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Proteinuria and hypertension in VEGF inhibition

Why proteinuria may occur

  • Proteinuria, or an excess of protein in the urine, can occur with cancer and some cancer therapies1-3

  • In a clinical setting, impairment of the glomeruli that make up the kidney may be a pathologic cause of persistent proteinuria4

  • In the preclinical setting, inhibition of VEGF, a key endothelial growth factor, has been shown to impair glomerular endothelial cells5

The kidney is made up of about 2.5 million glomeruli. Glomeruli are made up of a basement membrane, epithelial cells, and endothelial cells. Healthy glomerular endothelial cells help filter the plasma. Water and small solutes pass through the glomeruli, but not proteins or cells.6,7

Incidence of proteinuria in Avastin clinical trials1

  • In Studies 1, 3, 4, and 9, the incidence of NCI-CTC grade 3 and 4 proteinuria, characterized as >3.5 g/24 hours, ranged from 0.7% to 7.4% in Avastin-treated patients

  • Across clinical trials, nephrotic syndrome occurred in <1% of patients receiving Avastin, in some instances with fatal outcome

    • Avastin should be discontinued in patients who develop nephrotic syndrome

  • In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy

Proteinuria: Monitoring and management of Avastin

Diagnosing and monitoring proteinuria1

  • The incidence and severity of proteinuria are increased in patients receiving Avastin

  • Urine dipstick or urinalyses are performed to detect proteinuria in most cases

  • Patients should be monitored for the development or worsening of proteinuria with serial urinalyses

NCI Common Terminology Criteria—V4.038

Proteinuria monitoring and management overview algorithm

  • AE=adverse event.

  • Nephrotic syndrome involves protein levels in the urine of more than 3.5 g/24 hours, low blood levels, high cholesterol levels, high triglyceride levels, and edema9

  • A urine dipstick is generally reported as negative (<10 mg/dL), trace (10–20 mg/dL), 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), or 4+ (1000 mg/dL)10

Monitoring and management of proteinuria with Avastin1

  • Patients receiving Avastin should be monitored for proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses

    • Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection

  • Suspend Avastin administration for ≥2 g of proteinuria/24 hours and resume when proteinuria is <2 g/24 hours

  • Data from a postmarketing safety study showed poor correlation between UPCR and 24-hour urine protein

  • Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed

  • The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated

  • Avastin should be temporarily suspended in patients with moderate to severe proteinuria pending further evaluation

  • Discontinue Avastin in patients with nephrotic syndrome

Proteinuria: Monitoring and management of Avastin1

Proteinuria monitoring and management overview algorithm

Hypertension in VEGF inhibition

Why hypertension may occur

VEGF interacts with nitric oxide to regulate vascular tone

  • Nitric oxide is a messenger molecule (a molecule that carries signals between cells) that can regulate various physiologic functions, including BP11,12

  • Some studies suggest that VEGF increases nitric oxide production, resulting in vasodilation11-15

  • Reducing nitric oxide production results in vasoconstriction; it has been hypothesized that this process could play a role in hypertension11-16

The presence of VEGF is associated with the production of nitric oxide.11-15

Incidence of hypertension in Avastin clinical trials1

Incidence of hypertension in Avastin clinical trials

  • mRCC=metastatic renal cell carcinoma; NSCLC=non-small cell lung cancer; IFN=interferon alfa; PC=paclitaxel/carboplatin.

  • Grade 3 hypertension is defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg that requires medical intervention with therapy or more intensive therapy than previously required. Grade 4 hypertension is defined as hypertension with life-threatening consequences, such as hypertensive crisis8

  • Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy

Monitoring BP1

  • The incidence of severe hypertension is increased in patients receiving Avastin

  • BP monitoring should be conducted every 2 to 3 weeks during treatment with Avastin

  • Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their BP monitored at regular intervals

Management of hypertension with Avastin1

  • In clinical trials, appropriate antihypertensives were used in the management of hypertension

  • Avastin should be temporarily suspended in patients with severe hypertension that is not controlled with medical management and discontinued in patients with hypertensive crisis or hypertensive encephalopathy

Hypertension: Monitoring and management of Avastin1

Hypertension monitoring and management overview algorithm

Indication

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS
  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)
Additional serious adverse events
  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • Non-GI fistula formation (≤0.3%)
    • Arterial thromboembolic events (grade ≥3, 2.4%)
    • Proteinuria including nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included
    • Hypertension (grade 3–4, 5%–18%)
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
Most common adverse events
  • Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were
    – Epistaxis
    – Headache
    – Hypertension
    – Rhinitis
    – Proteinuria
    – Taste alteration
    – Dry skin
    – Rectal hemorrhage
    – Lacrimation disorder
    – Back pain
    – Exfoliative dermatitis
  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions
Pregnancy warning
  • Avastin may impair fertility
  • Based on animal data, Avastin may cause fetal harm
  • Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin
  • For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother
  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Next: MCRC Downloads

References:
  1. Avastin Prescribing Information. Genentech, Inc. September 2011.
  2. Rudman D, Chawla RK, Nixon DW. Trans Assoc Am Physicians. 1978;91:229-241.
  3. Ferrari S, Pieretti F, Verri E, et al. Anticancer Drugs. 2005;16:733-738.
  4. Oberbauer R, Haas M, Regele H, et al. J Clin Invest. 1995;96:22-29.
  5. Ostendorf T, Kunter U, Eitner F, et al. J Clin Invest. 1999;104:913-923.
  6. Sugimoto H, Hamano Y, Charytan D, et al. J Biol Chem. 2003;278:12605-12608.
  7. Holechek MJ. Nephrol Nurs J. 2003;30:285-290.
  8. National Cancer Institute. Common terminology criteria for adverse events, version 4.03. June 14, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed February 4, 2010.
  9. Nephrotic syndrome. MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/ency/article/000490.htm. Updated August 13, 2009. Accessed January 14, 2011.
  10. Carroll MF, Temte JL. Am Fam Physician. 2000;62:1333-1340.
  11. Wu HM, Huang Q, Yuan Y, Granger HJ. Am J Physiol. 1996;271(6 pt 2):H2735-H2739.
  12. Hood JD, Meininger CJ, Ziche M, Granger HJ. Am J Physiol. 1998;274(3 pt 2):H1054-H1058.
  13. Hariawala MD, Horowitz JR, Esakof D, et al. J Surg Res. 1996;63:77-82.
  14. Shen BQ, Lee DY, Zioncheck TF. J Biol Chem. 1999;274:33057-33063.
  15. Yang R, Thomas GR, Bunting S, et al. J Cardiovasc Pharmacol. 1996;27:838-844.
  16. Kimura H, Esumi H. Acta Biochem Pol. 2003;50:49-59.