Skip to main content

Advertisement

SpringerLink
Log in

Proteinuria is a late-onset adverse event in patients treated with cabozantinib

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

The use of tyrosine kinase inhibitors (TKIs) in thyroid cancer patients is often limited by toxicities. Some have a long-term onset and potentially could impact patients’ survival. Among them, there is the nephrotoxicity, mainly represented by proteinuria. The aim of the study was to evaluate the prevalence of proteinuria in medullary thyroid cancer patients treated with cabozantinib, to examine whether it could be a marker for treatment monitoring and to evaluate histological kidney alterations.

Methods

We collected data of 31 medullary thyroid cancer patients enrolled in the EXAM trial. Proteinuria was defined and evaluated using the National Cancer Institute’s Common Terminology Criteria for Adverse Events. In two symptomatic cases with high-grade proteinuria, a kidney biopsy was performed.

Results

Proteinuria was observed in 4/18 patients (22.2%) and occurred after a mean period of 38 months (median: 35.5 months). It was significantly associated with previous chemotherapy (p = 0.005) and/or treatment with other TKIs (p = 0.04), a prolonged use of cabozantinib (p = 0.0004), and a better radiological response at the end of follow-up (p = 0.002). The kidney biopsy showed pathognomonic features of thrombotic microangiopathy in both cases and a focal amyloid deposit in one.

Conclusion

Proteinuria is a quite frequent adverse event during cabozantinib treatment. It is relatively well manageable with the early detection and correction of risk factors, the temporary discontinuation of cabozantinib and/or its dose reduction, and the use of anti-proteinuric and renoprotective drugs in patient with hypertension. The histological findings confirmed some typical features of the anti-VEGF inhibition injury, already described for other TKIs.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Viola D, Valerio L, Molinaro E et al (2016) Treatment of advanced thyroid cancer with targeted therapies: ten years of experience. Endocr Relat Cancer. https://doi.org/10.1530/ERC-15-0555

    Article  PubMed  Google Scholar 

  2. Wells SA, Robinson BG, Gagel RF et al (2012) Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. https://doi.org/10.1200/JCO.2011.35.5040

    Article  PubMed  PubMed Central  Google Scholar 

  3. Elisei R, Schlumberger MJ, Müller SP et al (2013) Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2012.48.4659

    Article  PubMed  PubMed Central  Google Scholar 

  4. Matrone A, Valerio L, Pieruzzi L et al (2017) Protein kinase inhibitors for the treatment of advanced and progressive radio refractory thyroid tumors: From the clinical trials to the real life. Best Pract Res Clin Endocrinol Metab 31(3):319–334

    Article  CAS  PubMed  Google Scholar 

  5. Gurevich F, Perazella MA (2009) Renal effects of anti-angiogenesis therapy: update for the Internist. Am J Med 122(4):322–328

    Article  CAS  PubMed  Google Scholar 

  6. Izzedine H, Massard C, Spano JP et al (2010) VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. https://doi.org/10.1016/j.ejca.2009.11.001

    Article  PubMed  Google Scholar 

  7. Cabanillas ME, De Souza JA, Geyer S et al (2017) Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II international thyroid oncology group trial. J Clin Oncol. https://doi.org/10.1200/JCO.2017.73.0226

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schlumberger M, Jarzab B, Cabanillas ME et al (2016) A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-15-1127

    Article  PubMed  Google Scholar 

  9. Schlumberger MJ, Elisei R, Bastholt L et al (2009) Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2008.18.7815

    Article  PubMed  Google Scholar 

  10. Loh AHL, Cohen AH (2009) Drug-induced kidney disease - Pathology and current concepts. Ann Acad Med Singapore 38(3):240–250

    PubMed  Google Scholar 

  11. Usui J, Glezerman IG, Salvatore SP et al (2014) Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature. Hum Pathol. https://doi.org/10.1016/j.humpath.2014.05.015

    Article  PubMed  Google Scholar 

  12. Izzedine H, Escudier B, Lhomme C, Pautier P, Rouvier P, Gueutin V, Baumelou A, Derosa L, Bahleda R, Hollebecque A, Djillali Sahali JCS (2014) Kidney diseases associated with anti-vascular endothelial growth factor (vegf): an 8-year observational study at a single center. Med 93:333–339. https://doi.org/10.1017/CBO9781107415324.004

    Article  CAS  Google Scholar 

  13. Bollée G, Patey N, Cazajous G et al (2009) Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfn657

    Article  PubMed  Google Scholar 

  14. Ollero M, Sahali D (2015) Inhibition of the VEGF signalling pathway and glomerular disorders. Nephrol Dial Transplant 30(9):1449–1455

    Article  CAS  PubMed  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. https://doi.org/10.1093/jnci/92.3.205

    Article  PubMed  Google Scholar 

  16. National Cancer Institute (2003) Cancer therapy evaluation program. Common terminology criteria for adverse events. Version 3.0, DCTD, NCI, NIH, DHHS

  17. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med. https://doi.org/10.7326/0003-4819-150-9-200905050-00006

