September 9, 2011 — The incidence of thromboembolic events in patients receiving cisplatin-based chemotherapy is unacceptably high, according to research published in the September 10 issue of the Journal of Clinical Oncology.
The anticancer drugs thalidomide and lenalidomide have long been linked to a higher incidence of thromboembolic events. Cisplatin should be added to that list, senior author Hani Hassoun, MD, from Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News.
"We have known that cancer patients, particularly cancer patients undergoing chemotherapy, have a higher incidence of thrombosis," Dr. Hassoun said. "The 2 agents that have been identified in this regard are thalidomide and lenalidomide. Patients who receive either of these drugs for the treatment of multiple myeloma have an 18% to 22% risk for thrombosis. In fact, it is recommended that they receive prophylaxis with either aspirin or heparin."
When he came to Sloan-Kettering some 9 years ago, Dr. Hassoun said he was struck by the number of thrombotic events he was seeing in cancer patients.
"There were young patients who had aortic thrombosis, which is extremely unusual. After seeing a few cases, I thought that we should be looking at the incidence of thrombosis more carefully," he said. "Also, several studies began to appear which showed that chemotherapy enhanced the risk of thromboembolic events, so those results, as well as our clinical experience, prompted this study."
Retrospective Analysis
Dr. Hassoun and his group performed a retrospective analysis of 932 patients who represented all patients treated with cisplatin-based chemotherapy for any type of malignancy at Sloan-Kettering in 2008. They noted that all thromboembolic events occurred between the start of treatment and 4 weeks after the last dose of cisplatin.
They found that, overall, 169 patients (18.1%; 95% confidence interval, 15.7% to 20.8%) developed a thromboembolic event either during treatment or within 4 weeks of their last cisplatin dose.
Almost half of the thromboembolic events were deep vein thrombosis (DVT) alone, which occurred in 84 patients (49.7%). Pulmonary embolus (PE) alone occurred in 43 patients (25.4%), DVT plus PE occurred in 23 patients (13.6%), arterial thrombosis alone occurred in 14 patients (8.3%), and DVT plus arterial thrombosis occurred in 5 patients (3.0%).
Many of the thromboembolic events (56%) were symptomatic, and 43.8% were found incidentally, Dr. Hassoun noted. "We consider that most if not all events would warrant therapeutic intervention."
Most events (88%) occurred within the first 100 days of starting cisplatin. The median time until the occurrence of an event was 48 days (interquartile range, 26 to 73 days).
There were 31 deaths during cisplatin treatment or within 4 weeks of the last cisplatin dose. Of these, 13 patients were known to have suffered a major thromboembolic event within days of their demise. Two patients had events that were "highly suggestive" of a catastrophic thromboembolic event, although this was not proven. The remaining patients had advanced disease during their last hospitalization but the immediate cause of death was not investigated.
The investigators also found that age, Karnofsky Performance Status Scale score, the presence of a central venous catheter, and Khorana score were significant risk factors for the occurrence of a thromboembolic event.
"We probably did not capture 100% of the events," Dr. Hassoun said. "I suspect that there may be some we missed, because this was a retrospective study. But the overall incidence of 18% is unacceptably high."
Dr. Hassoun said he is now trying to get a study in place to look at ways to prevent these events in patients receiving cisplatin.
"Should we give an anticoagulant to prevent these events? The issue is going to be whether this should be a phase 2 trial, which is something we are trying to put in place. It would be a 1-arm study, where all patients would be anticoagulated, and the outcomes would be compared to historical controls," Dr. Hassoun said. "At any rate, prospective studies are urgently needed."
Cisplatin might be toxic to endothelial cells or might affect platelet activity or von Willebrand factor — the exact mechanism of action of its involvement with thromboembolic events is not yet known.
"The mechanism seems to be quite special because it affects not only the venous system but the arterial system as well. These patients present with venous and arterial occlusion," he said.
An Important Paper
Medscape Medical News asked Alok Khorana, MD, from the James P. Wilmot Cancer Center in Rochester, New York, who has studied thromboembolic events in cancer patients and who devised the Khorana score, for his views on this study.
"This paper...represents an important finding because it documents the actual, real-world incidence of thromboembolic events in patients with cancer, and particularly in the subgroup receiving chemotherapy," he noted. "This is particularly important because in clinical trials of cancer patients, event rates are not found to be that high, and one concern is that patients who are truly high risk are not being enrolled in studies."
Dr. Khorana agrees that the incidence of thromboembolic events with cisplatin is "unacceptably high."
"Given that there are ways to prevent clots and that thromboembolic events can contribute to mortality and to morbidity, it is important that we try to prevent them," he said.
Dr. Khorana added that this study validates the risk score that he and his colleagues developed.
"Although rates in even the low-risk subgroup were high, this study documents that you can clearly risk-stratify patients based on the simple clinical and laboratory variables that constitute the score. This finding has implications for other populations of cancer patients — for instance, those who are not receiving cisplatin."
