• Refer to the local Avastin label for the incidence rates of proteinuria, and management strategies approved by relevant regulatory authorities.
• The mechanism of Avastin-associated proteinuria is unknown; however, VEGF inhibition may compromise the renal glomerular filtration barrier.
• Risk factors for developing proteinuria include a history of hypertension, and receiving high-dose Avastin. Several systematic reviews have identified other potential risk factors.
• Recommendations
• Patients should be tested for proteinuria prior to the start of Avastin therapy.
• Whilst there are no formal recommendations on the frequency of monitoring proteinuria during Avastin therapy, patients in Avastin pivotal trials were assessed at the start of every or every other treatment cycle.
• AEs should be managed per local Avastin label.
• Several published guidelines describe strategies for the monitoring and management of Avastin-associated proteinuria.

AE= Adverse event

EMA= European Medicines Agency

FDA= Food and Drug Administration

SPC= Summary of Product Characteristics

UPC= Urine protein creatinine

VEGF= Vascular endothelial growth factor

Proteinuria is considered a class effect of anti-VEGF agents [1], such as Avastin. The mechanism of Avastin-associated proteinuria is unknown, though several hypotheses exist.

VEGF plays a pivotal role in maintaining the endothelial fenestrations and podocytes of the renal glomerular filtration barrier.[2] Inhibition of VEGF signaling is thought to lead to [1-3]

• loss of endothelial fenestrations,
• loss of podocytes, and
• glomerular thrombotic microangiopathy with endotheliosis.

This may result in the disruption of the glomerular filtration barrier and result in excess protein excretion in the urine.[1,4]

In clinical trials, proteinuria was reported within the range of 0.7% to 54.7% of patients receiving Avastin5. Risk factors for developing proteinuria with Avastin include

• history of hypertension, and
• receiving high-dose Avastin [5].

Several meta-analyses and retrospective analyses have additionally identified other proteinuria risk factors, though findings are not consistent between analyses. Other proposed risk factors include

• renal cell carcinoma [6]
• renal failure [7]
• history of diabetes,[8] and
• number of Avastin cycles [9]

Avastin-induced proteinuria is thought to be reversible, though long term effects are not known [10].

Test for proteinuria prior to the start of Avastin therapy. Beyond this, Roche does not provide recommendations on how to test renal function prior to Avastin therapy, or renal function limits on when to initiate Avastin.

The decision whether to use Avastin in patients with proteinuria lies with the physician and should be based on an appropriate assessment of the likely risk:benefit ratio. If Avastin were to be prescribed in this condition, we would advise appropriate clinical caution and monitoring.

Assessment of baseline renal function in Avastin pivotal trials  

Several assessments were used to catagorise renal function at enrolment of Avastin pivotal trials, including assessing serum creatinine levels, performing urine dipstick analysis and calculating UPC levels [11-18].

Patients with compromised renal function were excluded from pivotal Avastin clinical trials.‎ In many pivotal trials, proteinuria was allowed at a low level [11-14], defined as urine dipstick proteinuria <2+.

Patients with ≥2+ proteinuria on dipstick urinalysis at baseline underwent 24 hours urine collection and must have demonstrated ≤1 g of protein/24 hr before they were allowed to be enroled.

• Please refer to individual Clinical Trial protocols for further details on renal inclusion criteria, as some clinical trials had more stringent criteria.

Roche does not provide recommendations on the frequency of monitoring proteinuria during Avastin therapy [5]. General recommendations are available in certain local Avastin product labels:

• EMA SPC —[19] Test for proteinuria by dipstick urinalysis during Avastin therapy.
• FDA label — [20] Monitor for the development or worsening of proteinuria with serial urinalysis during Avastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment, such as a 24-hour urine collection.

Monitoring of renal function in Avastin pivotal trials  

In pivotal clinical trials, patients were monitoring for proteinuria every, or every other treatment cycle.[11-18]

Manage AEs as per local Avastin Label.

• Discontinue Avastin if nephritic syndrome (grade 4 proteinuria) arises.

