Patrice Wendling

LAKE BUENA VISTA, FLA. – The Trauma-Related Injury Severity Score is outdated and should be replaced by a survival prediction model derived from more contemporary mortality rates, a study showed.

The score, known as TRISS, is the workhorse of outcome prediction in trauma. It is integral to the federal Performance Improvement and Patient Safety plan for trauma, is used for benchmarking hospital performance and comparing interhospital performance, and has been incorporated into most commercial trauma registries, including the National Trauma Registry System and the National Trauma Data Bank (NTDB).

Unfortunately, it is based on data collected in the Major Trauma Outcome Study (MTOS) during the 1980s, and its coefficients of survival prediction were last updated in 1995, said lead author Dr. Frederick Rogers, medical director of the Lancaster (Pa.) General Health Trauma Center.

"Few of us have really complained about TRISS up until this point because TRISS is what we consider an easy grader, making our results much better than they really are by comparing ourselves to trauma care in the last century," he said at the annual meeting of the Eastern Association for the Surgery of Trauma (EAST). "We really must be honest with ourselves.

"We must retire TRISS and create a mortality prediction model for the next century that reflects contemporary results."

Invited discussant Dr. Avery Nathens, director of the American College of Surgeons’ Trauma Quality Improvement Program and trauma director at St. Michael’s Hospital in Toronto, said, "I feel like we just heard the obituary for TRISS."

He said the study confirms many of the concerns regarding TRISS and pointed out that no fewer than 93 publications over the last 5 years have used TRISS to compare their outcomes.

"Dr. Rogers’ work could not have come too soon," he remarked.

To get an overall snapshot of mortality, the first part of the study compared outcomes from the 1982-1987 MTOS database for 80,544 patients from 139 U.S. and Canadian hospitals with those from 1.9 million patients from 900 U.S. trauma centers in the 2002-2006 NTDB. Patients were then stratified by mortality and age into 5-year age groups, up to 85-89 years.

In all age groups examined, there was a significant decrease in mortality in the NTDB data set, compared with the MTOS data set (P less than .001), he said. Overall mortality was more than double in the MTOS at 9.0% vs. just 4.4% in the NTDB.

To determine how well TRISS predicts survival over time, the researchers then compared observed to expected (O/E) mortality ratios using TRISS longitudinally and data on 451,868 patients in the Pennsylvania Trauma Outcome Study (PTOS) from 1990 to 2010.

PTOS entry criteria are ICU admission, a hospital length of stay greater than 48 hours, transfers in, and transfers out. The data are drawn from 31 accredited trauma centers and are maintained with strict internal and external auditing, Dr. Rogers said.

The O/E mortality ratios declined significantly over time for all patients in the PTOS database compared with TRISS. This was also true for the 403,935 patients with blunt trauma injuries (P less than .001 for both), indicative of improved outcomes over what would be predicted.

There was a more gradual decline in the O/E mortality ratio among the 47,933 patients with penetrating trauma injuries (P = .73), suggesting that mortality has not improved as much in this population, he said.

If TRISS were accurate, it would have an O/E ratio equal to 1, but the scoring system fell short of this in the PTOS analysis by about 20%, Dr. Rogers said.

"TRISS is drifting out of calibration," he said.

The obvious reason is that trauma care has significantly improved over the last 30 years, particularly in blunt trauma management, and, as expected, O/E mortality ratios have dropped.

In addition, TRISS is based in part on the Injury Severity Score (ISS) and Revised Trauma Score, and as such inherits their limitations. Dr. Rogers pointed out that the ISS isn’t monotonic with respect to death and isn’t linear in the logit of death. Also, the Glasgow Coma Scale can’t be computed for many patients at the highest risk of dying because of endotracheal tubes and chemical paralytic agents. Attempts to fill this gap have been made by data imputation, which he described as a form of mathematical trickery.

"In short, we believe continued attempts to resuscitate TRISS as an outcome predictor are untenable," he said. "With the incredible talent in EAST and other trauma organizations, we believe we can do better."

Dr. Rogers called for a prediction model with a fundamentally sound statistical underpinning that would minimize missing variables such as Glasgow Coma Scale scores, maintain accuracy over time, and contain a clear mechanism for periodic updating.

During the discussion of the study, Dr. Rogers said they compared mortality across ISS categories in the NTDB and PCOS databases and that their comparison confirmed the PTOS finding that mortality has declined over time, after controlling for both ISS and age, in blunt trauma and less convincingly for penetrating trauma.

He suggested that outcomes may have improved in blunt trauma patients because CT scanning has allowed more accurate probing of injuries and that improved field care may be allowing more penetrating trauma patients to survive long enough to get into the data set, but not necessarily out of the hospital.

