Anemia Drugs Tied to Deaths in Cancer Patients

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SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT

For a related video, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT

For a related video, go to www.youtube.com/InternalMedicineNews

SAN FRANCISCO — Cancer patients on erythropoiesis-stimulating agents are 17% more likely to die of any cause while in clinical trials and 6% less likely to be alive at the longest available follow-up, researchers reported at the annual meeting of the American Society of Hematology.

Dr. Julia Bohlius and her collaborators conducted the most far-reaching meta-analysis to date of clinical studies of anemia drugs. Not relying on published literature, the group collected individual patient data from 53 randomized, controlled trials that included 13,933 patients.

This sample included 10,441 patients in chemotherapy trials. The impact of erythropoiesis-stimulating agents (ESAs) was less dramatic in chemotherapy patients, but they, too, had 10% higher mortality while in “the active study phase,” and their survival rate was 4% worse at the longest available follow-up.

“ESAs increased on-study mortality and worsened overall survival in cancer patients. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded,” Dr. Bohlius of the University of Bern (Switzerland) said at a press briefing, where she revealed the new data prior to a late-breaking abstract session. Mortality and overall survival were significantly worse (P = .002 and P = .05, respectively) for all cancer patients in the meta-analysis.

As an acknowledged “uncertainty,” chemotherapy patients were not statistically different from 737 patients on radiochemotherapy, 799 on radiotherapy, 266 who were receiving other treatments, and 1,690 who were not treated.

“If you ask two statisticians how to interpret these results, you will get three opinions,” Dr. Bohlius said.

Possible next steps include evaluations of post-treatment hemoglobin levels on mortality and the effects of ESAs on thromboembolic events, tumor progression, quality of life, and transfusion needs.

“What we don't really know is why patients die,” said her coauthor, Dr. Andreas Engert. He cited two theories—the ESAs promote tumor progression or high hemoglobin levels increase the chance of fatal thromboembolic events.

“I think it is underreporting of thromboembolic events. There [are] no strong data that tumor progression is the cause,” said Dr. Engert, chairman and professor of internal medicine, hematology, and oncology at the University of Cologne (Germany). Because these trials enroll cancer patients, many with advanced disease, autopsies that might uncover other causes of death are rarely, if ever, performed.

The results confirm earlier data that led ASH and the American Society for Clinical Oncology to revise their guidelines for ESA use, said Dr. Samuel M. Silver, head of ASH's reimbursement committee. In 2009, “a new guideline panel will be put together by ASH and ASCO, and a discussion of [these] data is going to be incredibly important,” said Dr. Silver, assistant dean for research and professor of internal medicine, University of Michigan, Ann Arbor.

Use of ESAs has decreased and blood transfusions are up substantially in the wake of tightened Food and Drug Administration and Medicare directives on ESAs. The drugs are now indicated in cancer for patients with chemotherapy-induced anemia only. The impact ranges from surgeries being postponed because of reduced blood supplies, to reduced availability of outpatient beds for transfusions, to exacerbated comorbidities.

A steering committee guided the meta-analysis, which was done independently in two academic departments. Representatives of the three ESA manufacturers—Amgen Inc., Johnson & Johnson, and Hoffmann-La Roche Inc.—served on the advisory board and contributed data, Dr. Bohlius said, but “had no involvement in the study design, analysis, and interpretation of data and in the writing of the report.”

All funding came from two industry-independent sources: the German Ministry of Education and Research and OncoSuisse. Median follow-up was 4 months for the on-study mortality data, and 6 months for overall survival rates.

Dr. Bohlius, Dr. Engert, and Dr. Silver said they had no conflicts of interest.

'If you ask two statisticians how to interpret these results, you will get three opinions.' DR. BOHLIUS

'There [are] no strong data that tumor progression is the cause' of the increase in deaths. DR. ENGERT