What are the contraindications, precautions, monitoring requirements, and special considerations (including specific populations) for using bevacizumab?

Bevacizumab: Contraindications, Precautions, Monitoring, and Special Considerations

Absolute Contraindications

Bevacizumab must be permanently discontinued in patients who develop Grade 4 hemorrhage, hypertensive crisis, hypertensive encephalopathy, or gastrointestinal perforation. 1, 2, 3

• Squamous cell carcinoma histology in lung cancer is an absolute contraindication due to catastrophic hemoptysis risk, with 5 deaths occurring in early phase 2 studies 1, 2
• Clinically significant hemoptysis (>2.5 mL of blood) excludes bevacizumab use 1
• Recent surgery within 6 weeks or planned elective surgery within 6-8 weeks requires bevacizumab discontinuation due to severe wound healing complications 1, 2, 3, 4
• Extensive prior intra-abdominal surgery increases gastrointestinal perforation risk and contraindicates use 2
• Uncontrolled hypertension (≥180/110 mmHg) requires bevacizumab to be withheld until blood pressure is controlled 1

Relative Contraindications and High-Risk Populations

Bevacizumab should be avoided in patients with ECOG performance status >1, clinically significant cardiovascular disease, or inadequate organ function. 1

• Patients ≥65 years have significantly increased risk of arterial thromboembolic events, particularly stroke 1, 2
• Treated brain metastases are no longer an absolute contraindication, but require no evidence of progression or hemorrhage on imaging within 1 week of treatment, and at least 3 months must have elapsed since neurosurgery 2
• Full-dose anticoagulation is no longer contraindicated, but avoid combining bevacizumab with antiplatelet therapy in patients with end-stage renal disease 2
• Patients with thrombophilia or atrial fibrillation should use tranexamic acid (an antifibrinolytic) with caution, as it represents a relative contraindication 1

Blood Pressure Monitoring and Management

Blood pressure must be measured before every bevacizumab infusion, with a threshold of <160/100 mmHg clinic BP or <150/95 mmHg on ambulatory/home monitoring required to proceed with treatment. 1

Pre-Treatment Assessment

• Baseline blood pressure must be <160/100 mmHg to initiate bevacizumab 1
• If clinic BP ≥160/100 mmHg, arrange ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) before starting therapy 1
• Pre-existing hypertension with BP <160/100 mmHg should not prevent bevacizumab initiation 1

During Treatment Monitoring

• Clinic BP <160/100 mmHg: Continue bevacizumab as scheduled 1
• Clinic BP ≥160/100 mmHg or increase of ≥20/10 mmHg: Omit bevacizumab dose and arrange ABPM/HBPM 1
• Clinic BP ≥180/110 mmHg: Omit bevacizumab dose, initiate or intensify antihypertensive therapy, reassess after ≥2 weeks 1
• Hypertensive crisis: Permanently discontinue bevacizumab and arrange emergency admission 1

Antihypertensive Treatment Algorithm

For antihypertensive-naive patients developing hypertension on bevacizumab, start amlodipine 5 mg daily as first-line therapy. 1

• Step 1: Amlodipine 5 mg daily 1
• Step 2: Add ACE inhibitor (perindopril 2 mg daily) OR ARB (losartan 50 mg daily) 1
• Step 3: Add indapamide 2.5 mg daily 1
• Step 4: Increase dose of ≥1 drug AND/OR add low-dose spironolactone (if K+ <4.5 mmol/L and normal renal function) AND/OR refer to hypertension specialist 1

Post-Treatment Blood Pressure Management

• Hypertension typically resolves after bevacizumab completion, with median resolution time of 87 days (range 3-236 days) 1
• Arrange primary care follow-up within 4 weeks of stopping bevacizumab to reassess need for ongoing antihypertensive therapy 1
• Monitor blood pressure annually once normalized 1

Proteinuria Monitoring

Monitor urine protein every 3-4 weeks during bevacizumab therapy using dipstick testing. 4, 5

• Proteinuria ≥2+ persistent: Discontinue bevacizumab permanently 4
• Overall incidence of all-grade proteinuria is 18% and high-grade proteinuria is 2.4% 6
• Risk of proteinuria increases 5.5-fold compared to controls 6
• Monitor for nephrotic syndrome signs (edema, hypoalbuminemia, hyperlipidemia) 3, 4

Hemorrhage Risk Management

Permanently discontinue bevacizumab for Grade 4 hemorrhage or any life-threatening bleeding event. 2, 3

• Incidence of clinically significant hemoptysis is highest in squamous cell lung cancer (contraindicated) 2, 5
• Monitor for signs of unusual bleeding including coughing or spitting blood 3
• Central nervous system hemorrhage risk is increased in patients with brain metastases 5
• Gastrointestinal bleeding risk is elevated, particularly with concurrent anticoagulation 7, 4