Finally, TRISS founder and former EAST president Dr. Howard Champion rose from the audience to congratulate the authors on the study and for pointing out the "obvious frailties of TRISS." He suggested the issue revolves around three problematic elements: taxonomy coding, the model, and the coefficients attached to the model.

He pointed out that the United States uses the ICD-9 code, while the rest of the world uses the ICD-10 code and the ICD-11 code is on the horizon. "In other words, we are about two generations behind."

He went on to say that the Abbreviated Injury Score, which is integral to the ISS, was developed in the 1960s and 1970s for engineers and had 78 codes. That number has mushroomed to more than 2,000, and up to 80% of those codes are not used. "There are huge inter-reliability problems with it, suggesting that the Abbreviated Injury Score needs another careful look, as well as the models and the coefficients."

He closed by saying, "There’s a lot to be done. It is not a simple problem; it’s a very challenging problem."

Dr. Rogers said progress will be made by identifying better, more robust predictors for use in trauma outcome models.

Dr. Rogers, his coauthors, and Dr. Nathens reported no conflicts of interest.

LAKE BUENA VISTA, FLA. – The Trauma-Related Injury Severity Score is outdated and should be replaced by a survival prediction model derived from more contemporary mortality rates, a study showed.

The score, known as TRISS, is the workhorse of outcome prediction in trauma. It is integral to the federal Performance Improvement and Patient Safety plan for trauma, is used for benchmarking hospital performance and comparing interhospital performance, and has been incorporated into most commercial trauma registries, including the National Trauma Registry System and the National Trauma Data Bank (NTDB).

Unfortunately, it is based on data collected in the Major Trauma Outcome Study (MTOS) during the 1980s, and its coefficients of survival prediction were last updated in 1995, said lead author Dr. Frederick Rogers, medical director of the Lancaster (Pa.) General Health Trauma Center.

"Few of us have really complained about TRISS up until this point because TRISS is what we consider an easy grader, making our results much better than they really are by comparing ourselves to trauma care in the last century," he said at the annual meeting of the Eastern Association for the Surgery of Trauma (EAST). "We really must be honest with ourselves.

"We must retire TRISS and create a mortality prediction model for the next century that reflects contemporary results."

Invited discussant Dr. Avery Nathens, director of the American College of Surgeons’ Trauma Quality Improvement Program and trauma director at St. Michael’s Hospital in Toronto, said, "I feel like we just heard the obituary for TRISS."

He said the study confirms many of the concerns regarding TRISS and pointed out that no fewer than 93 publications over the last 5 years have used TRISS to compare their outcomes.

"Dr. Rogers’ work could not have come too soon," he remarked.

To get an overall snapshot of mortality, the first part of the study compared outcomes from the 1982-1987 MTOS database for 80,544 patients from 139 U.S. and Canadian hospitals with those from 1.9 million patients from 900 U.S. trauma centers in the 2002-2006 NTDB. Patients were then stratified by mortality and age into 5-year age groups, up to 85-89 years.

In all age groups examined, there was a significant decrease in mortality in the NTDB data set, compared with the MTOS data set (P less than .001), he said. Overall mortality was more than double in the MTOS at 9.0% vs. just 4.4% in the NTDB.

To determine how well TRISS predicts survival over time, the researchers then compared observed to expected (O/E) mortality ratios using TRISS longitudinally and data on 451,868 patients in the Pennsylvania Trauma Outcome Study (PTOS) from 1990 to 2010.

PTOS entry criteria are ICU admission, a hospital length of stay greater than 48 hours, transfers in, and transfers out. The data are drawn from 31 accredited trauma centers and are maintained with strict internal and external auditing, Dr. Rogers said.

The O/E mortality ratios declined significantly over time for all patients in the PTOS database compared with TRISS. This was also true for the 403,935 patients with blunt trauma injuries (P less than .001 for both), indicative of improved outcomes over what would be predicted.

There was a more gradual decline in the O/E mortality ratio among the 47,933 patients with penetrating trauma injuries (P = .73), suggesting that mortality has not improved as much in this population, he said.

If TRISS were accurate, it would have an O/E ratio equal to 1, but the scoring system fell short of this in the PTOS analysis by about 20%, Dr. Rogers said.

"TRISS is drifting out of calibration," he said.

The obvious reason is that trauma care has significantly improved over the last 30 years, particularly in blunt trauma management, and, as expected, O/E mortality ratios have dropped.

