Bruce Jancin

DENVER – A four-factor prothrombin complex concentrate bettered plasma for urgent reversal of warfarin and other vitamin K antagonists in patients experiencing major bleeding.

Marketed as Beriplex, the product had a higher rate of INR reversal than did plasma at 30 minutes after the start of infusion, based on results from a phase IIIb prospective, multicenter, randomized clinical trial.

The prothrombin complex concentrate (PCC) also proved more successful than plasma at early replacement of depleted coagulation factors and was noninferior to plasma in terms of blinded investigator–rated hemostatic efficacy in the first 24 hours, Dr. Joshua N. Goldstein said at the annual meeting of the American College of Emergency Physicians.

The study included 202 adults on warfarin or another vitamin K antagonist who presented with acute major bleeding. The objectives were to correct their INR as quickly as possible and thereby reduce their blood loss. Participants were randomized to INR- and weight-based dosing of the PCC or to plasma on top of background vitamin K given by slow intravenous infusion in all cases.

Thirty minutes after the start of the infusion, the mean INR was significantly lower in patients on the PCC than in those given plasma. The higher the baseline INR, the greater the benefit of the PCC. For example, in 58 patients with a baseline INR above 6, the mean INR dropped from 10.6 preinfusion to 1.5 at 30 minutes in the PCC group and to 3.7 in the plasma recipients, reported Dr. Goldstein of the University of Rochester (N.Y.).

In 44 patients with a baseline INR of 4-6, the INR fell from a mean of 4.6 preinfusion to 1.4 at 30 minutes in the PCC group and to 3.2 in patients on plasma. And in patients with a baseline INR of 2 to less than 4, mean INR fell from 2.9 preinfusion to 1.6 in the PCC group and to 2.2 in the plasma recipients.

One hour after the start of infusion, roughly 70% of PCC recipients had corrected their INR as defined by an INR of 1.3 or less, compared with less than 5% of plasma recipients.

Median factor levels were below 50% at baseline. Levels increased significantly more within 30 minutes of starting PCC infusion than with plasma. This wasn’t particularly surprising, since the PCC contains factors II, VII, IX, and X, along with proteins C and S, Dr. Goldstein observed.

Blinded investigators rated hemostatic efficacy in the first 24 hours as good or excellent in 72% of the PCC group and in 65% of patients on plasma, a nonsignificant difference.

Thromboembolic event rates through 51 days of follow-up were 7.8% with the PCC and 5.5% with plasma.

Dr. Goldstein reported that he serves as a consultant to and advisory board member for CSL Behring, which markets Beriplex and sponsored the study.

DENVER – A four-factor prothrombin complex concentrate bettered plasma for urgent reversal of warfarin and other vitamin K antagonists in patients experiencing major bleeding.

Marketed as Beriplex, the product had a higher rate of INR reversal than did plasma at 30 minutes after the start of infusion, based on results from a phase IIIb prospective, multicenter, randomized clinical trial.

The prothrombin complex concentrate (PCC) also proved more successful than plasma at early replacement of depleted coagulation factors and was noninferior to plasma in terms of blinded investigator–rated hemostatic efficacy in the first 24 hours, Dr. Joshua N. Goldstein said at the annual meeting of the American College of Emergency Physicians.

The study included 202 adults on warfarin or another vitamin K antagonist who presented with acute major bleeding. The objectives were to correct their INR as quickly as possible and thereby reduce their blood loss. Participants were randomized to INR- and weight-based dosing of the PCC or to plasma on top of background vitamin K given by slow intravenous infusion in all cases.

Thirty minutes after the start of the infusion, the mean INR was significantly lower in patients on the PCC than in those given plasma. The higher the baseline INR, the greater the benefit of the PCC. For example, in 58 patients with a baseline INR above 6, the mean INR dropped from 10.6 preinfusion to 1.5 at 30 minutes in the PCC group and to 3.7 in the plasma recipients, reported Dr. Goldstein of the University of Rochester (N.Y.).

In 44 patients with a baseline INR of 4-6, the INR fell from a mean of 4.6 preinfusion to 1.4 at 30 minutes in the PCC group and to 3.2 in patients on plasma. And in patients with a baseline INR of 2 to less than 4, mean INR fell from 2.9 preinfusion to 1.6 in the PCC group and to 2.2 in the plasma recipients.

One hour after the start of infusion, roughly 70% of PCC recipients had corrected their INR as defined by an INR of 1.3 or less, compared with less than 5% of plasma recipients.

