Managing Bevacizumab-Related Toxicities in Patients with ...

HOW WE DO IT 

Managing Bevacizumab-Related Toxicities 

in Patients with Colorectal Cancer 

M. Wasif Saif, MD, MBBS 

B 

evacizumab (Avastin) is the first antiangiogenic 

agent clinically proven to 

extend survival and in combination with 

5-fluorouracil (5-FU)–based chemotherapy 

has been approved by the US Food and 

Drug Administration (FDA) for the first-line or 

second-line treatment of metastatic colorectal 

cancer (CRC). 

In the pivotal phase III study in the first-line 

setting, bevacizumab provided, a 30% increase in 

median overall survival (OS, 20.3 vs 15.6 months; 

hazard ratio [HR], 0.66; P < 0.001) and a 71% 

increase in progression-free survival (PFS, 10.6 

vs 6.2 months; HR, 0.54; P < 0.001) when combined 

with IFL (irinotecan/5-FU/leucovorin [LV]) 

versus IFL alone. 1 Clinical benefit, as measured by 

OS, was observed across all patient subgroups analyzed. 

Increased OS and PFS with bevacizumab 

added to chemotherapy have also been observed in 

other trials in the first-line setting using oxali platin 

(Eloxatin)-based regimens 2,3 and 5-FU/LV. 4,5 

The Eastern Cooperative Oncology Group 

E3200, a randomized phase III trial, confirmed 

the increased efficacy of FOLFOX4 (oxaliplatin/ 

LV/5-FU) plus bevacizumab among patients who 

had experienced disease progression on first-line 

therapy. 6 Patients were randomized to be treated 

with FOLFOX4, FOLFOX4 plus bevacizumab 

(10 mg/kg every 2 weeks), or bevacizumab monotherapy. 

There was a significant improvement in 

median OS with FOLFOX plus bevacizumab (12.9 

months) versus FOLFOX alone (10.7 months). 

This study confirmed the activity of bevacizumab 

in the second-line setting when combined with 

FOLFOX, and it provided data about the safety 

profile at a dose of 10 mg/kg (every 2 weeks). 

Manuscript submitted May 28, 2009; 

accepted July 7, 2009. 

Correspondence to: M. Wasif Saif, MD, Associate Professor, 

Division of Medical Oncology, Yale University School of Medicine, 

333 Cedar Street, FMP 116, New Haven, CT 06520; 

telephone: (203) 737-1569; fax: (203) 785-3788; e-mail: wasif. 

saif@yale.edu 

J Support Oncol 2009;7:245–251 

© 2009 Elsevier Inc. All rights reserved. 

As bevacizumab is becoming widely used in 

general oncology practice, it is important to understand 

the toxicities that can arise. Currently, 

there are no practice guidelines for their management. 

The author describes his experience in 

administering bevacizumab safely, and provides 

recommendations for toxicity management. 

Adverse Events of Treatment 

Bevacizumab offers the potential to increase 

survival without substantially altering the toxicity 

profile in the treatment of metastatic CRC. Many 

adverse events related to anticancer therapy were 

reported in the trials involving bevacizumab with 

cytotoxic chemotherapy. Because bevacizumab 

was used in combination with other chemotherapy 

agents, it can be difficult to determine which 

adverse effects are solely caused by bevacizumab. 

However, the adverse effects associated with the 

chemotherapy agents are well characterized, and 

any new or unexpected adverse effects can thus 

be reasonably attributed to bevacizumab. Fortunately, 

bevacizumab does not have any overlapping 

hematologic or gastrointestinal (GI) toxicities 

with chemotherapeutic agents. 

