar 

  44. Bellmunt J et al (2018) Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma. Br J Cancer 119(6):707–712

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Vennepureddy A et al (2017) Evolution of ramucirumab in the treatment of cancer—a review of literature. J Oncol Pharm Prac 23(7):525–539

    CAS  Google Scholar 

  46. Petrylak DP et al (2016) Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase Ii trial. J Clin Oncol 34(13):1500–1509

    CAS  PubMed  Google Scholar 

  47. Petrylak DP et al (2017) Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (range): a randomised, double-blind, phase 3 trial. Lancet 390(10109):2266–2277

    CAS  PubMed  Google Scholar 

  48. De Wit R et al (2018) Ramucirumab (RAM) exposure-response (ER) relationship in RANGE, a randomized phase III trial of docetaxel (DOC) with or without RAM in advanced urothelial carcinoma (UC) patients (pts) who progressed on or after platinum therapy. J Clin Oncol 36:4526–4526

    Google Scholar 

  49. Drakaki A et al (2018) Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): prespecified subgroup analysis from the phase 3 range trial. J Clin Oncol 36:434–434

    Google Scholar 

  50. Bellmunt J et al (2011) Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol 22(12):2646–2653

    CAS  PubMed  Google Scholar 

  51. Dreicer R et al (2009) Phase 2 trial of sorafenib in patients with advanced urothelial cancer. Cancer 115(18):4090–4095

    CAS  PubMed  Google Scholar 

  52. Choueiri TK et al (2012) Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol 30(5):507–512

    CAS  PubMed  Google Scholar 

  53. Jones RJ et al (2016) TOUCAN: a randomised phase II trial of carboplatin and gemcitabine +/− vandetanib in first line treatment of advanced urothelial cell cancer in patients who are not suitable to receive cisplatin. J Clin Oncol 34:448–448

    Google Scholar 

  54. A B. Apolo 2019 Cabozantinib S-malate and nivolumab with or without ipilimumab in treating patients with metastatic genitourinary. Tumors, https://ClinicalTrials.gov/show/NCT02496208.

  55. Twardowski P et al (2010) Phase II study of aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer, a california cancer consortium trial. Urology 76(4):923–926

    PubMed  Google Scholar 

  56. Atkins MB, Tannir NM (2018) Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 70:127–137

    CAS  PubMed  Google Scholar 

  57. Atezolizumab with bevacizumab in previously untreated metastatic/unresectable urothelial cancer. https://ClinicalTrials.gov/show/NCT03272217.

  58. Gemcitabine hydrochloride and cisplatin with or without bevacizumab in treating patients with advanced urinary tract cancer. https://ClinicalTrials.gov/show/NCT00942331.

  59. A study of ramucirumab plus pembrolizumab in participants with gastric or gej adenocarcinoma, nsclc, transitional cell carcinoma of the urothelium, or biliary tract cancer. https://ClinicalTrials.gov/show/NCT02443324.

  60. A phase ii trial of pembrolizumab and ramucirumab in patients with progressive transitional cell carcinoma after treatment with an immune checkpoint inhibitor. https://ClinicalTrials.gov/show/NCT04179110.

Download references

Author information

Author notes

  1. Sanaz Ghafouri and Aaron Burkenroad are co-first authors.

Authors and Affiliations

  1. Division of Hematology and Oncology, David Geffen School of Medicine, UCLA, Los Angeles, USA

    Sanaz Ghafouri, Bara Almomani, John Shen & Alexandra Drakaki

  2. Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, USA

    Aaron Burkenroad

  3. Lewis Katz School of Medicine, Temple University, Philadelphia, USA

    Morgan Pantuck

  4. University of Athens Medical School, Athens, Greece

    Dimitris Stefanoudakis

Authors
  1. Sanaz Ghafouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron Burkenroad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Morgan Pantuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bara Almomani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dimitris Stefanoudakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandra Drakaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexandra Drakaki.

Ethics declarations

Conflict of interest

Dr. Drakaki does consulting for Astra Zeneca, served in advisory board for Seattle Genetics/Astellas and Janssen, receives research funding from KITE/Gilead, and receives travel support from Eli Lilly and Astra Zeneca. Her institution receives research support from BMS, MERCK, GENENTECH, ASTRA ZENECA, KITE/GILEAD, ELI LILLY.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghafouri, S., Burkenroad, A., Pantuck, M. et al. VEGF inhibition in urothelial cancer: the past, present and future. World J Urol 39, 741–749 (2021). https://doi.org/10.1007/s00345-020-03213-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-020-03213-z

Keywords

Search

Navigation