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22 november 2008: Bron: Medscape

Avastin - Bevacizumab blijkt een sterk verhoogd risico te geven op (venous thromboembolism (VTE)) een vorm van trombose die zeer ernstige schade kan veroorzaken bij kankerpatienten. Dit bljikt uit een meta analyse van 15 gerandomiseerde studies bij totaal 7945 patienten. Vooral de darmkankerpatienten en longkankerpatienten was het risico heel veel hoger dan met alleen chemo, maar ook borstkankerpatienten liepen nog een verhoogd risico. Veneuse trombose is meestal in de aderen van de benen en deze kunnen longemboliën veroorzaken. Arteriële trombose is nog gevaarlijker omdat dit trombose is in een slagader en bv. herseninfarcten kan veroorzaken of een hartstilstand. Maar lees hier een uitgebreid artikel uit Medscape dat aan duidelijkheid niets te wensen overlaat. De onderzoekers merken ook op dat deze studie gevolgen zal moeten hebben voor de klinische toepassing van Avastin - Bevacizumab.

Bevacizumab Significantly Increases Venous Thromboembolism Risk CME

November 21, 2008 — The angiogenesis inhibitor bevacizumab (Avastin, Genentech/Roche) significantly increases the risk for venous thromboembolism (VTE), a new meta-analysis concludes. Because the drug is being increasingly used in the routine treatment of cancer patients, the authors suggest that this new finding might merit a black-box warning.

Currently, the product information includes only arterial thromboembolic events in its warnings section. That finding comes from a meta-analysis of 5 clinical trials involving 7945 patienten, which did not find an increase in the risk for VTE (J Natl Cancer Inst. 2007;99:1232-1239).

However, many more trials have been conducted since then, and this new, much larger, meta-analysis found a significant increase in the risk for VTE. The finding is reported in the November 19 issue of the Journal of the American Medical Association.

The new meta-analysis examined 15 randomized controlled clinical trials involving 7956 patients with various advanced cancers, and found that the risk of developing VTE for patients taking bevacizumab was 33% greater than for controls (relative risk , 1.33; 95% confidence interval, 1.13 - 1.56; P < .001).

"It is imperative for physicians and patients to recognize this risk," write the authors, headed by Shobha Rani Nalluri, MD, from Stony Brook University, in New York. "In the event of venous thromboembolism, anticoagulation is indicated and bevacizumab may be continued if the benefits of the drugs outweigh the risk," they add.

Not Surprising, But of Concern Clinically

The finding is of concern because of the risk for morbidity and mortality related to VTE, senior author Shenhong Wu, MD, PhD, assistant professor of medical oncology at Stony Brook, commented to Medscape Oncology. Patients with cancer undergoing treatment are already at an increased risk of developing VTE, he explained — the incidence of all-grade VTE among such patients is about 9.9%. This new result suggests that bevacizumab raises this risk by 29%, he added.

The finding is not particularly surprising, commented George Sledge, MD, from Indiana University Cancer Center, in Indianapolis. Dr. Sledge was not involved in the study, and serves as an expert site advisor to Medscape Oncology. He pointed out that arterial thromboembolic events are already a known complication, so "it is not particularly surprising that the incidence of VTE events is modestly increased; these are, after all, drugs that affect blood vessels."

Bevacizumab is a monoclonal antibody that neutralizes vascular endothelial growth factor (VEGF), which results in the inhibition of angiogenesis.

VTE is an "emerging complication" of many angiogenesis inhibitors, Dr. Wu and colleagues write. Thalidomide and its derivative lenalidomide, which both act on VEGF and other factors, have also been associated with this complication — VTE has been reported at an incidence of 12% with thalidomide and 8% with lenalidomide, which compares with the 11.9% incidence now reported with bevacizumab, the authors note.