In addition, TRISS is based in part on the Injury Severity Score (ISS) and Revised Trauma Score, and as such inherits their limitations. Dr. Rogers pointed out that the ISS isn’t monotonic with respect to death and isn’t linear in the logit of death. Also, the Glasgow Coma Scale can’t be computed for many patients at the highest risk of dying because of endotracheal tubes and chemical paralytic agents. Attempts to fill this gap have been made by data imputation, which he described as a form of mathematical trickery.

"In short, we believe continued attempts to resuscitate TRISS as an outcome predictor are untenable," he said. "With the incredible talent in EAST and other trauma organizations, we believe we can do better."

Dr. Rogers called for a prediction model with a fundamentally sound statistical underpinning that would minimize missing variables such as Glasgow Coma Scale scores, maintain accuracy over time, and contain a clear mechanism for periodic updating.

During the discussion of the study, Dr. Rogers said they compared mortality across ISS categories in the NTDB and PCOS databases and that their comparison confirmed the PTOS finding that mortality has declined over time, after controlling for both ISS and age, in blunt trauma and less convincingly for penetrating trauma.

He suggested that outcomes may have improved in blunt trauma patients because CT scanning has allowed more accurate probing of injuries and that improved field care may be allowing more penetrating trauma patients to survive long enough to get into the data set, but not necessarily out of the hospital.

Finally, TRISS founder and former EAST president Dr. Howard Champion rose from the audience to congratulate the authors on the study and for pointing out the "obvious frailties of TRISS." He suggested the issue revolves around three problematic elements: taxonomy coding, the model, and the coefficients attached to the model.

He pointed out that the United States uses the ICD-9 code, while the rest of the world uses the ICD-10 code and the ICD-11 code is on the horizon. "In other words, we are about two generations behind."

He went on to say that the Abbreviated Injury Score, which is integral to the ISS, was developed in the 1960s and 1970s for engineers and had 78 codes. That number has mushroomed to more than 2,000, and up to 80% of those codes are not used. "There are huge inter-reliability problems with it, suggesting that the Abbreviated Injury Score needs another careful look, as well as the models and the coefficients."

He closed by saying, "There’s a lot to be done. It is not a simple problem; it’s a very challenging problem."

Dr. Rogers said progress will be made by identifying better, more robust predictors for use in trauma outcome models.

Dr. Rogers, his coauthors, and Dr. Nathens reported no conflicts of interest.

LAKE BUENA VISTA, FLA. – The Trauma-Related Injury Severity Score is outdated and should be replaced by a survival prediction model derived from more contemporary mortality rates, a study showed.

The score, known as TRISS, is the workhorse of outcome prediction in trauma. It is integral to the federal Performance Improvement and Patient Safety plan for trauma, is used for benchmarking hospital performance and comparing interhospital performance, and has been incorporated into most commercial trauma registries, including the National Trauma Registry System and the National Trauma Data Bank (NTDB).

Unfortunately, it is based on data collected in the Major Trauma Outcome Study (MTOS) during the 1980s, and its coefficients of survival prediction were last updated in 1995, said lead author Dr. Frederick Rogers, medical director of the Lancaster (Pa.) General Health Trauma Center.

"Few of us have really complained about TRISS up until this point because TRISS is what we consider an easy grader, making our results much better than they really are by comparing ourselves to trauma care in the last century," he said at the annual meeting of the Eastern Association for the Surgery of Trauma (EAST). "We really must be honest with ourselves.

"We must retire TRISS and create a mortality prediction model for the next century that reflects contemporary results."

Invited discussant Dr. Avery Nathens, director of the American College of Surgeons’ Trauma Quality Improvement Program and trauma director at St. Michael’s Hospital in Toronto, said, "I feel like we just heard the obituary for TRISS."

He said the study confirms many of the concerns regarding TRISS and pointed out that no fewer than 93 publications over the last 5 years have used TRISS to compare their outcomes.

"Dr. Rogers’ work could not have come too soon," he remarked.

To get an overall snapshot of mortality, the first part of the study compared outcomes from the 1982-1987 MTOS database for 80,544 patients from 139 U.S. and Canadian hospitals with those from 1.9 million patients from 900 U.S. trauma centers in the 2002-2006 NTDB. Patients were then stratified by mortality and age into 5-year age groups, up to 85-89 years.

In all age groups examined, there was a significant decrease in mortality in the NTDB data set, compared with the MTOS data set (P less than .001), he said. Overall mortality was more than double in the MTOS at 9.0% vs. just 4.4% in the NTDB.

To determine how well TRISS predicts survival over time, the researchers then compared observed to expected (O/E) mortality ratios using TRISS longitudinally and data on 451,868 patients in the Pennsylvania Trauma Outcome Study (PTOS) from 1990 to 2010.