Median factor levels were below 50% at baseline. Levels increased significantly more within 30 minutes of starting PCC infusion than with plasma. This wasn’t particularly surprising, since the PCC contains factors II, VII, IX, and X, along with proteins C and S, Dr. Goldstein observed.

Blinded investigators rated hemostatic efficacy in the first 24 hours as good or excellent in 72% of the PCC group and in 65% of patients on plasma, a nonsignificant difference.

Thromboembolic event rates through 51 days of follow-up were 7.8% with the PCC and 5.5% with plasma.

Dr. Goldstein reported that he serves as a consultant to and advisory board member for CSL Behring, which markets Beriplex and sponsored the study.

DENVER – A four-factor prothrombin complex concentrate bettered plasma for urgent reversal of warfarin and other vitamin K antagonists in patients experiencing major bleeding.

Marketed as Beriplex, the product had a higher rate of INR reversal than did plasma at 30 minutes after the start of infusion, based on results from a phase IIIb prospective, multicenter, randomized clinical trial.

The prothrombin complex concentrate (PCC) also proved more successful than plasma at early replacement of depleted coagulation factors and was noninferior to plasma in terms of blinded investigator–rated hemostatic efficacy in the first 24 hours, Dr. Joshua N. Goldstein said at the annual meeting of the American College of Emergency Physicians.

The study included 202 adults on warfarin or another vitamin K antagonist who presented with acute major bleeding. The objectives were to correct their INR as quickly as possible and thereby reduce their blood loss. Participants were randomized to INR- and weight-based dosing of the PCC or to plasma on top of background vitamin K given by slow intravenous infusion in all cases.

Thirty minutes after the start of the infusion, the mean INR was significantly lower in patients on the PCC than in those given plasma. The higher the baseline INR, the greater the benefit of the PCC. For example, in 58 patients with a baseline INR above 6, the mean INR dropped from 10.6 preinfusion to 1.5 at 30 minutes in the PCC group and to 3.7 in the plasma recipients, reported Dr. Goldstein of the University of Rochester (N.Y.).

In 44 patients with a baseline INR of 4-6, the INR fell from a mean of 4.6 preinfusion to 1.4 at 30 minutes in the PCC group and to 3.2 in patients on plasma. And in patients with a baseline INR of 2 to less than 4, mean INR fell from 2.9 preinfusion to 1.6 in the PCC group and to 2.2 in the plasma recipients.

One hour after the start of infusion, roughly 70% of PCC recipients had corrected their INR as defined by an INR of 1.3 or less, compared with less than 5% of plasma recipients.

Median factor levels were below 50% at baseline. Levels increased significantly more within 30 minutes of starting PCC infusion than with plasma. This wasn’t particularly surprising, since the PCC contains factors II, VII, IX, and X, along with proteins C and S, Dr. Goldstein observed.

Blinded investigators rated hemostatic efficacy in the first 24 hours as good or excellent in 72% of the PCC group and in 65% of patients on plasma, a nonsignificant difference.

Thromboembolic event rates through 51 days of follow-up were 7.8% with the PCC and 5.5% with plasma.

Dr. Goldstein reported that he serves as a consultant to and advisory board member for CSL Behring, which markets Beriplex and sponsored the study.

DENVER – An emergency department protocol for observing patients who present with unexplained syncope substantially reduced health care services and costs with no evidence of harm, compared with routine hospital admission for observation.

The findings were seen in a multicenter randomized trial conducted in five diverse hospital settings, indicating the syncope observation protocol is applicable in EDs regardless of whether they’re located in academic medical centers, small community hospitals, or big county public hospitals, Dr. Benjamin Sun noted at the annual meeting of the American College of Emergency Physicians.

The observation protocol is designed for syncope patients over age 50 identified in the ED as being at intermediate risk for subsequent serious events such as stroke, MI, or life-threatening arrhythmia.

Patients clearly at high risk, such as those who presented with syncope related to a dangerous arrhythmia or an MI, were routinely admitted straightaway for inpatient care. Those whose syncope was identified in the ED as low-risk – that is, likely due to a benign cause such as vasovagal or orthostatic syncope – were quickly discharged, explained Dr. Sun of Oregon Health and Sciences University, Portland.

The core elements of the observation protocol consisted of serial troponin testing, 12-24 hours of ECG monitoring, and selective use of echocardiography. Head CT and other ancillary testing was done at physician’s discretion and varied widely among the study sites according to local practice. The ED syncope observation units were run by emergency physicians and staffed by mid-level providers.

Dr. Sun reported on 124 intermediate-risk patients at five participating EDs who were randomized to the ED observation protocol or to routine inpatient unstructured care, which is how such patients are typically managed in the United States.