Phase III/IV trials of bevacizumab in CRC have 

identified hypertension (grade 3/4, 1%–18%), proteinuria 

(grade 3, 0%–2%), wound healing complications 

(1%), GI perforation (0%–2%), arterial 

thromboembolism (< 1%–2%), and bleeding 

(grade 3/4, < 1%–6%) as bevacizumab-associated 

adverse effects (Table 1). 1,5–8 The incidence of bevacizumab-related 

toxicities was similar in clinical 

trials 1–6 and in community-based registry studies 

(BRiTE and first BEAT). 7,8 The BEAT study, conducted 

in 41 countries around the world, and the 

BRiTE registry, its US counterpart, investigated 

the use of bevacizumab in advanced CRC in combination 

with standard chemotherapies, including 

oxaliplatin, irinotecan, or 5-FU, and/or capecitabine 

(Xeloda). The BEAT and BRiTE studies 

also evaluated the safety of bevacizumab with different 

chemotherapies in a broad patient popula- 

Dr. Saif is Director, GI 

Cancers Program, and 

Associate Professor, 

Yale Cancer Center, 

Yale University School 

of Medicine, New 

Haven, Connecticut. 

Vo l u m e 7, Nu m b e r 6 ■ November/December 2009 

www.SupportiveOncology.net 

245

Managing Bevacizumab-Related Toxicities in Patients with Colorectal Cancer 

Table 1 

Major Toxicities of Bevacizumab 

Frequency of ADVERSE EVENTS (%) 

HYPERTENSION PROTEINURIA BLEEDING Gastrointestinal WOUND 

STUDY BEVACIZUMAB DOSE (GRADE 3) (GRADE 3) THROMBOSIS (GRADE 3/4) PERFORATION HEALING 

AVF2107g 1,5 5 mg/kg every 2 weeks 11 1 19 a 3 2 nR 

E3200 6 10 mg/kg every 2 weeks 5 1 3 (VTE) 3 1 nR 

1 (ATE) 

BRiTE 7 5 mg/kg every 2 weeks 16 b NR 2 (ATE) 2 2 1 

First BEAT 8 5 mg/kg every 2 weeks (5-Fu 1 nR 1 (ATE) 1 1 nR 

regimens) or 7.5 mg/kg every 

2 (VTE) 

3 weeks (capecitabine regimens) 

5-FU = 5-fluorouracil; NR = not reported; VTE = venous thromboembolic event; ATE = arterial thromboembolic event 

a 

Thromboembolism (listed as “any thrombotic event”) 

b 

Specified as hypertension requiring medication 

tion. Results from these studies show that bevacizumab’s safety 

profile/tolerability is consistent with the safety observations 

from other studies. 

It is also importunate to note that these toxicities are a class 

effect for all anti-VEGF (vascular endothelial growth factor) 

therapy. As the clinical use of bevacizumab continues to increase 

in the treatment of CRC as well as other malignancies, 

it is prudent to understand the toxicities that can arise and 

know how to manage them. Therefore, the discussion that follows 

explores these toxicities and offers management recommendations 

based on experience and review of the literature. 

Selected Bevacizumab-Associated Toxicities 

HYPERTENSION 

Incidence. Grade 3 hypertension is the most common toxicity 

associated with bevacizumab treatment. Grade 3 hypertension 

is defined as hypertension requiring the addition or modification 

of antihypertensive agents. The overall rate of grade 3 

hypertension in phase III/IV studies is 1%–18%. 5 Hypertension 

can occur at any time during the course of treatment, and preexisting 

hypertension does not predispose patients to grade 2/3 

hypertension. No deaths from bevacizumab-associated hypertension 

have been reported. More than 1% of patients have 

discontinued bevacizumab therapy because of hypertension. 

Grade 4 hypertension is rare (single case in breast cancer phase 

II study). Blood pressure is typically controlled with a single 

antihypertensive agent. 

Treatment Guidelines. Patients receiving bevacizumab 

should always be observed for the development or worsening of 

hypertension through frequent blood pressure measurements. 

We encourage daily home monitoring, if possible. Blood pressure 

measurements should occur after the patient has been in a 

resting position for ≥ 5 minutes. Repeat measurement of blood 

pressure for verification should be undertaken if the initial 

reading is ≥ 140 mm Hg systolic and/or ≥ 90 mm Hg diastolic. 

