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Managing Bevacizumab-Related Toxicities in Patients with Colorectal Cancer Table 4 Bevacizumab-Associated Wound Healing Complications (Noninfectious): Guidelines for Dosing and Schedule Modification Grade a DESCRIPTION MANAGEMENT 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 Grade based on National Cancer Institute–Common Toxicity Criteria, v 3.0 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 248 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 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 a DESCRIPTION MANAGEMENT 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 Grade based on National Cancer Institute–Common Toxicity Criteria, v 3.0 b Defined as a dose titrated to maintain an INR of ≥ 1.5 for warfarin or its equivalent for other anticoagulant medications Vo l u m e 7, Nu m b e r 6 ■ November/December 2009 www.SupportiveOncology.net 249
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