The ED-run protocol resulted in dramatic savings: Only 11% of patients assigned to that strategy were ultimately admitted to the hospital. Roughly 80% of those admissions occurred because an arrhythmia was identified during ED observation, while the other 20% were due to troponin leaks. The mean length of stay for syncope patients assigned to ED observation was 29 hours, compared with 46 hours for controls. Thirty-day hospital costs averaged $2,100 in the ED observation group compared with $3,500 for controls.

Rates of serious adverse events such as stroke, MI, or pulmonary embolism within 30 days and 6 months post discharge were in similarly low single figures in both study arms. Quality of life scores in the two groups were also similar, bolstering the conclusion that the ED syncope observation protocol saved money without causing harm, Dr. Sun continued.

The ED protocol was developed in an effort to come up with a better way to manage the more than 700,000 patients per year who present with syncope to EDs. Such patients are frequently hospitalized, even if they’re at low or intermediate risk. Hospitalizations for syncope account for more than $2.4 billion annually in health care costs with little evidence of benefit. Medicare has identified this line item as a high-priority target for cost reduction, he noted.

Dr. Sun reported having no financial conflicts.

DENVER – An emergency department protocol for observing patients who present with unexplained syncope substantially reduced health care services and costs with no evidence of harm, compared with routine hospital admission for observation.

The findings were seen in a multicenter randomized trial conducted in five diverse hospital settings, indicating the syncope observation protocol is applicable in EDs regardless of whether they’re located in academic medical centers, small community hospitals, or big county public hospitals, Dr. Benjamin Sun noted at the annual meeting of the American College of Emergency Physicians.

The observation protocol is designed for syncope patients over age 50 identified in the ED as being at intermediate risk for subsequent serious events such as stroke, MI, or life-threatening arrhythmia.

Patients clearly at high risk, such as those who presented with syncope related to a dangerous arrhythmia or an MI, were routinely admitted straightaway for inpatient care. Those whose syncope was identified in the ED as low-risk – that is, likely due to a benign cause such as vasovagal or orthostatic syncope – were quickly discharged, explained Dr. Sun of Oregon Health and Sciences University, Portland.

The core elements of the observation protocol consisted of serial troponin testing, 12-24 hours of ECG monitoring, and selective use of echocardiography. Head CT and other ancillary testing was done at physician’s discretion and varied widely among the study sites according to local practice. The ED syncope observation units were run by emergency physicians and staffed by mid-level providers.

Dr. Sun reported on 124 intermediate-risk patients at five participating EDs who were randomized to the ED observation protocol or to routine inpatient unstructured care, which is how such patients are typically managed in the United States.

The ED-run protocol resulted in dramatic savings: Only 11% of patients assigned to that strategy were ultimately admitted to the hospital. Roughly 80% of those admissions occurred because an arrhythmia was identified during ED observation, while the other 20% were due to troponin leaks. The mean length of stay for syncope patients assigned to ED observation was 29 hours, compared with 46 hours for controls. Thirty-day hospital costs averaged $2,100 in the ED observation group compared with $3,500 for controls.

Rates of serious adverse events such as stroke, MI, or pulmonary embolism within 30 days and 6 months post discharge were in similarly low single figures in both study arms. Quality of life scores in the two groups were also similar, bolstering the conclusion that the ED syncope observation protocol saved money without causing harm, Dr. Sun continued.

The ED protocol was developed in an effort to come up with a better way to manage the more than 700,000 patients per year who present with syncope to EDs. Such patients are frequently hospitalized, even if they’re at low or intermediate risk. Hospitalizations for syncope account for more than $2.4 billion annually in health care costs with little evidence of benefit. Medicare has identified this line item as a high-priority target for cost reduction, he noted.

Dr. Sun reported having no financial conflicts.

DENVER – An emergency department protocol for observing patients who present with unexplained syncope substantially reduced health care services and costs with no evidence of harm, compared with routine hospital admission for observation.

The findings were seen in a multicenter randomized trial conducted in five diverse hospital settings, indicating the syncope observation protocol is applicable in EDs regardless of whether they’re located in academic medical centers, small community hospitals, or big county public hospitals, Dr. Benjamin Sun noted at the annual meeting of the American College of Emergency Physicians.

The observation protocol is designed for syncope patients over age 50 identified in the ED as being at intermediate risk for subsequent serious events such as stroke, MI, or life-threatening arrhythmia.

Patients clearly at high risk, such as those who presented with syncope related to a dangerous arrhythmia or an MI, were routinely admitted straightaway for inpatient care. Those whose syncope was identified in the ED as low-risk – that is, likely due to a benign cause such as vasovagal or orthostatic syncope – were quickly discharged, explained Dr. Sun of Oregon Health and Sciences University, Portland.

