Adding Bevacizumab to Chemo Raises Treatment-Related Mortality

For a variety of advanced solid tumors, the incidence of fatal adverse effects is significantly higher when bevacizumab is added to chemotherapy than when chemotherapy is used alone, according to a meta-analysis published in the Feb. 2 issue of JAMA.

The most common fatal adverse effects associated with bevacizumab (Avastin), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), were hemorrhage, neutropenia, and gastrointestinal tract perforation, said Dr. Vishal Ranpura and associates at Stony Brook (N.Y.) University Medical Center.

The investigators conducted the meta-analysis because data from clinical trials have been conflicting, and bevacizumab’s role in fatal events in cancer patients "has not been definitively established." VEGF is key to vascular function and angiogenesis, and its inhibition by bevacizumab has been linked to wound dehiscence, bleeding, thromboembolic events, and bowel perforation.

The researchers scanned 385 potentially relevant clinical studies and chose 16 randomized controlled trials for inclusion in the meta-analysis. These comprised phase II and phase III trials involving 10,217 patients given either bevacizumab (5,589 subjects) or a placebo or control agent (4,628 subjects), in addition to standard chemotherapy, for the treatment of advanced colorectal, breast, renal cell, pancreatic, prostate, or non–small-cell lung cancer.

There were 148 fatal adverse events. The incidence was 2.5% among patients receiving bevacizumab, compared with 1.7% in the control patients. The summary relative risk was 1.46, indicating a significantly increased risk of fatal adverse events when bevacizumab was added to conventional chemotherapy.

Approximately 45% of the bevacizumab-associated fatalities were attributed to specific causes, chiefly hemorrhage, perforation of the gastrointestinal tract, and neutropenia. Fatal pulmonary hemorrhage was especially common, perhaps because bleeding in the lungs "is difficult to control and can cause immediate respiratory failure and death," Dr. Ranpura and colleagues said (JAMA 2011;305:487-94).

Treatment with taxanes and platinum agents appeared to raise the risk of fatal events associated with bevacizumab. This may reflect an interaction between these classes of drugs and bevacizumab, the researchers said.

Similarly, the risk of fatal events appeared to vary according to tumor type and bevacizumab dose, but these associations did not reach statistical significance, perhaps because the sample size was not large enough to detect a difference.

These results indicate that patients treated with bevacizumab should be monitored carefully so that potentially fatal adverse events can be quickly identified and treated, they noted.

This study was funded in part by the Research Foundation of the State University of New York at Stony Brook. An associate of Dr. Ranpura reported ties to Onyx, Novartis, Pfizer, Amgen, and Genentech.

For a variety of advanced solid tumors, the incidence of fatal adverse effects is significantly higher when bevacizumab is added to chemotherapy than when chemotherapy is used alone, according to a meta-analysis published in the Feb. 2 issue of JAMA.

The most common fatal adverse effects associated with bevacizumab (Avastin), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), were hemorrhage, neutropenia, and gastrointestinal tract perforation, said Dr. Vishal Ranpura and associates at Stony Brook (N.Y.) University Medical Center.

The investigators conducted the meta-analysis because data from clinical trials have been conflicting, and bevacizumab’s role in fatal events in cancer patients "has not been definitively established." VEGF is key to vascular function and angiogenesis, and its inhibition by bevacizumab has been linked to wound dehiscence, bleeding, thromboembolic events, and bowel perforation.

The researchers scanned 385 potentially relevant clinical studies and chose 16 randomized controlled trials for inclusion in the meta-analysis. These comprised phase II and phase III trials involving 10,217 patients given either bevacizumab (5,589 subjects) or a placebo or control agent (4,628 subjects), in addition to standard chemotherapy, for the treatment of advanced colorectal, breast, renal cell, pancreatic, prostate, or non–small-cell lung cancer.

There were 148 fatal adverse events. The incidence was 2.5% among patients receiving bevacizumab, compared with 1.7% in the control patients. The summary relative risk was 1.46, indicating a significantly increased risk of fatal adverse events when bevacizumab was added to conventional chemotherapy.

Approximately 45% of the bevacizumab-associated fatalities were attributed to specific causes, chiefly hemorrhage, perforation of the gastrointestinal tract, and neutropenia. Fatal pulmonary hemorrhage was especially common, perhaps because bleeding in the lungs "is difficult to control and can cause immediate respiratory failure and death," Dr. Ranpura and colleagues said (JAMA 2011;305:487-94).

Treatment with taxanes and platinum agents appeared to raise the risk of fatal events associated with bevacizumab. This may reflect an interaction between these classes of drugs and bevacizumab, the researchers said.

Similarly, the risk of fatal events appeared to vary according to tumor type and bevacizumab dose, but these associations did not reach statistical significance, perhaps because the sample size was not large enough to detect a difference.

These results indicate that patients treated with bevacizumab should be monitored carefully so that potentially fatal adverse events can be quickly identified and treated, they noted.

This study was funded in part by the Research Foundation of the State University of New York at Stony Brook. An associate of Dr. Ranpura reported ties to Onyx, Novartis, Pfizer, Amgen, and Genentech.

For a variety of advanced solid tumors, the incidence of fatal adverse effects is significantly higher when bevacizumab is added to chemotherapy than when chemotherapy is used alone, according to a meta-analysis published in the Feb. 2 issue of JAMA.

The most common fatal adverse effects associated with bevacizumab (Avastin), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), were hemorrhage, neutropenia, and gastrointestinal tract perforation, said Dr. Vishal Ranpura and associates at Stony Brook (N.Y.) University Medical Center.

The investigators conducted the meta-analysis because data from clinical trials have been conflicting, and bevacizumab’s role in fatal events in cancer patients "has not been definitively established." VEGF is key to vascular function and angiogenesis, and its inhibition by bevacizumab has been linked to wound dehiscence, bleeding, thromboembolic events, and bowel perforation.

The researchers scanned 385 potentially relevant clinical studies and chose 16 randomized controlled trials for inclusion in the meta-analysis. These comprised phase II and phase III trials involving 10,217 patients given either bevacizumab (5,589 subjects) or a placebo or control agent (4,628 subjects), in addition to standard chemotherapy, for the treatment of advanced colorectal, breast, renal cell, pancreatic, prostate, or non–small-cell lung cancer.

There were 148 fatal adverse events. The incidence was 2.5% among patients receiving bevacizumab, compared with 1.7% in the control patients. The summary relative risk was 1.46, indicating a significantly increased risk of fatal adverse events when bevacizumab was added to conventional chemotherapy.

Approximately 45% of the bevacizumab-associated fatalities were attributed to specific causes, chiefly hemorrhage, perforation of the gastrointestinal tract, and neutropenia. Fatal pulmonary hemorrhage was especially common, perhaps because bleeding in the lungs "is difficult to control and can cause immediate respiratory failure and death," Dr. Ranpura and colleagues said (JAMA 2011;305:487-94).

Treatment with taxanes and platinum agents appeared to raise the risk of fatal events associated with bevacizumab. This may reflect an interaction between these classes of drugs and bevacizumab, the researchers said.

Similarly, the risk of fatal events appeared to vary according to tumor type and bevacizumab dose, but these associations did not reach statistical significance, perhaps because the sample size was not large enough to detect a difference.

These results indicate that patients treated with bevacizumab should be monitored carefully so that potentially fatal adverse events can be quickly identified and treated, they noted.

This study was funded in part by the Research Foundation of the State University of New York at Stony Brook. An associate of Dr. Ranpura reported ties to Onyx, Novartis, Pfizer, Amgen, and Genentech.