In most cases, a single-agent antihypertensive can control 

hypertension. Data from the BRiTE trial showed that for patients 

without baseline hypertension, 55% needed one medication, 

38% needed two medications, and 8% needed three or 

more medications. 7 

The selection of an antihypertensive regimen should be left 

to the treating physician. Standard antihypertensive therapy, 

typically angiotensin-converting enzyme (ACE) inhibitors, 

beta-blockers, calcium channel blockers, or diuretics, can be 

used to control grade 3 hypertension, and bevacizumab can be 

continued without dose modification. We generally use ACE 

inhibitors, based on some aspects of the biology of VEGF inhibitors 

and the possibility of decreasing the amount of proteinuria; 

however, standard guidelines for the selection of antihypertensive 

medications are appropriate. In addition to a mechanistic 

rationale, diuretics should also be used cautiously to treat 

bevacizumab-related hypertension due to potential worsening 

of dehydration secondary to chemotherapy-induced diarrhea. 

We generally practice as well as recommend assessing hypertension 

and other toxicities according to the National Cancer 

Institute–Common Toxicity Criteria (NCI–CTC) grading, 

as such an evaluation can help physicians to make a decision 

comparatively easily (Table 2). Several guidelines for managing 

hypertension associated with bevacizumab follow: 

• Bevacizumab should not be initiated in patients with uncontrolled 

hypertension. 

• Blood pressure should be measured at least every 2 to 3 

weeks in patients treated with bevacizumab. 

• Blood pressure monitoring may be required at more frequent 

intervals in patients who develop hypertension during 

treatment. 

• Blood pressure monitoring should continue at regular 

intervals in patients with bevacizumab-induced or bevacizumab-exacerbated 

hypertension, even if they have discontinued 

bevacizumab. 

• Bevacizumab should be suspended or permanently discontinued 

if hypertension cannot be managed with standard 

oral antihypertensive agents. 9 

• Bevacizumab should be permanently discontinued if a 

hypertensive crisis occurs. 

PROTEINURIA 

Incidence. Although the risk is minimal, severe proteinuria 

can occur in a few patients secondary to bevacizumab. In the 

246 www.SupportiveOncology.net Th e Jo u r n a l o f Su p p o rt i v e On c o l o g y

Saif 

Table 2 

Bevacizumab-Associated Hypertension: Guidelines for Dosing and Schedule Modification 

Grade a DESCRIPTION MANAGEMENT 

Grade 1 • Asymptomatic, transient (< 24 hours) increase in blood pressure by 20 mm Hg (diastolic) or to No action needed 

> 150/100 mm Hg if previously within normal limits; intervention not indicated 

• Pediatric: asymptomatic, transient (< 24 hours) increase in blood pressure beyond upper limit 

of normal; intervention not indicated 

Grade 2 • Recurrent or persistent (≥ 24 hours) or symptomatic increase by > 20 mm Hg (diastolic) or to No action needed 

> 150/100 mm Hg if previously within normal limits; monotherapy may be indicated 

• Pediatric: recurrent or persistent (≥ 24 hours) increase in blood pressure beyond upper limit 

of normal; monotherapy may be indicated 

Grade 3 Requiring more than one drug or more intensive therapy than used previously If not controlled with medication, 

discontinue bevacizumab 

Grade 4 Life-threatening consequences (eg, hypertensive crisis) Discontinue bevacizumab 

a 

Grade based on National Cancer Institute–Common Toxicity Criteria, v 3.0 

Table 3 

Bevacizumab-Associated Proteinuria: Guidelines for Dosing and Schedule Modification 


Grade 1 ≥ 1 g of protein or 0.15–1 g/24 h no action needed 

Grade 2 ≥ 2 to ≥ 3 g of protein or > 1–3.5 g/24 h • Hold bevacizumab until proteinuria improves to ≤ 2 g of protein per 24 hours 

• Discontinue bevacizumab in a patient with > 2 g proteinuria per 24 hours that does not 

resolve within 3 months after holding bevacizumab 

• Workup for proteinuria, such as renal biopsy, should be considered 

Grade 3 ≥ 4 g of protein or > 3.5 g/24 h Discontinue bevacizumab 

Grade 4 Nephrotic syndrome Discontinue bevacizumab 

a 


randomized trial by Hurwitz et al as well as in TREE-2, the 

incidence of grade 3 proteinuria was the same in both groups. 1,2 

Similarly, in E3200, the risk of grade 3 proteinuria was 1% or 

less in the groups that received FOLFOX/bevacizumab. 6 There 

appears to be no correlation between proteinuria and hypertension 

in patients treated with bevacizumab. 