The core elements of the observation protocol consisted of serial troponin testing, 12-24 hours of ECG monitoring, and selective use of echocardiography. Head CT and other ancillary testing was done at physician’s discretion and varied widely among the study sites according to local practice. The ED syncope observation units were run by emergency physicians and staffed by mid-level providers.

Dr. Sun reported on 124 intermediate-risk patients at five participating EDs who were randomized to the ED observation protocol or to routine inpatient unstructured care, which is how such patients are typically managed in the United States.

The ED-run protocol resulted in dramatic savings: Only 11% of patients assigned to that strategy were ultimately admitted to the hospital. Roughly 80% of those admissions occurred because an arrhythmia was identified during ED observation, while the other 20% were due to troponin leaks. The mean length of stay for syncope patients assigned to ED observation was 29 hours, compared with 46 hours for controls. Thirty-day hospital costs averaged $2,100 in the ED observation group compared with $3,500 for controls.

Rates of serious adverse events such as stroke, MI, or pulmonary embolism within 30 days and 6 months post discharge were in similarly low single figures in both study arms. Quality of life scores in the two groups were also similar, bolstering the conclusion that the ED syncope observation protocol saved money without causing harm, Dr. Sun continued.

The ED protocol was developed in an effort to come up with a better way to manage the more than 700,000 patients per year who present with syncope to EDs. Such patients are frequently hospitalized, even if they’re at low or intermediate risk. Hospitalizations for syncope account for more than $2.4 billion annually in health care costs with little evidence of benefit. Medicare has identified this line item as a high-priority target for cost reduction, he noted.

Dr. Sun reported having no financial conflicts.

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES  – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the annual scientific sessions of the American Heart Association.

Bruce Jancin/IMNG Medical Media

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

SAN ANTONIO – Five years of adjuvant tamoxifen in women with estrogen receptor–positive early breast cancer is well established as being excellent therapy with a long-term carryover effect. Now 10 years has been shown to be even better.

A new analysis from the large international ATLAS trial demonstrated that participants randomized to 10 years of adjuvant tamoxifen had a 25% reduction in recurrences and a 29% lower mortality due to breast cancer in years 10-14 after diagnosis, compared with women who stopped the drug after the standard 5 years, Richard Gray, M.Sc., reported at the San Antonio Breast Cancer Symposium.

These findings from ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) are all the more impressive in light of the 2011 Early Breast Cancer Trialists’ Collaborative Group overview analysis, which features 15 years of follow-up of more than 10,000 women in randomized trials pitting 5 years of tamoxifen versus no tamoxifen (Lancet 2011;378:771-84). The meta-analysis showed that 5 years of tamoxifen reduced deaths due to breast cancer by 34% during the first 5 years after treatment ended and by 27% in the subsequent 5 years.

Thus, 10 years of tamoxifen had to compete against a big carryover effect of 5 years of the drug, noted Mr. Gray, professor of medical statistics at the University of Oxford (U.K.).

By multiplying the risk reduction ratios from ATLAS and the Oxford overview, he estimated that 10 years of tamoxifen reduces breast cancer mortality by one-third in the first decade following diagnosis and by fully half in the second decade, compared with no tamoxifen.

Benefits Far Outweigh Risks

The ATLAS analysis involved 6,846 randomized women with estrogen receptor–positive disease. The cumulative risk of recurrence during years 5-14 after diagnosis was 21.4% in women assigned to 10 years of tamoxifen and 25.1% in controls. Breast cancer mortality during years 5-14 was 12.2% in patients on 10 years of tamoxifen and 15.0% in those who stopped after 5 years, for an absolute mortality reduction of 2.8%.

The benefits of 10 years of tamoxifen compared with 5 far outweighed the risks, Prof. Gray continued. The cumulative risk of endometrial cancer in years 5-14 was 3.1% for women randomized to continue therapy for 10 years, compared with 1.6% for controls. Mortality due to endometrial cancer was rare, however: 0.4% in the extended therapy group and 0.2% in controls.

"I think these ATLAS results are relevant to quite a wide range of women. And the findings encourage one to think that aromatase inhibitors, too, might be more effective with longer therapy," he said.

Indeed, ongoing clinical trials are comparing outcomes with 10 versus the standard 5 years of adjuvant aromatase inhibitor therapy.