PTOS entry criteria are ICU admission, a hospital length of stay greater than 48 hours, transfers in, and transfers out. The data are drawn from 31 accredited trauma centers and are maintained with strict internal and external auditing, Dr. Rogers said.

The O/E mortality ratios declined significantly over time for all patients in the PTOS database compared with TRISS. This was also true for the 403,935 patients with blunt trauma injuries (P less than .001 for both), indicative of improved outcomes over what would be predicted.

There was a more gradual decline in the O/E mortality ratio among the 47,933 patients with penetrating trauma injuries (P = .73), suggesting that mortality has not improved as much in this population, he said.

If TRISS were accurate, it would have an O/E ratio equal to 1, but the scoring system fell short of this in the PTOS analysis by about 20%, Dr. Rogers said.

"TRISS is drifting out of calibration," he said.

The obvious reason is that trauma care has significantly improved over the last 30 years, particularly in blunt trauma management, and, as expected, O/E mortality ratios have dropped.

In addition, TRISS is based in part on the Injury Severity Score (ISS) and Revised Trauma Score, and as such inherits their limitations. Dr. Rogers pointed out that the ISS isn’t monotonic with respect to death and isn’t linear in the logit of death. Also, the Glasgow Coma Scale can’t be computed for many patients at the highest risk of dying because of endotracheal tubes and chemical paralytic agents. Attempts to fill this gap have been made by data imputation, which he described as a form of mathematical trickery.

"In short, we believe continued attempts to resuscitate TRISS as an outcome predictor are untenable," he said. "With the incredible talent in EAST and other trauma organizations, we believe we can do better."

Dr. Rogers called for a prediction model with a fundamentally sound statistical underpinning that would minimize missing variables such as Glasgow Coma Scale scores, maintain accuracy over time, and contain a clear mechanism for periodic updating.

During the discussion of the study, Dr. Rogers said they compared mortality across ISS categories in the NTDB and PCOS databases and that their comparison confirmed the PTOS finding that mortality has declined over time, after controlling for both ISS and age, in blunt trauma and less convincingly for penetrating trauma.

He suggested that outcomes may have improved in blunt trauma patients because CT scanning has allowed more accurate probing of injuries and that improved field care may be allowing more penetrating trauma patients to survive long enough to get into the data set, but not necessarily out of the hospital.

Finally, TRISS founder and former EAST president Dr. Howard Champion rose from the audience to congratulate the authors on the study and for pointing out the "obvious frailties of TRISS." He suggested the issue revolves around three problematic elements: taxonomy coding, the model, and the coefficients attached to the model.

He pointed out that the United States uses the ICD-9 code, while the rest of the world uses the ICD-10 code and the ICD-11 code is on the horizon. "In other words, we are about two generations behind."

He went on to say that the Abbreviated Injury Score, which is integral to the ISS, was developed in the 1960s and 1970s for engineers and had 78 codes. That number has mushroomed to more than 2,000, and up to 80% of those codes are not used. "There are huge inter-reliability problems with it, suggesting that the Abbreviated Injury Score needs another careful look, as well as the models and the coefficients."

He closed by saying, "There’s a lot to be done. It is not a simple problem; it’s a very challenging problem."

Dr. Rogers said progress will be made by identifying better, more robust predictors for use in trauma outcome models.

Dr. Rogers, his coauthors, and Dr. Nathens reported no conflicts of interest.

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions.

The trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions.

The trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. "There is clearly a benefit for about 50% of patients compared to the placebo-control," he said.

The side effect profile was similar to that observed in the phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions.

The trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib "identifies itself as a potential new standard of care in this patient population," and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could "possibly become a component of standard therapies for colorectal cancer."

Dr. Grothey suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

"This is not unheard of that adding a kinase inhibitor to chemotherapy does not produce the desired result," he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. "In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful," he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

"Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency," he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

"The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated," Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – Adding the investigational protease inhibitor carfilzomib to lenalidomide and low-dose dexamethasone produced responses comparable with those achieved with the best frontline regimens in multiple myeloma, final results from a multicenter phase I/II study indicate.

Nearly all, 94%, of 49 evaluable patients with newly diagnosed multiple myeloma achieved at least a partial response with the triple combination, and 53% attained a near complete, complete, or stringent complete response (nCR/CR/sCR).

Responses also continued to improve with time, with 79% of patients reaching a nCR/CR/sCR after 12 cycles, Dr. Andrzej J. Jakubowiak reported at the annual meeting of the American Society of Hematology on behalf of the Multiple Myeloma Research Consortium. Although the data are still being evaluated, about half of the nCR/CR/sCRs were complete responses.