Nephrotic syndrome did occur in 5 of 1,032 patients who 

were treated with bevacizumab, according to data pooled from 

several industry-sponsored studies. 10 The renal dysfunction 

required dialysis in one patient, and a second patient with 

nephrotic syndrome died. In the three remaining patients, the 

amount of proteinuria decreased with time but did not normalize. 

On the other hand, no cases of nephrotic syndrome were 

reported among 1,960 patients in the BRiTE registry study. 7 

Monitoring. There is no clear consensus on the monitoring 

of proteinuria, and recommendations vary by investigators. 

However, we suggest that proteinuria be evaluated at baseline 

and then monitored regularly throughout treatment. 

• Patients treated with bevacizumab should be monitored 

for proteinuria by using the ratio of urine protein to 

creatinine. This index of proteinuria is commonly used in the 

nephrology literature and correlates well with 24-hour protein 

excretion. Using this ratio also avoids the inaccuracies 

associated with dipstick urine assays and the inconvenience 

of 24-hour collections. 

• If spot urine protein tests are not available, dipstick urine 

assays at regular intervals are useful. The frequency of testing 

should be every 2–8 weeks (before each dose and/or at each restaging), 

according to the severity of the previous proteinuria 

and any other relevant risk factors or considerations. 

• Dipstick values 2+ or higher should be confirmed by the 

ratio of urine protein to creatinine or 24-hour collection. 

Treatment Guidelines. Again, we encourage oncologists to 

follow the NCI–CTC grading to assess and manage proteinuria 

(Table 3). 

WOUND HEALING 

Incidence. Wound healing complications have been described 

in patients who underwent primary cancer surgery 

within 28–60 days before starting bevacizumab treatment and 

while on bevacizumab treatment. 1 Sixty-day postoperative adverse 

events that were recorded included abnormal healing, 

wound dehiscence, delayed wound healing, bowel perforation, 

fistula, abscess, and hemorrhage. In the preliminary BRiTE 

analysis, 1% of the patients had postoperative complications. 7 

Treatment Guidelines. Patients who undergo any invasive 

procedure while receiving bevacizumab might encounter problems 

with wound healing (Table 4). 11 Therefore, any known 

upcoming procedures, such as biopsies or venous access system 

placement, should be performed and the wound healed before 

initiating therapy with bevacizumab. 

There have been limited data regarding the safety of venous 



247


Table 4 

Bevacizumab-Associated Wound Healing Complications (Noninfectious): Guidelines for Dosing 

and Schedule Modification 


Grade 1 Incisional separation of ≤ 25% of wound, no deeper than superficial fascia no action needed 

Grade 2 Incisional separation > 25% of wound with local care; asymptomatic hernia no action needed 

Grade 3 Symptomatic hernia without evidence of strangulation; fascial disruption/dehiscence without evisceration; Discontinue bevacizumab 

primary wound closure or revision by operative intervention indicated; hospitalization or hyperbaric oxygen 

indicated 

Grade 4 Symptomatic hernia with evidence of strangulation; fascial disruption with evisceration; major reconstruction Discontinue bevacizumab 

flap, grafting, resection, or amputation indicated 

a 


access catheter insertion before bevacizumab treatment. An 

analysis of 534 patients who had catheters placed before treatment 

with bevacizumab and 5-FU or capecitabine-based therapy 

showed that the risk of wound healing complications was 

low (1.1%). 12 There were no bleeding events, and the catheterrelated 

thrombosis rate was 1.7% among all patients and 3.3% 

among those in whom the catheter was inserted within 7 days. 12 

In the past 2 years, we have had more than 18 patients receive 

bevacizumab within 24 hours after placement of a catheter, and 

not a single complication has been witnessed to date. 