But aromatase inhibitors are not an option in premenopausal patients because they’re ineffective in that setting. In addition, some postmenopausal breast cancer patients can’t tolerate aromatase inhibitors due to arthralgias, bone pain, or other side effects. And while aromatase inhibitors are now the standard of care for adjuvant therapy in postmenopausal patients in the United States and Europe, tamoxifen remains widely used in developing countries because it’s so much less expensive, he added.

Data Are Compelling

Dr. Peter Ravdin called the ATLAS data compelling.

"I think the results of this trial will have a major immediate impact on premenopausal women. For women who are now approaching 5 years of therapy, up until this point we’d have told them we’re going to be stopping the drug. Now we’re going to be telling them that there’s clinical evidence that 10 years is superior to 5 years. And I’m going to be comfortable doing that," said Dr. Ravdin, director of the breast health clinic at the Cancer Therapy and Research Center of the University of Texas, San Antonio.

"One of the things that I think is profoundly important about this study is that the biology of the disease shows that there are some women fated to have late relapse that our early treatments aren’t effective in blocking, but that we can do better by treating women with hormonal therapy beyond 5 years," he added.

Women with a relatively high risk of late relapse – that is, those with larger tumors and/or positive lymph nodes – will definitely be strong candidates for continuation of therapy. Those with small grade 1 tumors and a very low risk of both early and late relapse might rationally decide they don’t want to take tamoxifen for longer than 5 years, according to the oncologist.

The risk of tamoxifen-related endometrial cancer in premenopausal patients is negligible. But some women experience such problematic tamoxifen-induced hot flashes or vaginal symptoms that they may balk at continuing treatment beyond 5 years.

"I think that the amount of benefit they’ll get in continuing will be small enough that that would be a perfectly rational decision. An additional one-third reduction in a very small risk is still a very small benefit," Dr. Ravdin observed.

Simultaneous with Prof. Gray’s presentation in San Antonio, the ATLAS results were published online (Lancet 2012 Dec. 5 [doi: 10.1016/S0140-6736(12)61963-1]).

The ATLAS trial was funded by Cancer Research UK, the UK Medical Research Council, AstraZeneca, the U.S. Army, and EU Biomed. Dr. Gray reported having no financial conflicts.

SAN ANTONIO – Five years of adjuvant tamoxifen in women with estrogen receptor–positive early breast cancer is well established as being excellent therapy with a long-term carryover effect. Now 10 years has been shown to be even better.

A new analysis from the large international ATLAS trial demonstrated that participants randomized to 10 years of adjuvant tamoxifen had a 25% reduction in recurrences and a 29% lower mortality due to breast cancer in years 10-14 after diagnosis, compared with women who stopped the drug after the standard 5 years, Richard Gray, M.Sc., reported at the San Antonio Breast Cancer Symposium.

These findings from ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) are all the more impressive in light of the 2011 Early Breast Cancer Trialists’ Collaborative Group overview analysis, which features 15 years of follow-up of more than 10,000 women in randomized trials pitting 5 years of tamoxifen versus no tamoxifen (Lancet 2011;378:771-84). The meta-analysis showed that 5 years of tamoxifen reduced deaths due to breast cancer by 34% during the first 5 years after treatment ended and by 27% in the subsequent 5 years.

Thus, 10 years of tamoxifen had to compete against a big carryover effect of 5 years of the drug, noted Mr. Gray, professor of medical statistics at the University of Oxford (U.K.).

By multiplying the risk reduction ratios from ATLAS and the Oxford overview, he estimated that 10 years of tamoxifen reduces breast cancer mortality by one-third in the first decade following diagnosis and by fully half in the second decade, compared with no tamoxifen.

Benefits Far Outweigh Risks

The ATLAS analysis involved 6,846 randomized women with estrogen receptor–positive disease. The cumulative risk of recurrence during years 5-14 after diagnosis was 21.4% in women assigned to 10 years of tamoxifen and 25.1% in controls. Breast cancer mortality during years 5-14 was 12.2% in patients on 10 years of tamoxifen and 15.0% in those who stopped after 5 years, for an absolute mortality reduction of 2.8%.

The benefits of 10 years of tamoxifen compared with 5 far outweighed the risks, Prof. Gray continued. The cumulative risk of endometrial cancer in years 5-14 was 3.1% for women randomized to continue therapy for 10 years, compared with 1.6% for controls. Mortality due to endometrial cancer was rare, however: 0.4% in the extended therapy group and 0.2% in controls.

"I think these ATLAS results are relevant to quite a wide range of women. And the findings encourage one to think that aromatase inhibitors, too, might be more effective with longer therapy," he said.

Indeed, ongoing clinical trials are comparing outcomes with 10 versus the standard 5 years of adjuvant aromatase inhibitor therapy.