Nevertheless, this finding is important and "certainly of concern clinically, particularly in patients who are already at an increased risk for thromboembolic events," Dr. Sledge commented to Medscape Oncology. "It should represent part of the informed consent for clinical trials," he added, although the question of whether it warrants a black-box warning on the product label, as the authors suggest, is "within the [US Food and Drug Administration's] purview."

"At this point, clinicians should be aware of the potential risk for VTE, although the presence and exact size of any risk (if there is one) is still unclear and may be considered controversial," commented Herbert Hurwitz, MD, from Duke University Medical Center, in Durham, North Carolina. Dr. Hurwitz was the senior author of the previous smaller meta-analysis that found no increase in the risk for VTE.

"The most important issue for clinicians remains prompt and careful management of VTE if and when it occurs," Dr. Hurwitz told Medscape Oncology. "Fortunately, very few of these events were fatal," he pointed out (in the current meta-analysis, only 3 VTE-related deaths occurred, 2 in the bevacizumab group and 1 in the control group).

"To date, use of full-dose anticoagulation with bevacizumab has been shown to be safe in patients who have a clear indication for anticoagulation (i.e., the presence of a VTE), provided that the patient does not have other underlying risks," Dr. Hurwitz commented. "Nevertheless, anticoagulants have intrinsic risks, particularly if used broadly." Therefore, he said, "until this issue is further clarified, routine use of anticoagulants in bevacizumab-treated patients probably cannot be recommended at this time."

The other issue for clinicians and researchers is whether the background rate of VTE (independent of any increase related to bevacizumab) justifies the prophylactic use of anticoagulants more broadly, Dr. Hurwitz said. This is an issue that merits further study, he added. It is also a rather controversial subject, and is hotly debated by oncologists, most recently at the 33rd European Society of Medical Oncology Congress in Stockholm, Sweden, as reported at the time by Medscape Oncology.

According to Genentech/Roche, the manufacturer of bevacizumab, the incidence of VTEs reported in this meta-analysis is consistent with the drug's safety profile as documented in the product label and in previously presented data. "VTEs are typically managed with anticoagulant medication and can occur in people with cancer, regardless of the treatment they are receiving for their cancer," the company said.

Risk Varied Across Different Tumor Types

The meta-analysis found that bevacizumab increased the risk not only for all-grade VTE, but also for clinically significant high-grade VTE, the authors point out. The incidence was 11.9% for all-grade VTE and 6.3% for high-grade VTE. In addition, the risk was significantly and similarly increased by both the low dose (2.5 mg/kg per week) and the high dose (5 mg/kg per week).

However, there was difference in the risk seen among patients with different types of tumors. The highest incidence of all-grade VTE was observed among patients with colorectal cancer (19.1%), whereas the lowest risk was seen in patients with renal cancer (3%). In between were patients with non–small-cell lung cancer (14.9%) and patients with breast cancer (7.3%). A similar pattern across these tumor types was seen with the incidence of high-grade VTE.

This difference in VTE by cancer may be related to biology (for example, higher incidence in aerodigestive malignancies), but may also reflect other factors, such as previous treatment and performance status, say the authors.

Dr. Wu suggested that the high risk found in patients with colorectal cancer and lung cancer may warrant the use of prophylaxis in these patients, for example, with enoxaparin (Lovenox), warfarin (Coumadin), or acetylsalicylic acid (ASA). However, further studies on such prophylaxis need to be performed, he added.

The authors point out several limitations to their meta-analysis, including potential overlap between the various grades of VTE, and the fact that the incidence of VTE varied greatly across the individual clinical trials (ranging from 3% to 19%).

"What this analysis lacks is an exploration of predisposing factors for VTE events," commented Dr. Sledge. One such factor clearly appears to be tumor type, but other factors important for clots include history of clotting episodes, age, obesity, family history, and smoking history. "If these were examined, my suspicion is that we would be able to separate out low and high groups," he told Medscape Oncology.

