What guidance is available regarding urine protein monitoring frequency for bevacizumab?

Comment by InpharmD Researcher

There appears to be a lack of consensus on the definitive frequency of monitoring urine protein for bevacizumab. Literature suggests performing a urinary protein excretion assessment before each administration of bevacizumab or every 2 to 8 weeks depending on the frequency of bevacizumab administration, severity of the previous proteinuria, and other patient risk factors. Extended interval of urine protein monitoring (e.g., once every 3-6 cycles), may also be acceptable due to the low prevalence of severe proteinuria and did not lead to increased frequency of adverse events in retrospective studies.

Background

A 2015 review described the results of phase II and III clinical trials to compare the incidence of bevacizumab-related adverse events in different cancer types and categorized proteinuria as the second most common adverse event. These particular authors suggested performing a urinary protein excretion assessment before each administration of bevacizumab. The authors recommended utilizing a serial urinalysis dipstick with urine dipstick ≥ 2+ indicating subsequent 24-h urine collection for protein. If 24-h urine protein levels are > 2 g, bevacizumab was recommended to be temporarily suspended; whereas if the levels are <2 g, the treatment should be resumed. Treatment discontinuation was only recommended if 24-h urine protein is > 3.5 g (nephrotic syndrome). [1], [2]

A 2006 review compiled the recommendations of expert practitioners, the manufacturer of bevacizumab (Genentech, Inc, South San Francisco, CA), and the US Food and Drug Administration for the monitoring of bevacizumab-associated proteinuria. Urine protein to creatinine ratio is recommended to be used in order to avoid the inaccuracies associated with dipstick urine assays and the inconvenience of the 24-hour collection. Dipstick urine assays every 2 to 8 weeks (before each dose and/or at each restaging) are also useful If spot urine protein tests are not available, considering the severity of the previous proteinuria and other risk factors. The results of the dipstick (values ≥ 2+) should be confirmed by performing the ratio of urine protein to creatinine or 24-hour collection. Several studies have followed interruption in bevacizumab therapy in patients with proteinuria ≥ 2 g/24 hours. [3]

Another 2009 review recommended regular monitoring of proteinuria via urinalysis (e.g., dipstick urinalysis) every 2-8 weeks. The recommended urinalysis frequency can be considered based on the frequency of bevacizumab administration (once a month if bevacizumab is administered every two weeks and with each dose if bevacizumab is administered every three weeks). Proteinuria in patients with results of 2+ or higher should be confirmed by utilizing a timed urinalysis (i.e., 24-hour urine collection). Once bevacizumab-associated proteinuria develops, routine proteinuria monitoring, such as a 24-hour urine collection or urinary protein to creatinine ratio should be followed. [4]

References: [1] Brandes AA, Bartolotti M, Tosoni A, et al. Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist. 2015;20(2):166-175. doi:10.1634/theoncologist.2014-0330
[2] Majid N, Ghissassi I, Mrabti H, Errihani H. Bevacizumab in clinical practice. Gulf J Oncolog. 2015;1(19):33-37.
[3] Hurwitz H, Saini S. Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events. Semin Oncol. 2006;33(5 Suppl 10):S26-S34. doi:10.1053/j.seminoncol.2006.08.001
[4] Shord SS, Bressler LR, Tierney LA, Cuellar S, George A. Understanding and managing the possible adverse effects associated with bevacizumab. American Journal of Health-System Pharmacy. 2009;66(11):999-1013.
Relevant Prescribing Information

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome. [5]

References: [5] Avastin® (bevacizumab injection). [prescribing information]. Genentech, Inc.; 2021.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What guidance is available regarding urine protein monitoring frequency for bevacizumab?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab

Design

Single-center, retrospective chart review 

N= 55

Objective

To assess the safety of the extended interval for urine protein (UP) monitoring for bevacizumab treatment

Study Groups

All patients (N= 55)

Bevacizumab treatments (N= 388)

Inclusion Criteria

Aged ≥18 years; received at least four bevacizumab treatments

Exclusion Criteria

 Not specified

Methods

Patients were randomly selected, and medical records of patients who received bevacizumab were reviewed. The incidence and classification of grade 2–4 proteinuria were based on the classification of proteinuria according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 

Duration

Treatment period: January 4, 2017, to June 31, 2017

Outcome Measures

Primary: incidence of grade 2–4 proteinuria 

Secondary: frequency of UP dipstick monitoring, the number of treatment interruptions due to proteinuria

Baseline Characteristics

  

All patients (N= 55)

Mean age, years (range)

62 (37 to 86)

Male

20 (36.4%)

Pre-existing medical conditions

Hypertension

Diabetes

Renal dysfunction*

 

21 (38.2%)

13 (23.6%)

2 (3.6%)

Median bevacizumab treatments (range)

6 (4 to13)

Diagnosis

Breast

Colon/rectal

Glioblastoma

Lung

Gynecologic

Other

 

2 (3.6%)

22 (40%)

7 (12.7%)

9 (16.4%)

9 (16.4%)

6 (10.9%)

*Defined as baseline serum creatinine > 1.5 mg/dL or CrCl < 30.