But aromatase inhibitors are not an option in premenopausal patients because they’re ineffective in that setting. In addition, some postmenopausal breast cancer patients can’t tolerate aromatase inhibitors due to arthralgias, bone pain, or other side effects. And while aromatase inhibitors are now the standard of care for adjuvant therapy in postmenopausal patients in the United States and Europe, tamoxifen remains widely used in developing countries because it’s so much less expensive, he added.

Data Are Compelling

Dr. Peter Ravdin called the ATLAS data compelling.

"I think the results of this trial will have a major immediate impact on premenopausal women. For women who are now approaching 5 years of therapy, up until this point we’d have told them we’re going to be stopping the drug. Now we’re going to be telling them that there’s clinical evidence that 10 years is superior to 5 years. And I’m going to be comfortable doing that," said Dr. Ravdin, director of the breast health clinic at the Cancer Therapy and Research Center of the University of Texas, San Antonio.

"One of the things that I think is profoundly important about this study is that the biology of the disease shows that there are some women fated to have late relapse that our early treatments aren’t effective in blocking, but that we can do better by treating women with hormonal therapy beyond 5 years," he added.

Women with a relatively high risk of late relapse – that is, those with larger tumors and/or positive lymph nodes – will definitely be strong candidates for continuation of therapy. Those with small grade 1 tumors and a very low risk of both early and late relapse might rationally decide they don’t want to take tamoxifen for longer than 5 years, according to the oncologist.

The risk of tamoxifen-related endometrial cancer in premenopausal patients is negligible. But some women experience such problematic tamoxifen-induced hot flashes or vaginal symptoms that they may balk at continuing treatment beyond 5 years.

"I think that the amount of benefit they’ll get in continuing will be small enough that that would be a perfectly rational decision. An additional one-third reduction in a very small risk is still a very small benefit," Dr. Ravdin observed.

Simultaneous with Prof. Gray’s presentation in San Antonio, the ATLAS results were published online (Lancet 2012 Dec. 5 [doi: 10.1016/S0140-6736(12)61963-1]).

The ATLAS trial was funded by Cancer Research UK, the UK Medical Research Council, AstraZeneca, the U.S. Army, and EU Biomed. Dr. Gray reported having no financial conflicts.

SAN ANTONIO – Five years of adjuvant tamoxifen in women with estrogen receptor–positive early breast cancer is well established as being excellent therapy with a long-term carryover effect. Now 10 years has been shown to be even better.

A new analysis from the large international ATLAS trial demonstrated that participants randomized to 10 years of adjuvant tamoxifen had a 25% reduction in recurrences and a 29% lower mortality due to breast cancer in years 10-14 after diagnosis, compared with women who stopped the drug after the standard 5 years, Richard Gray, M.Sc., reported at the San Antonio Breast Cancer Symposium.

These findings from ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) are all the more impressive in light of the 2011 Early Breast Cancer Trialists’ Collaborative Group overview analysis, which features 15 years of follow-up of more than 10,000 women in randomized trials pitting 5 years of tamoxifen versus no tamoxifen (Lancet 2011;378:771-84). The meta-analysis showed that 5 years of tamoxifen reduced deaths due to breast cancer by 34% during the first 5 years after treatment ended and by 27% in the subsequent 5 years.

Thus, 10 years of tamoxifen had to compete against a big carryover effect of 5 years of the drug, noted Mr. Gray, professor of medical statistics at the University of Oxford (U.K.).

By multiplying the risk reduction ratios from ATLAS and the Oxford overview, he estimated that 10 years of tamoxifen reduces breast cancer mortality by one-third in the first decade following diagnosis and by fully half in the second decade, compared with no tamoxifen.

Benefits Far Outweigh Risks

The ATLAS analysis involved 6,846 randomized women with estrogen receptor–positive disease. The cumulative risk of recurrence during years 5-14 after diagnosis was 21.4% in women assigned to 10 years of tamoxifen and 25.1% in controls. Breast cancer mortality during years 5-14 was 12.2% in patients on 10 years of tamoxifen and 15.0% in those who stopped after 5 years, for an absolute mortality reduction of 2.8%.

The benefits of 10 years of tamoxifen compared with 5 far outweighed the risks, Prof. Gray continued. The cumulative risk of endometrial cancer in years 5-14 was 3.1% for women randomized to continue therapy for 10 years, compared with 1.6% for controls. Mortality due to endometrial cancer was rare, however: 0.4% in the extended therapy group and 0.2% in controls.

"I think these ATLAS results are relevant to quite a wide range of women. And the findings encourage one to think that aromatase inhibitors, too, might be more effective with longer therapy," he said.