Additional recommendations from the Avastin FDA label are outlined on Table 1.

 Table 1: FDA label recommendations for proteinuria 

Study protocols from pivotal clinical trials varied with regard to the evaluation of proteinuria and management of Avastin between the time of elevated dipstick urinalysis and 24-hour urine collection, though many [11,12,14] resembled the recommendations outlined in the FDA label.

Several publications describe monitoring and management strategies for proteinuria in Avastin patients. [10,21,22] We refer the interested reader to the publications for more information.

1. Eremina V, Jefferson J, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129-36. https://www.ncbi.nlm.nih.gov/pubmed/18337603
2. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707-16. https://www.ncbi.nlm.nih.gov/pubmed/12618525
3. Schrijvers B, Flyvbjerg A, De VA. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int 2004;65:2003-17. https://www.ncbi.nlm.nih.gov/pubmed/15149314
4. Gurevich F, Perazella M. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med 2009;122:322-8. https://www.ncbi.nlm.nih.gov/pubmed/19332223
5. Roche Internal Regulatory Document (Accessed July 2023).
6. Wu S, Kim C, Baer L, et al. Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol 2010;21:1381-9. https://www.ncbi.nlm.nih.gov/pubmed/20538785
7. Odia Y, Shih J, Kreisl T, et al. Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort. J Neurooncol 2014;120:431-40. https://www.ncbi.nlm.nih.gov/pubmed/25098701
8. Lafayette R, McCall B, Li N, et al. Incidence and relevance of proteinuria in bevacizumab-treated patients: pooled analysis from randomized controlled trials. Am J Nephrol 2014;40:75-83. https://www.ncbi.nlm.nih.gov/pubmed/25059491
9. Alwan L, Sun X, Lee C. Routine proteinuria monitoring for bevacizumab in patients with gynecologic malignancies. JOPP. E-pub Date: August 2014. DOI # 10.1177/1078155215609987. https://www.ncbi.nlm.nih.gov/pubmed/26447100
10. Miles D, Bridgewater J, Ellis P, et al. Using bevacizumab to treat metastatic cancer: UK consensus guidelines. Br J Hosp Med (Lond) 2010;71:670-7. https://www.ncbi.nlm.nih.gov/pubmed/21135762
11. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013;14:29-37. https://www.ncbi.nlm.nih.gov/pubmed/23168366
12. Clinicaltrials.gov: Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Advanced, Metastatic, or Recurrent Non-Small Cell Lung Cancer. Available at https://classic.clinicaltrials.gov/ct2/show/NCT00021060. Accessed on July 18, 2023.
13. Clinicaltrials.gov: A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1). Available at https://classic.clinicaltrials.gov/ct2/show/NCT00262067. Accessed on July 18, 2023.
14. Pujade-Lauraine E, Hilpert F, Weber B. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. E-pub Date: May 2014. DOI # 10.1200/JCO.2013.51.4489. https://pubmed.ncbi.nlm.nih.gov/24637997/
15. Food and Drug Administration. Center for Drug Evaluation and Research approval package for: application number: STN-125085/0: medical review(s):69-70. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/STN-125085_Avastin_medr_P1.pdf
16. Burger R, Brady M, Bookman M, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83. https://www.ncbi.nlm.nih.gov/pubmed/22204724
17. Aghajanian C, Blank S, Goff B, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30:2039-45. https://www.ncbi.nlm.nih.gov/pubmed/22529265
18. Finn R, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-1905. https://www.ncbi.nlm.nih.gov/pubmed/32402160
19. Avastin Summary of Product Characteristics. Available at https://www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf. Accessed on August 4, 2023.
20. FDA Avastin Highlights of Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125085s225lbl.pdf. Accessed on August 4, 2023.
21. Izzedine H, Massard C, Spano J, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer 2010;46:439-48. https://www.ncbi.nlm.nih.gov/pubmed/20006922
22. Shord S, Bressler L, Tierney L, et al. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm 2009;66:999-1013. https://www.ncbi.nlm.nih.gov/pubmed/19451611