    Article  PubMed  PubMed Central  Google Scholar 

  18. La Manna G, Baraldi O, Corradetti V, Comai G (2018) Cabozantinib-induced renal thrombotic microangiopathy. Nephrology

  19. Kerbel RS (2008) Tumor angiogenesis. N. Engl. J, Med

    Google Scholar 

  20. Eskens FALM, Verweij J (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. https://doi.org/10.1016/j.ejca.2006.09.015

    Article  PubMed  Google Scholar 

  21. Zhang W, Feng LJ, Teng F et al (2020) Incidence and risk of proteinuria associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis of randomized controlled trials. Expert Rev Clin Pharmacol. https://doi.org/10.1080/17512433.2020.1734450

    Article  PubMed  Google Scholar 

  22. Schlumberger M, Tahara M, Wirth LJ et al (2015) Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1406470

    Article  PubMed  Google Scholar 

  23. Brose MS, Nutting CM, Jarzab B et al (2014) Sorafenib in radioactive iodine-refractory, locally advanced or metastatic diff erentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. https://doi.org/10.1016/S0140-6736(14)60421-9

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wu S, Kim C, Baer L, Zhu X (2010) Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol 21(8):1381–1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Khoja L, Kumaran G, Zee YK et al (2014) Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer. J Clin Gastroenterol. https://doi.org/10.1097/MCG.0b013e3182a8804c

    Article  PubMed  Google Scholar 

  26. Horsley L, Marti K, Jayson GC (2012) Is the toxicity of anti-angiogenic drugs predictive of outcome? A review of hypertension and proteinuria as biomarkers of response to anti-angiogenic therapy. Expert Opin Drug Metab Toxicol 8(3):283–293

    Article  CAS  PubMed  Google Scholar 

  27. Cavalieri S, Cosmai L, Genderini A et al (2018) Lenvatinib-induced renal failure: two first-time case reports and review of literature. Expert Opin Drug Metab Toxicol. https://doi.org/10.1080/17425255.2018.1461839

    Article  PubMed  Google Scholar 

  28. Ronco PM (1999) Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int. https://doi.org/10.1046/j.1523-1755.1999.00548.x

    Article  PubMed  Google Scholar 

  29. Koopman T, Niedlich-den Herder C, Stegeman CA et al (2017) Kidney involvement in systemic calcitonin amyloidosis associated with medullary thyroid carcinoma. Am J Kidney Dis. https://doi.org/10.1053/j.ajkd.2016.09.027

    Article  PubMed  Google Scholar 

  30. Peterson JC, Adler S, Burkart JM et al (1995) Blood pressure control, proteinuria, and the progression of renal disease: the modification of diet in renal disease study. Ann Intern Med. https://doi.org/10.7326/0003-4819-123-10-199511150-00003

    Article  PubMed  Google Scholar 

  31. Perkovic V, Verdon C, Ninomiya T et al (2008) The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med. https://doi.org/10.1371/journal.pmed.0050207

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tesarová P, Tesar V (2013) Proteinuria and hypertension in patients treated with inhibitors of the VEGF signalling pathway-incidence, mechanisms and management. Folia Biol Czech Repub 59(1):15–25

    Google Scholar 

  33. Kandula P, Agarwal R (2011) Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int 80(12):1271–1277

    Article  CAS  PubMed  Google Scholar 

  34. Evans TRJ, Kudo M, Finn RS et al (2019) Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma. Br J Cancer. https://doi.org/10.1038/s41416-019-0506-6

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Douglas Clary and Exelixis to allow us to publish these data.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy

    V. Cappagli, V. Bottici, R. Elisei & D. Viola

  2. Nephrology, Transplant and Dialysis Division, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy

    D. Moriconi, D. Giannese & M. Francesca Egidi

  3. Department of Translational Research on New Technologies in Medicine and Surgery, University Hospital of Pisa, Pisa, Italy

    A. G. Bonadio

  4. Nephrology, Dialysis and Renal Transplant Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    Gaetano La Manna & G. Comai

  5. Nephrology and Dialysis Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, University of Rome, Rome, Italy

    G. Vischini

Authors
  1. V. Cappagli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Moriconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. G. Bonadio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Giannese
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gaetano La Manna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Francesca Egidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Comai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Vischini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. V. Bottici
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Elisei
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D. Viola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Elisei.

Ethics declarations

Conflict of interest

Elisei Rossella has been a consultant for Exelixis for cabozantinib development. However, these commitments did not have any influence on this study which has been developed independently and there was no conflict of interest in writing paper. The other authors have nothing to disclose.

Ethics approval

The study was approved by the Local Ethical Committee of University of Pisa.

Consent

Informed consent was obtained from all patients to use their data for scientific purpose including this study.

Availability of data and material

Data are available from the corresponding author on reasonable request.

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

Cappagli, V., Moriconi, D., Bonadio, A.G. et al. Proteinuria is a late-onset adverse event in patients treated with cabozantinib. J Endocrinol Invest 44, 95–103 (2021). https://doi.org/10.1007/s40618-020-01272-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01272-y

Keywords

Search

Navigation