Indeed, ongoing clinical trials are comparing outcomes with 10 versus the standard 5 years of adjuvant aromatase inhibitor therapy.

But aromatase inhibitors are not an option in premenopausal patients because they’re ineffective in that setting. In addition, some postmenopausal breast cancer patients can’t tolerate aromatase inhibitors due to arthralgias, bone pain, or other side effects. And while aromatase inhibitors are now the standard of care for adjuvant therapy in postmenopausal patients in the United States and Europe, tamoxifen remains widely used in developing countries because it’s so much less expensive, he added.

Data Are Compelling

Dr. Peter Ravdin called the ATLAS data compelling.

"I think the results of this trial will have a major immediate impact on premenopausal women. For women who are now approaching 5 years of therapy, up until this point we’d have told them we’re going to be stopping the drug. Now we’re going to be telling them that there’s clinical evidence that 10 years is superior to 5 years. And I’m going to be comfortable doing that," said Dr. Ravdin, director of the breast health clinic at the Cancer Therapy and Research Center of the University of Texas, San Antonio.

"One of the things that I think is profoundly important about this study is that the biology of the disease shows that there are some women fated to have late relapse that our early treatments aren’t effective in blocking, but that we can do better by treating women with hormonal therapy beyond 5 years," he added.

Women with a relatively high risk of late relapse – that is, those with larger tumors and/or positive lymph nodes – will definitely be strong candidates for continuation of therapy. Those with small grade 1 tumors and a very low risk of both early and late relapse might rationally decide they don’t want to take tamoxifen for longer than 5 years, according to the oncologist.

The risk of tamoxifen-related endometrial cancer in premenopausal patients is negligible. But some women experience such problematic tamoxifen-induced hot flashes or vaginal symptoms that they may balk at continuing treatment beyond 5 years.

"I think that the amount of benefit they’ll get in continuing will be small enough that that would be a perfectly rational decision. An additional one-third reduction in a very small risk is still a very small benefit," Dr. Ravdin observed.

Simultaneous with Prof. Gray’s presentation in San Antonio, the ATLAS results were published online (Lancet 2012 Dec. 5 [doi: 10.1016/S0140-6736(12)61963-1]).

The ATLAS trial was funded by Cancer Research UK, the UK Medical Research Council, AstraZeneca, the U.S. Army, and EU Biomed. Dr. Gray reported having no financial conflicts.

SAN ANTONIO – Fulvestrant administered at 500 mg in women with locally advanced or metastatic breast cancer results in clinically meaningful improvement in survival without increased toxicity compared with the formerly standard monthly 250-mg dose, according to the final analysis of overall survival in the CONFIRM trial.

CONFIRM (Comparison of Faslodex in Recurrence of Metastatic Breast Cancer) was a phase III, randomized, double-blind clinical trial involving 736 postmenopausal women at 128 centers in 17 countries. All had estrogen receptor–positive locally advanced or metastatic disease. They were randomized to 250 mg of intramuscular fulvestrant (Faslodex) every 28 days, which was then the approved dose, or to 500 mg on days 0, 14, and 28 and every 28 days thereafter.

"Based on the results of the present trial, we believe that whenever fulvestrant is considered for the treatment of postmenopausal patients with estrogen receptor-positive advanced breast cancer, the recommended dose is 500 mg," Dr. Angelo Di Leo declared in presenting the CONFIRM update at the annual San Antonio Breast Cancer Symposium.

The final data confirm an earlier interim analysis (J. Clin. Oncol. 2010;28:4594-600), which also showed a survival advantage for the doubled dose. Observers commented that the new analysis provides clinicians with reassurance that the Food and Drug Administration was correct in 2010 when, on the strength of the interim CONFIRM analysis, the agency replaced the 250-mg dose with 500 mg as the approved dose.

The final overall survival analysis was performed when 75% of study participants had died. Fulvestrant at 500 mg was associated with a "clinically meaningful" 4.1-month increase in overall survival: 26.4 months as compared with 22.3 months in the 250-mg group (P = .016). This translated to a 19% reduction in the risk of death, said Dr. Di Leo, head of the department of medical oncology at the Tuscan Tumor Institute at the Hospital of Prato (Italy).

The safety findings were particularly striking. The high and low doses of fulvestrant were associated with similar rates of serious adverse events. There were five serious adverse events leading to death in the 500-mg group and seven in the 250-mg group. Coupled with the survival advantage, the safety data show "without any doubt" that 500 mg monthly is the correct dose, he noted in an interview with this publication.

The CONFIRM trial was sponsored by AstraZeneca. Dr. Di Leo reported that he serves as an adviser to the pharmaceutical company.

