Managing Bevacizumab-Related Toxicities in Patients with ...

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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 a DESCRIPTION MANAGEMENT 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 Grade based on National Cancer Institute–Common Toxicity Criteria, v 3.0 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 Vo l u m e 7, Nu m b e r 6 ■ November/December 2009 www.SupportiveOncology.net 247
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