Further guidelines regarding bevacizumab-associated 

wound healing complications follow: 

• If a patient has been on bevacizumab, it should be held 

for 30–60 days before elective surgery, such as resection of metastasis 

or other procedures, is performed. 

• For emergency surgery, the patient, surgeon, and nursing 

staff should be aware of the possible risks of bevacizumab. 

• In general, clear communication with the surgeon is 

necessary, especially when a combined-modality approach to 

care is being taken. 

GI PERFORATION 

Incidence. GI perforation was first observed in the pivotal 

phase III trial, in which six events occurred in the bevacizumab 

group (1.5%), compared with no events in the control group. 1 

Since then, similar rates of GI perforation have been observed 

in other large trials, as well as in the BRiTE study. 7 

The common clinical and radiologic manifestations of patients 

with GI perforations while on bevacizumab include subdiaphragmatic 

air on a kidney-ureter-bladder radiograph not 

Table 5 

Arterial Thromboembolism Events 

Associated with Bevacizumab 

EVENT IFL + BEVACIZUMAB IFL + PLACEBO 

Cerebrovascular events 4 patients 0 patients 

Myocardial infarction 6 patients 3 patients 

Deep venous thrombosis 34 patients 19 patients 

Intra-abdominal thrombosis 13 patients 5 patients 

IFL = irinotecan/5-fluorouracil/leucovorin 

requiring surgery; a perforated stomach ulcer; colonic perforation 

associated with carcinomatosis or an abdominal abscess; 

a small bowel obstruction, abscess, and perforated transverse 

colon; and bowel obstruction, ileal necrosis, and perforation. 

There seems to be no apparent pattern in the location of the 

perforation or its presentation. 

It is important to note that GI perforation can occur at any 

time while a patient is on therapy with bevacizumab. BRiTE 

data showed that half the perforations occur after 3 months 

of therapy and that almost 25% occur after 6 months of treatment. 

Similarly, in E3200, the incidence of bowel perforations 

in each bevacizumab-containing arm was 1%. 6 

Risk Factors. GI perforation is a rare but potentially lifethreatening 

toxicity of bevacizumab. Sugrue et al evaluated 

possible risk factors for GI perforations in patients with metastatic 

CRC receiving bevacizumab plus chemotherapy in the 

BRiTE study. 13 The rate of GI perforations was similar among 

patients with or without a baseline history of peptic ulcer disease 

(1.8% vs 1.7%), diverticulosis (1.8% vs 1.7%), or chronic 

use of acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory 

drugs (0% vs 1.7%). 9 There appeared to be a higher 

incidence of GI perforations in patients with a primary tumor 

intact (3.3% vs 1.4%), a recent history of sigmoidoscopy or 

colonoscopy (2.6% vs 1.5%), or previous adjuvant radiation 

therapy (2.3% vs 1.6%). However, it is necessary to confirm 

these preliminary findings with multivariate analyses. 

The randomized phase III study also indicated that the risk 

of GI perforation is increased among patients who have surgery 

within 60 days before receiving bevacizumab and among patients 

who have surgery while receiving bevacizumab. 1 Therefore, a high 

index of suspicion should be reserved for patients with vomiting, 

constipation, and abdominal pain. Any concerning symptoms 

should be followed by physical examination and radiographic imaging. 

Furthermore, the treatment team’s nurses, physicians assistants, 

and fellows should be educated about GI perforations in 

these patients to promptly attend to such an emergency. 

Treatment Guidelines. The use of bevacizumab before and 

after surgery requires a multidisciplinary approach, with close, 

clear communication between the surgeon and the oncologist. 

For elective operations, bevacizumab should be discontinued 

at least 30–60 days before a scheduled surgery. How 

long to hold bevacizumab is unknown and may be related to 


Saif 

the difference in peripheral half-life versus the tissue half-life. 