Dr. Wu has disclosed acting as a speaker for Pfizer, receiving honoraria from Onyx Pharmaceuticals, and being partially supported by the Research Foundation of the State University of New York. The other study authors have disclosed no relevant financial relationships.

JAMA. 2008;300:2277-2285.

Clinical Context

Arterial thromboembolic events have been reported for bevacizumab in previous trials, but studies had not examined the risk for VTE among those treated with bevacizumab. This drug is increasingly used in colorectal cancer, non–small-cell lung cancer, breast cancer, and renal cell carcinoma.

This is a systematic review and meta-analysis of randomized controlled trials to examine and compare the effect of bevacizumab vs placebo or other agents on the risk for VTE in patients with cancer.

Study Highlights

An independent review was conducted for citations from PubMed from 1996 to 2008 and from the Web of Science.
Only randomized controlled trials for patients with cancer treated with or without bevacizumab were included.
Prospective phase 2 trials and randomized controlled trials with patients with cancer in which outcomes of VTE were reported were included.
Phase 1 and single-group phase 2 trials were excluded.
Most trials excluded patients with significant cardiovascular disease, coagulation disorders, and those using anticoagulants or anti-inflammatory drugs.
From a total of 209 studies, 7956 patients from 15 phase 2 and 3 randomized controlled trials (bevacizumab group, n = 4292 and control group, n = 3664) were included for analysis.
6 studies included colorectal cancer; 4 included non–small-cell lung cancer; 2 included breast cancer; and 1 each included pancreatic cancer, malignant mesothelioma, and renal cell carcinoma.
Study size ranged from 98 to 1369.
VTE outcomes were extracted by examining data on adverse events and by contacting authors.
VTE was defined and recorded according to the National Cancer Institute's common toxicity criteria.
Grading of VTE from grade 2 to 4 was adopted.
Grade 2 was defined as thrombosis without intervention being indicated.
Grade 3 was defined as deep venous thrombosis or cardiac thrombosis requiring anticoagulation.
Grade 4 was defined as pulmonary embolism with life-threatening thrombus or death.
High-grade VTE was defined as grade 3 or higher.
Bevacizumab effects were examined by dose (2.5 vs 5.0 mg/kg/week).
Many trials permitted patients to use warfarin.
Both the fixed-effects and random-effects models were used in analysis.
There was no evidence of publication bias.
A total of 2279 patients with colorectal cancer, breast cancer, renal cell cancer, and non–small-cell lung cancer were included from 6 studies for all-grade VTE.
The incidence ranged from 3.0% to 19.1% in the studies, highest in the colorectal studies and lowest in the renal cell carcinoma studies.
The summary incidence of all-grade VTE was 11.9%.
The overall RR for all-grade VTE was 1.33, a 33% increase in risk vs control.
The summary incidence of high-grade VTE was 6.3% (range, 2% - 17%).
The summary RR for high-grade VTE was 1.38 vs control.
Most of the high-grade VTE was grade 3 to 5.
The incidence of grade 3 VTE was 2.9% (RR, 2.21).
For grade 4 VTE, the incidence was 2.1% (RR, 0.75).
There were only 3 deaths from VTE.
The 5-mg/kg/week dose was associated with an RR for VTE of 1.31 (P = .04), whereas the 2.5-mg/kg/week dose was associated with an RR of 1.31 (P = .007).
Thus, both high and low doses were associated with a significant increase in the risk for VTE.
The risk for all-grade VTE varied by tumor type, with the highest incidence seen for colorectal cancer (19.1%) and the lowest incidence seen with renal cancer (3.0%).
For high-grade VTE, the summary incidence was 7.3% for colorectal cancer and 2.0% for renal cancer.
The authors suggested that a black-box warning for bevacizumab may be warranted based on this increased risk for VTE.
They also suggested that the high risk seen for patients with colorectal cancer and lung cancer may warrant the use of prophylaxis in these patients (eg, enoxaparin).