Results

Endpoint

Bevacizumab treatments (N= 388)

Incidence of proteinuria

Grade 2

Grade 3-4

 

7.2%

0%

Frequency of UP dipstick monitoring

Every other treatment

Every treatment

Not monitored

 

206 (52.5%)

126 (33%)

55 (14.4%)

There were 10 instances of proteinuria among four different patients who had a UP ≥2+. Two of these patients performed a 24-h timed urine test.

Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria.

No treatments were held due to proteinuria.

Adverse Events

See results section for incidences of proteinuria

Study Author Conclusions

Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is monitored prior to every third bevacizumab treatment, reducing unnecessary lab and chair time.

InpharmD Researcher Critique

In addition to the retrospective nature of the study that may lead to selection bias, the low incidence of proteinuria may be due to the short-term follow-up (6 months). Moreover, the results were not adjusted for other confounding factors that may have impacted the high proteinuria. Results from a single institution may not be readily generalized to other health systems. 

 

References:
[1] Schiffer M, Zukovic L, Hall S, Merl MY. Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab. J Oncol Pharm Pract. 2021;27(4):902-906. doi:10.1177/1078155220943959
[2]

 

Routine proteinuria monitoring for bevacizumab in patients with gynecologic malignancies

Design

Single-center, retrospective chart review

N= 89

Objective

To determine the prevalence and severity of proteinuria during bevacizumab administration to patients with gynecologic malignancies, and to evaluate risk factors associated with this toxicity; a secondary objective was to evaluate the cost of routine proteinuria monitoring to assess for opportunities for cost containment that could change clinical practice

Study Groups

Bevacizumab patients (N= 89)

Inclusion Criteria

Women age ≥ 18 years, diagnosed with gynecologic malignancy and receiving bevacizumab

Exclusion Criteria

Receiving < 3 doses of bevacizumab

Methods

Lab values were obtained via patient medical records. Urinary protein and creatinine concentrations were measured quantitatively per criteria under the National Cancer Institute’s CTCAE version 4.03 and cost assessment was performed using institution-specific cost data for urine dipstick tests and urine protein-to-creatinine (UPC) ratio tests.

Duration

January 1, 2005 to December 30, 2011

Outcome Measures

Prevalence and grade of proteinuria, cost of routine monitoring

Baseline Characteristics

  

Bevacizumab patients (N= 89)

Age group, years 

30–39

40–49

50–59

60–65

>65

 

7 (8%)

15 (17%)

33 (37%)

17 (19%)

17 (19%) 

Type of cancer

Ovarian

Cervical

Endometrial

Unknown primary

 

56 (63%)

15 (17%)

17 (19%)

1 (1%) 

Baseline comorbidities

Hypertension

Diabetes (I or II)

Chronic kidney disease

Hepatitis

Cirrhosis

 

29 (33%)

13 (15%)

2 (2%)

1 (1%)

2 (2%)

Results

Endpoint

Bevacizumab patients (N= 89)

Average number of bevacizumab cycles

Average dose of bevacizumab, mg/kg

13

14.5

Proteinuria

Grade 1

Grade 2

Grade 3

 

22 (25%)

8 (9%)

2 (2%)

When evaluating risk factors for proteinuria, there was a trend toward correlation between the number of cycles of bevacizumab and proteinuria (p= 0.05). By using urine dipstick tests instead of UPC ratio tests in the evaluation for proteinuria, it was estimated $31,000 could be saved annually. 

Adverse Events

 N/A

Study Author Conclusions

Monitoring of urine protein-to-creatinine ratios with each cycle may be unnecessary due to the low prevalence of grade 3 proteinuria observed. Additionally, urine protein-to-creatinine ratios may not provide an adequate assessment of proteinuria toxicity associated with bevacizumab therapy. Potential cost savings opportunities for the institution can be realized with a cost-reductive monitoring algorithm that will utilize less costly laboratory techniques for patients at high risk of developing proteinuria.

InpharmD Researcher Critique

The study was limited based on its small sample size, retrospective and single-center nature limiting the external validity of the results. However, given the low incidence of severe proteinuria in this particular patient population, the authors recommended routine monitoring for proteinuria using a urine dipstick every 6 cycles without 24-hour urine protein monitoring. 



References:
[1] Lee CS, Alwan LM, Sun X, McLean KA, Urban RR. Routine proteinuria monitoring for bevacizumab in patients with gynecologic malignancies. J Oncol Pharm Pract. 2016;22(6):771-776. doi:10.1177/1078155215609987