However, the long half-life of 20 days should be taken into account. 

After surgery, bevacizumab should be held for a period 

of 30–60 days, and the surgical wound should be completely 

healed before initiating treatment. This practice of ours has 

been adapted from clinical trials. In cases of emergency procedures, 

bevacizumab should be held and patients followed 

closely for complications. 14 

Any NCI–CTC grade of GI perforation warrants discontinuation 

of bevacizumab. 

VENOUS AND ARTERIAL THROMBOTIC EVENTS 

Incidence. In the randomized, double-blind, phase III study 

evaluating bevacizumab in combination with IFL as first-line 

treatment of metastatic CRC, the incidence of all venous and 

arterial thrombotic events was 19.4% in the IFL/bevacizumab 

group and 16.2% in the IFL plus placebo group (P = 0.26). 1 

The incidence of grade 3/4 thromboembolic events in patients 

receiving IFL/bevacizumab as compared with patients receiving 

IFL plus placebo is shown in Table 5. 

A pooled analysis was conducted from five randomized trials 

(CRC, non–small-cell lung cancer [NSCLC], and breast cancer) 

that included 1,745 patients: AVF0757g (lung), AVF0780g 

(CRC), AVF2119g (breast), AVF2192g (CRC), and AVF2107g 

(CRC). 15 The rate of arterial thromboembolic events (ATEs) in 

the chemotherapy-only group was 1.9%, whereas the rate in 

the bevacizumab plus chemotherapy group was 4.4%. 

A multivariate risk analysis identified two risk factors associated 

with ATE 16 : previous ATE and age > 65 years. Other 

risk factors might include hypertension and smoking. It is notable, 

however, that overall, patients with these risk factors still 

showed substantial clinical benefit in the pivotal phase III trial. 

Patients aged ≥ 65 years had a 43% reduction in the risk of 

disease progression and a 39% reduction in the risk of death, 

and patients with a history of arterial thromboembolism had 

a 39% reduction in the risk of disease progression and a 62% 

reduction in the risk of death. 

Although patients aged > 65 years have an increased risk of 

arterial thromboembolism, oncologists must use their own medical 

judgment in assessing the overall risk/benefit of bevacizumab 

therapy. 16 In the pivotal bevacizumab trial, there were 271 patients 

aged ≥ 65 years. 1 This group of patients continued to have 

a benefit in terms of PFS (HR, 0.57) and OS (HR, 0.61), despite 

the higher risk of ATEs. In addition, patients who had a history 

of arterial events and were aged > 65 years also had a PFS and 

OS benefit, with HRs of 0.55 and 0.59, respectively. The data 

on the benefit of bevacizumab in patients aged > 65 years are 

important, but the interaction of age and previous ATEs must be 

considered in certain patients (eight-fold increase in risk), and 

therefore therapy with bevacizumab must be individualized. 

Table 6 

Bevacizumab-Associated Thrombosis/Thromboembolism: Guidelines for Dosing and Schedule Modification 


Grade 1 (venous) Not applicable – 

Grade 2 (venous) Deep vein thrombosis or cardiac thrombosis; No action needed 

intervention (eg, anticoagulation, lysis, filter, 

invasive procedure) not indicated 

Grade 3 (venous) Deep vein thrombosis or cardiac thrombosis; Withhold bevacizumab 

intervention (eg, anticoagulation, lysis, filter, If the planned duration of therapeutic-dose anticoagulant therapy b 

invasive procedure) indicated 

is ≤ 2 weeks, bevacizumab should be withheld until the period of 

therapeutic-dose anticoagulant therapy is over. 