SAN ANTONIO – Fulvestrant administered at 500 mg in women with locally advanced or metastatic breast cancer results in clinically meaningful improvement in survival without increased toxicity compared with the formerly standard monthly 250-mg dose, according to the final analysis of overall survival in the CONFIRM trial.

CONFIRM (Comparison of Faslodex in Recurrence of Metastatic Breast Cancer) was a phase III, randomized, double-blind clinical trial involving 736 postmenopausal women at 128 centers in 17 countries. All had estrogen receptor–positive locally advanced or metastatic disease. They were randomized to 250 mg of intramuscular fulvestrant (Faslodex) every 28 days, which was then the approved dose, or to 500 mg on days 0, 14, and 28 and every 28 days thereafter.

"Based on the results of the present trial, we believe that whenever fulvestrant is considered for the treatment of postmenopausal patients with estrogen receptor-positive advanced breast cancer, the recommended dose is 500 mg," Dr. Angelo Di Leo declared in presenting the CONFIRM update at the annual San Antonio Breast Cancer Symposium.

The final data confirm an earlier interim analysis (J. Clin. Oncol. 2010;28:4594-600), which also showed a survival advantage for the doubled dose. Observers commented that the new analysis provides clinicians with reassurance that the Food and Drug Administration was correct in 2010 when, on the strength of the interim CONFIRM analysis, the agency replaced the 250-mg dose with 500 mg as the approved dose.

The final overall survival analysis was performed when 75% of study participants had died. Fulvestrant at 500 mg was associated with a "clinically meaningful" 4.1-month increase in overall survival: 26.4 months as compared with 22.3 months in the 250-mg group (P = .016). This translated to a 19% reduction in the risk of death, said Dr. Di Leo, head of the department of medical oncology at the Tuscan Tumor Institute at the Hospital of Prato (Italy).

The safety findings were particularly striking. The high and low doses of fulvestrant were associated with similar rates of serious adverse events. There were five serious adverse events leading to death in the 500-mg group and seven in the 250-mg group. Coupled with the survival advantage, the safety data show "without any doubt" that 500 mg monthly is the correct dose, he noted in an interview with this publication.

The CONFIRM trial was sponsored by AstraZeneca. Dr. Di Leo reported that he serves as an adviser to the pharmaceutical company.

SAN ANTONIO – Fulvestrant administered at 500 mg in women with locally advanced or metastatic breast cancer results in clinically meaningful improvement in survival without increased toxicity compared with the formerly standard monthly 250-mg dose, according to the final analysis of overall survival in the CONFIRM trial.

CONFIRM (Comparison of Faslodex in Recurrence of Metastatic Breast Cancer) was a phase III, randomized, double-blind clinical trial involving 736 postmenopausal women at 128 centers in 17 countries. All had estrogen receptor–positive locally advanced or metastatic disease. They were randomized to 250 mg of intramuscular fulvestrant (Faslodex) every 28 days, which was then the approved dose, or to 500 mg on days 0, 14, and 28 and every 28 days thereafter.

"Based on the results of the present trial, we believe that whenever fulvestrant is considered for the treatment of postmenopausal patients with estrogen receptor-positive advanced breast cancer, the recommended dose is 500 mg," Dr. Angelo Di Leo declared in presenting the CONFIRM update at the annual San Antonio Breast Cancer Symposium.

The final data confirm an earlier interim analysis (J. Clin. Oncol. 2010;28:4594-600), which also showed a survival advantage for the doubled dose. Observers commented that the new analysis provides clinicians with reassurance that the Food and Drug Administration was correct in 2010 when, on the strength of the interim CONFIRM analysis, the agency replaced the 250-mg dose with 500 mg as the approved dose.

The final overall survival analysis was performed when 75% of study participants had died. Fulvestrant at 500 mg was associated with a "clinically meaningful" 4.1-month increase in overall survival: 26.4 months as compared with 22.3 months in the 250-mg group (P = .016). This translated to a 19% reduction in the risk of death, said Dr. Di Leo, head of the department of medical oncology at the Tuscan Tumor Institute at the Hospital of Prato (Italy).

The safety findings were particularly striking. The high and low doses of fulvestrant were associated with similar rates of serious adverse events. There were five serious adverse events leading to death in the 500-mg group and seven in the 250-mg group. Coupled with the survival advantage, the safety data show "without any doubt" that 500 mg monthly is the correct dose, he noted in an interview with this publication.

The CONFIRM trial was sponsored by AstraZeneca. Dr. Di Leo reported that he serves as an adviser to the pharmaceutical company.