Dr. Hassoun and Dr. Khorana have disclosed no relevant financial relationships.
The anticancer drugs thalidomide and lenalidomide have long been linked to a higher incidence of thromboembolic events. Cisplatin should be added to that list, senior author Hani Hassoun, MD, from Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News.
"We have known that cancer patients, particularly cancer patients undergoing chemotherapy, have a higher incidence of thrombosis," Dr. Hassoun said. "The 2 agents that have been identified in this regard are thalidomide and lenalidomide. Patients who receive either of these drugs for the treatment of multiple myeloma have an 18% to 22% risk for thrombosis. In fact, it is recommended that they receive prophylaxis with either aspirin or heparin."
When he came to Sloan-Kettering some 9 years ago, Dr. Hassoun said he was struck by the number of thrombotic events he was seeing in cancer patients.
"There were young patients who had aortic thrombosis, which is extremely unusual. After seeing a few cases, I thought that we should be looking at the incidence of thrombosis more carefully," he said. "Also, several studies began to appear which showed that chemotherapy enhanced the risk of thromboembolic events, so those results, as well as our clinical experience, prompted this study."
Retrospective Analysis
Dr. Hassoun and his group performed a retrospective analysis of 932 patients who represented all patients treated with cisplatin-based chemotherapy for any type of malignancy at Sloan-Kettering in 2008. They noted that all thromboembolic events occurred between the start of treatment and 4 weeks after the last dose of cisplatin.
They found that, overall, 169 patients (18.1%; 95% confidence interval, 15.7% to 20.8%) developed a thromboembolic event either during treatment or within 4 weeks of their last cisplatin dose.
Almost half of the thromboembolic events were deep vein thrombosis (DVT) alone, which occurred in 84 patients (49.7%). Pulmonary embolus (PE) alone occurred in 43 patients (25.4%), DVT plus PE occurred in 23 patients (13.6%), arterial thrombosis alone occurred in 14 patients (8.3%), and DVT plus arterial thrombosis occurred in 5 patients (3.0%).
Many of the thromboembolic events (56%) were symptomatic, and 43.8% were found incidentally, Dr. Hassoun noted. "We consider that most if not all events would warrant therapeutic intervention."
Most events (88%) occurred within the first 100 days of starting cisplatin. The median time until the occurrence of an event was 48 days (interquartile range, 26 to 73 days).
There were 31 deaths during cisplatin treatment or within 4 weeks of the last cisplatin dose. Of these, 13 patients were known to have suffered a major thromboembolic event within days of their demise. Two patients had events that were "highly suggestive" of a catastrophic thromboembolic event, although this was not proven. The remaining patients had advanced disease during their last hospitalization but the immediate cause of death was not investigated.
The investigators also found that age, Karnofsky Performance Status Scale score, the presence of a central venous catheter, and Khorana score were significant risk factors for the occurrence of a thromboembolic event.
"We probably did not capture 100% of the events," Dr. Hassoun said. "I suspect that there may be some we missed, because this was a retrospective study. But the overall incidence of 18% is unacceptably high."
Dr. Hassoun said he is now trying to get a study in place to look at ways to prevent these events in patients receiving cisplatin.
"Should we give an anticoagulant to prevent these events? The issue is going to be whether this should be a phase 2 trial, which is something we are trying to put in place. It would be a 1-arm study, where all patients would be anticoagulated, and the outcomes would be compared to historical controls," Dr. Hassoun said. "At any rate, prospective studies are urgently needed."
Cisplatin might be toxic to endothelial cells or might affect platelet activity or von Willebrand factor — the exact mechanism of action of its involvement with thromboembolic events is not yet known.
"The mechanism seems to be quite special because it affects not only the venous system but the arterial system as well. These patients present with venous and arterial occlusion," he said.
An Important Paper
Medscape Medical News asked Alok Khorana, MD, from the James P. Wilmot Cancer Center in Rochester, New York, who has studied thromboembolic events in cancer patients and who devised the Khorana score, for his views on this study.
"This paper...represents an important finding because it documents the actual, real-world incidence of thromboembolic events in patients with cancer, and particularly in the subgroup receiving chemotherapy," he noted. "This is particularly important because in clinical trials of cancer patients, event rates are not found to be that high, and one concern is that patients who are truly high risk are not being enrolled in studies."
Dr. Khorana agrees that the incidence of thromboembolic events with cisplatin is "unacceptably high."
"Given that there are ways to prevent clots and that thromboembolic events can contribute to mortality and to morbidity, it is important that we try to prevent them," he said.
Dr. Khorana added that this study validates the risk score that he and his colleagues developed.
"Although rates in even the low-risk subgroup were high, this study documents that you can clearly risk-stratify patients based on the simple clinical and laboratory variables that constitute the score. This finding has implications for other populations of cancer patients — for instance, those who are not receiving cisplatin."
Dr. Hassoun and Dr. Khorana have disclosed no relevant financial relationships.
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