If the planned duration of therapeutic-dose anticoagulant therapy b 

is > 2 weeks, bevacizumab should be withheld for 2 weeks and then 

may be resumed during the period of therapeutic-dose anticoagulant 

therapy as soon as all of the following criteria are met: 

• The patient must be on a stable dose of anticoagulant medication 

and, if on warfarin, have an INR within the target range (usually between 

2 and 3) before restarting study drug treatment 

• The patient has no history of grade 3/4 hemorrhagic events before 

restarting bevacizumab 

• The patient has no evidence of tumor invading or abutting major 

blood vessels on any previous CT scan 

Grade 4 (venous) Embolic event, including pulmonary embolism Same as for grade 3 

or life-threatening thrombus 

Incidentally discovered pulmonary embolus, Same as for grade 3 

first occurrence 

Symptomatic grade 4 venous thromboembolic Discontinue bevacizumab 

event, first occurrence 

Any grade of arterial – Discontinue bevacizumab 

thromboembolic event 

INR = international normalized ratio 

a 


b 

Defined as a dose titrated to maintain an INR of ≥ 1.5 for warfarin or its equivalent for other anticoagulant medications 



249


Table 7 

Bevacizumab-Associated Hemorrhage: Guidelines for Dosing and Schedule Modification 


Grade 1 Mild, intervention (other than iron supplements) not indicated no action needed 

Grade 2 Symptomatic and medical intervention or minor cauterization indicated no action needed 

Grade 3 Transfusion, interventional radiology, endoscopic, or operative intervention indicated; radiation therapy Discontinue bevacizumab 

(ie, hemostasis of bleeding site) 

a 


Figure 1 Fluid-Attenuated Inversion Recovery MRI 

Scan Taken the Day of Neurologic Symptom 

Development Showing a Bilateral Occipital 

and Posterior Parietal Abnormality 

Reproduced, with permission, from Allen JA, Adlakha A, Bergethon PR. 

Reversible posterior leukoencephalopathy syndrome after bevacizumab/ 

FOLFIRI regimen for metastatic colon cancer. Arch Neurol 2006;63:1475–1478 

Treatment Guidelines. A high degree of suspicion should be 

developed in the presence of clinical manifestations (Table 6). 

Patients with a severe ATE (any grade) during bevacizumab 

treatment should discontinue treatment permanently. 

Many patients with a previous ATE are routinely treated with 

low-dose ASA. When these patients entered clinical trials of bevacizumab, 

they were able to continue low-dose ASA therapy 

without any evidence of an increased risk of bleeding. 17 Because 

of the limited number of patients on ASA who developed a new 

ATE during bevacizumab therapy, there are insufficient data at 

this time to determine whether low-dose ASA reduces the risk 

of future events while on bevacizumab. This is an important topic 

for future study because of the number of patients aged > 65 

years who could potentially benefit from bevacizumab therapy. 

The use of high-dose ASA cannot be recommended because of 

the lack of safety data. An upcoming trial will evaluate whether 

the addition of low-dose warfarin therapy can safely prevent 

thrombotic and thromboembolic complications. 

BLEEDING/HEMORRHAGE 

Incidence. Epistaxis was the common bleeding event encountered 

in the phase II dose-finding study of bevacizumab (46%, 

5 mg/kg; 53%, 10 mg/kg, compared with FU/LV (11%). Most 

epistaxis events were transient (< 5 minutes). Although three 

patients in the 10-mg/kg arm had grade 3/4 bleeding, the relationship 

to the bevacizumab dose was unclear. No grade 3/4 

bleeding occurred in the 5-mg/kg group or in the control group. 

In the phase III pivotal trial, there was not a significantly 

increased risk of grade 3/4 bleeding with the addition of bevacizumab 

(5 mg/kg) to chemotherapy. 1 In E3200, which used 

the 10-mg/kg dose of bevacizumab, there was only a marginal 

increase in bleeding of 1%, compared with < 1% for the control 

arm without bevacizumab. However, in the first BEAT study, 

although the incidence of serious bleeding events was only 

1.3%, there were eight deaths from bleeding (three of these patients 

also had GI perforation). 8 The BRiTE data registered a 

2.2% rate of serious bleeding events. 