Thromboembolic Event Monitoring

Bevacizumab increases risk of both arterial and venous thromboembolic events, requiring vigilant monitoring and immediate discontinuation for life-threatening events. 3, 4, 5

• Arterial thromboembolic events (stroke, myocardial infarction, transient ischemic attack) occur more frequently in patients ≥65 years 1, 2
• Venous thromboembolism should be managed per American College of Chest Physicians guidelines 4
• Discontinue bevacizumab for new life-threatening arterial or venous thromboembolism 4
• Monitor for signs of stroke, chest pain, shortness of breath, or leg swelling 3

Gastrointestinal Perforation Risk

Monitor for gastrointestinal perforation throughout therapy, with immediate discontinuation required if perforation occurs. 3, 7, 4

• Patients should immediately contact healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting 3
• Risk is highest in patients with extensive prior intra-abdominal surgery 2
• Bowel perforation shares similar pathophysiology with impaired wound healing and bleeding 4
• Permanently discontinue bevacizumab if gastrointestinal perforation develops 3

Surgical Considerations and Wound Healing

Discontinue bevacizumab at least 6 weeks before elective surgery and do not reinitiate until at least 6-8 weeks postoperatively. 1, 2, 3, 4

• Bevacizumab interferes with wound healing through VEGF inhibition 1, 4
• Patients should not undergo surgery without first discussing bevacizumab-related wound healing risks 3
• For emergency surgery, assess risk-benefit ratio carefully given impaired healing potential 4
• Monitor surgical sites closely for dehiscence or delayed healing 4

Specific Populations

Pregnancy and Reproductive Considerations

Bevacizumab causes fetal harm and is contraindicated in pregnancy; females of reproductive potential must use effective contraception during treatment and for 6 months after the last dose. 3

• Advise females to inform healthcare provider of known or suspected pregnancy 3
• Bevacizumab may lead to ovarian failure; discuss fertility preservation options before starting treatment 3
• Do not breastfeed during treatment and for 6 months after the last dose 3

Renal Impairment

• Standard bevacizumab dosing does not require adjustment for renal impairment, but nephrotoxic effects must be considered 2
• Monitor renal function regularly given risk of proteinuria and nephrotic syndrome 3, 4

Elderly Patients

• Patients ≥65 years have increased risk of arterial thromboembolic events, especially stroke 1, 2
• More cautious blood pressure management may be needed, but age alone should not prevent bevacizumab use 1

Hereditary Hemorrhagic Telangiectasia (HHT)

For HHT patients with severe liver vascular malformations, bevacizumab dosing is 5 mg/kg every 2 weeks for 4-6 induction doses, followed by variable maintenance dosing (5 mg/kg every 1-3 months). 1

• Monitor for hypertension, proteinuria, infection, delayed wound healing, and venous thromboembolism 1
• Risk of long-term maintenance therapy is unknown 1
• Bevacizumab's unpredictable efficacy, non-negligible toxicity, and revascularization following withdrawal require careful consideration 1
• Critical issues include problems with wound and anastomosis healing, which could be critical in patients requiring emergency liver transplantation 1

Cardiovascular Monitoring

Monitor for congestive heart failure signs and symptoms throughout bevacizumab therapy. 3

• Bevacizumab increases risk of developing congestive heart failure 3
• Patients should immediately contact healthcare provider for dyspnea, orthopnea, or peripheral edema 3
• Baseline echocardiographic evaluation should be considered in patients with liver vascular malformations, particularly if severe (grade 3-4) 1

Neurological Monitoring

Monitor for posterior reversible encephalopathy syndrome (PRES) with immediate discontinuation required for new onset or worsening neurological symptoms. 3, 4

• PRES presents with headache, seizure, lethargy, confusion, blindness, or altered mental function 4
• Advise patients to immediately contact healthcare provider for new onset or worsening neurological function 3
• PRES is generally reversible with bevacizumab discontinuation and supportive care 4

Infusion-Related Reactions

Monitor patients during and after bevacizumab infusion for hypersensitivity reactions. 3, 4

• Infusion-related reactions are uncommon but can occur 4
• Patients should contact healthcare provider immediately for signs of infusion reactions 3
• Skin rash may occur as an adverse event 4

Common Pitfalls to Avoid

• Do not continue bevacizumab beyond progression: Insufficient data support continuation with second-line regimens after progression on bevacizumab-containing first-line therapy 2
• Do not combine bevacizumab with anti-EGFR antibodies (cetuximab or panitumumab): Combination therapy involving cytotoxics, anti-EGFRs, and anti-VEGFs is not recommended 2
• Do not use maintenance bevacizumab with pemetrexed: This combination has no survival advantage and significantly increased toxicity compared to maintenance pemetrexed or bevacizumab alone 1
• Do not assume blood pressure reduction alone guarantees safety: Close monitoring for all bevacizumab-associated adverse events is required regardless of blood pressure control 8, 4