Bevacizumab Assessed in Three Safety Studies of Bleeding, Wound Healing Complications in CRC

SOUTH SAN FRANCISCO- Three related safety studies assessing bleeding and wound healing complications in colorectal cancer patients whose chemotherapy included the recombinant humanized monoclonal antibody bevacizumab(Drug information on bevacizumab) (Avastin) have yielded some promising results (abstracts 3528, 3529, and 3530), according to investigators. Investigators found no increased risk of venous thromboembolism in patients with metastatic colorectal cancer, no increase in hemorrhagic complications in metastatic colorectal cancer patients receiving bevacizumab concurrent with full-dose anticoagulant therapy during chemotherapy, and no increase in wound healing or bleeding complications when bevacizumab was given with chemotherapy 28 to 60 days following primary surgery for colon or rectal cancer. However, an increase in arterial thromboembolism was seen with the drug. Further, caution must be exercised in colorectal cancer patients already on bevacizumab who then need to undergo surgery, a fourth study has concluded (abstract 3702). Careful Scrutiny
"Since Avastin represents the first survival benefit ever shown with an antiangiogenic drug, we wanted to see if it's really safe to block angiogenesis," said Susan Desmond-Hellmann, MD, MPH, president of Product De- velopment, Genentech, and adjunct associate professor of Epidemiology and Biostatistics at the University of California, San Francisco. Participating in the studies were researchers from Genentech and from multiple institutions, including Duke University Cancer Center, UCLA, Vanderbilt University, Kaiser Perma- nente, US Oncology, Sarah Cannon Cancer Center, and the Hematology/ Oncology Association of Northeast Pennsylvania. In discussing the results in a poster presentation, the investigators concluded that the findings are encouraging for planned further evaluation of bevacizumab in the treatment of colorectal cancer. Concurrent Anticoagulation
One of the safety studies (Hambleton et al, abstract 3528) was done to evaluate the effect of bevacizumab (BV) on bleeding complications in patients with metastatic colorectal cancer receiving full-dose anticoagulation therapy (FDAC); owing to the bleeding seen in NSCLC patients in phase II studies, patients on FDAC had been excluded from a major phase III trial of BV that showed improved survival when it was added to IFL (irinotecan [CPT-11, Camptosar]/5-FU/leucovorin [LV]), with the hazard of death reduced by 34% vs IFL alone (median survival increased from 15.6 to 20.3 months;P < .001). To analyze the outcome of patients with metastatic colorectal cancer who had a thrombotic event while on BV or placebo and remained on study following FDAC, the investigators randomized patients with previously untreated metastatic colorectal cancer to two study arms: arm 1 patients (n = 411) received IFL plus placebo, with irinotecan(Drug information on irinotecan) 125 mg/m², plus 5-FU 500 mg/m², and LV 20 mg/m² once weekly for 4 weeks, with a placebo IV given every 2 weeks; and arm 2 patients (n = 402) received the same IFL regimen but with 5 mg/kg BV intravenously every 2 weeks. Chemotherapy was continued for 96 weeks or until disease progression. Warfarin(Drug information on warfarin) was used as FDAC therapy. Nearly half (43%) of the patients had an ECOG (Eastern Cooperative Oncology Group) performance status greater than 0. Venous Events Comparable
The overall rate of arterial and venous thrombolic events was about 16% in arm 1 (n = 396) and 19% in arm 2 (n = 392). Venous events were comparable in both arms, at about 15% in arm 1 and nearly 17% in arm 2. Overall incidence of grade 3/4 bleeding was about 3% in both arms. Concomitant FDAC in patients who had a thrombotic event did not increase the incidence of grade 3/4 bleeding, which occurred in 2 of 30 (about 7%) patients in arm 1 and in 2 of 53 (about 4%) patients in arm 2. Two Patient Populations
Researchers conducted two subsequent randomized, double-blind, multicenter, placebo-controlled trials, one phase II and the other phase III, in patients with metastatic colorectal cancer (Novotny et al, abstract 3529). The phase II study patients were a median of 10 years older than patients in the phase III study, and 72% had an ECOG performance status greater than 0, compared with 43% of the phase III study group. Phase II and III Studies
The design and results of the phase III trial are as described in abstract 3528, with arm 1 (n = 396) patients receiving IFL plus placebo, and arm 2 patients (n = 392) receiving IFL plus BV. Deep venous thrombophlebitis occurred in about 6% of patients in arm 1 vs 9% of those in arm 2. A thrombotic event resulted in death in four patients in arm 1 and four patients in arm 2, with time to first onset of a thromboembolic event during first-line therapy similar in both arms. Arterial events occurred in about 1% of patients in arm 1 and in 3% of those in arm 2. Phase II Patients Unsuited to Irinotecan
The phase II trial tested the efficacy and safety of adding BV to 5-FU/LV chemotherapy in patients with metastatic colorectal cancer who were unsuited to receive first-line treatment with irinotecan. Arm 1 patients (n = 104) and arm 2 patients (n = 100) received the Roswell Park regimen of 5-FU/LV weekly for 6 weeks with either placebo or BV, respectively, given every 2 weeks). Treatment was continued until disease progression, unacceptable toxicity, or a maximum of 96 weeks. The overall incidence of thromboembolic adverse events in this older patient population was comparable, at about 18% for both arms. Venous events occurred in about 14% of patients in arm 1 vs 9% in arm 2, and arterial events occurred in about 5% of patients in arm 1 vs 10% in arm 2. The investigators concluded that "the high background rate of thromboembolic disease in patients with metastatic CRC highlights the need for well-designed, placebo-controlled clinical trials to assess the safety profile of new oncologic agents in this patient population." Safety Post Ca Surgery
The third report was a randomized, double-blind, placebo-controlled phase III trial, to assess wound healing and bleeding complications in patients who had undergone colonic or rectal cancer surgery 28 to 60 days prior to initial use of BV (Scappaticci et al, abstract 3530). A total of 155 patients who received only bolus IFL plus placebo postsurgery were compared with 150 patients who received IFL plus BV (with regimens as described in abstract 3528) vs a third arm of 37 patients who received postsurgery therapy with 5-FU/ LV/BV (5-FU 500 mg/m² IV, LV 20 mg/m² once a week for 6 weeks, with the cycle repeated every 8 weeks, and BV 5 mg/kg IV every 2 weeks). Incidence of grade 3/4 wound healing or bleeding complications was 1 patient (0.65%) receiving only IFL, 3 patients (2.0%) receiving bolus IFL/ BV, and zero patients in the 5-FU/LV/ BV group. All four patients were able to resume study treatment. "These results suggest that initating BV in patients within a 28- to 60-day time period after surgery does not lead to a significantly increased incidence of wound healing/bleeding complications," the investigators wrote. Surgery While on BV: Caution
Caution is warranted in cases of surgery on patients who are already receiving bevacizumab, noted Genentech researcher Julie S. Hambleton, MD. One study (Hurwitz et al, abstract 3702), she said, shows "4 of 40 patients who had surgery while on Avastin [plus bolus IFL] had postoperative wound healing complications [as well as 1 of 15 on BV/5-FU/LV], so we need to be cautious about taking patients to the operating room if they're actually on an antiangiogenic drug." Prior to their surgery, Hurwitz et al. reported, the five patients had been off BV for 13 to 89 days, with four off therapy for at least 1 month. In conclusion, they advised that "investigators should consider the risks and benefits of surgery when subjects are being treated with BV."