A notable toxicity in the E4599 NSCLC study was the occurrence 

of two deaths from hemoptysis, prompting the exclusion 

of patients with a history of significant hemoptysis and centrally 

located squamous cell tumors from receiving bevacizumab. 18 

Treatment Guidelines. Among patients with colon cancer who 

experience grade 3 hemorrhage while receiving full-dose anticoagulation 

(within the therapeutic range or increased range), bevacizumab 

should be discontinued (Table 7). For patients with 

grade 3 hemorrhage who are not receiving full-dose anticoagulation, 

bevacizumab should be held until the bleeding has resolved, 

there is no coagulation disorder that would increase the 

risk of subsequent bleeding, and there is no anatomic or pathologic 

condition that increases the risk of hemorrhage. If the patient 

experiences a repeat grade 3 or a new grade 4 hemorrhagic 

event, bevacizumab should be permanently discontinued. 

REVERSIBLE POSTERIOR 

LEUKOENCEPHALOPATHY SYNDROME 

Incidence and Diagnosis. The prescribing information for bevacizumab 

has been updated to include warnings regarding a rare 

brain-capillary leak syndrome called reversible posterior leuko- 


Saif 

encephalopathy syndrome (RPLS). Clinical studies and postmarketing 

data reveal that RPLS occurs at a rate of < 0.1%. 19 

Signs and symptoms of RPLS include headache, seizure, lethargy, 

confusion, blindness, and hypertension. It is hypothesized 

that in these patients, bevacizumab might have induced vasospasm 

that coupled with hypertension led to RPLS. 

The diagnosis of RPLS is made by clinical and radiologic 

findings. MRI reveals patchy areas of increased fluid-attenuated 

inversion recovery signal intensity in the brain, as shown in 

Figure 1, consistent with RPLS. Clinicians should be aware of 

this potential complication and should control blood pressure 

strictly during and after bevacizumab infusion. 

Treatment Guidelines. Bevacizumab should be discontinued in 

patients with MRI-confirmed RPLS, and hypertension should be 

treated if necessary. Controlling hypertension and discontinuing 

the offending agent appear to help reverse the complication. 

Conclusion 

Bevacizumab, the first FDA-approved VEGF-targeted 

agent, significantly increases PFS and OS (first-line and 

second-line) in combination with standard chemotherapy 

regimens in patients with metastatic CRC. Phase II/III trials 

have demonstrated the efficacy of bevacizumab in combination 

with 5-FU/LV, IFL, FOLFOX, FOLFIRI (5-FU/LV/ 

irinotecan), CAPOX (capecitabine/oxaliplatin), and cetuximab 

(Erbitux)/bevacizumab. The efficacy and toxicity of 

bevacizumab have primarily been evaluated in patients 

with advanced disease, and the preliminary results of the 

National Surgical Adjuvant Breast and Bowel Project C08 

study in adjvant treatment of stage II and III CRC showed 

no unexpected side effects. However, long-term follow-up 

continues. 

As current trials mature, safety data will be clarified further, 

and specific guidelines for the management of bevacizumabrelated 

toxicities will become more detailed. As the use of 

bevacizumab increases, more information will be necessary to 

identify specific factors placing patients at higher risk of complications. 

The key to administering bevacizumab treatment 

safely will be through education of patients, nurses, and other 

healthcare providers. 

Conflicts of interest: Dr. Saif is on the speakers bureau of Genentech. 

References 

PubMed ID in brackets 

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leucovorin for metastatic colorectal cancer. N Engl J 

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Hainsworth JD, Hedrick EE, Childs BH. Safety and 

efficacy of oxaliplatin/fluoropyrimidine regimens 

with or without bevacizumab as first-line treatment 

of metastatic colorectal cancer: final analysis of the 

TREE study. J Clin Oncol 2006;24(18S):3510. 

3. Saltz L, Clarke S, Diaz-Rubio E, et al. 

Bevacizumab (Bev) in combination with XELOX or 

FOLFOX4: updated efficacy results from XELOX-1/ 

NO16966, a randomized phase III trial in firstline 

metastatic colorectal cancer. J Clin Oncol 

2007;25(18S):4028. 

4. Kabbinavar FF, Hambleton J, Mass RD, Hurwitz 

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