"These response rates appear to compare favorably to the best frontline regimens in myeloma and, I would dare to say, they compare favorably to treatment sequences with transplant," said Dr. Jakubowiak, director of the multiple myeloma program at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone previously posted an encouraging overall response rate of 78% and a nCR/CR rate of 40% with a low toxicity profile in the relapsed and/or refractory setting, providing the rationale for two ongoing phase III trials. The ASPIRE trial is evaluating lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma; the FOCUS trial, to support registration in Europe, is evaluating single-agent carfilzomib in relapsed/refractory myeloma.

Onyx Pharmaceuticals has announced that the U.S. Food and Drug Administration is giving carfilzomib a standard review in the treatment of relapsed and refractory myeloma, with a decision expected by July 27.

An expanded access program is also underway in partnership with the Multiple Myeloma Research Foundation for eligible patients in the United States with relapsed and refractory myeloma for whom no satisfactory treatment alternatives are available.

The carfilzomib, lenalidomide, and dexamethasone (CRd) regimen was one of several (including such novel therapies as oral MLN9708 protease inhibitor and the so-called BiRD regimen of clarithromycin [Biaxin] with lenalidomide and dexamethasone) for which impressive results were reported at the ASH meeting. "All of these drugs will find their own place" Dr. Jakubowiak said, but, he added, CRd is "the strongest regimen I’ve used, and I’ve used a variety of these regimens."

He noted that his patients continue to come to the clinic with no complaints of toxicity and that their responses continue to improve, providing further stimulus for those trying to sort through the abundance of novel myeloma therapies.

The current study included 53 patients who were eligible or ineligible for transplant: they received eight cycles of induction therapy with IV carfilzomib 20, 27, or 36 mg/m²; oral lenalidomide 25 mg, and oral dexamethasone at 40 mg for cycles 1-4 and at 20 mg for cycles 5-8, followed by maintenance therapy at the doses tolerated at the end of the eight cycles until disease progression or toxicity. Patients with at least a partial response after four cycles could proceed to stem cell transplant.

Their median age was 59 years, and 60% had advanced myeloma and 33% had unfavorable cytogenetics including deletion 17p.

After a median of 9.5 months follow-up, only one patient progressed and all patients were alive. Of these, 88% of patients remained on treatment, and 24 of 27 patients who began maintenance therapy continued on CRd maintenance, said Dr. Jakubowiak.

Dose modifications were required in 16 patients, and one patient discontinued therapy because of toxicity. Peripheral neuropathy was reported in almost one-quarter of patients, but all cases were grade 1/2. Dyspnea was reported in about one-third of patients, but it was quickly resolving, he noted.

Responses in the 16 patients with unfavorable cytogenetics were similar to all other patients, and included at least a partial response in 100% and nCR/CR/sCR in 56%, Dr. Jakubowiak said.

Dr. Ravi Vij of Washington University, St. Louis, presented final results of single-agent carfilzomib in bortezomib (Velcade)-naive patients in the separate phase II PX-171-004 study in myeloma that had relapsed after one to three lines of therapy.

The trial enrolled 165 patients, with one cohort receiving IV carfilzomib 20 mg/m² for all 12 cycles and the second cohort given carfilzomib 20 mg/m² for cycle 1 with escalation to 27 mg/m² in all subsequent cycles.

A total of 129 patients were bortezomib-naive, including 59 in cohort 1 and 70 in cohort 2. At baseline, 15% had unfavorable cytogenetics, 52% had neuropathy, and two-thirds were refractory to their most recent therapy.

The overall response rate was 42% in cohort 1 and 52% in cohort 2, Dr. Vij reported. The median time to disease progression was 8.3 months and median duration of response was 13.1 months in cohort 1. Neither end point had been reached in cohort 2.

Dr. Vij noted that the higher response rates in cohort 2 do not appear to be associated with higher side effects. Mild to moderate peripheral neuropathy was reported in 14% of cohort 1 and 19% of cohort 2. Only one case of grade-3 peripheral neuropathy was reported in cohort 1 and none in cohort 2.

The most common adverse events in cohort 1 and cohort 2, respectively, were fatigue (71%, 54%), nausea (54%, 44%), anemia (46%, 39%), dyspnea (49%, 30%), cough (39%, 30%) and pyrexia (36%, 33%). The majority were grade 1/2; adverse events leading to carfilzomib discontinuation occurred in 22% of cohort 1 and 10% of cohort 2, he said.

These data are suggestive of a dose-response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007, Dr. Vij said.

The trials were sponsored by Onyx Pharmaceuticals. Dr. Jakubowiak and his coauthors and Dr. Vij and his coauthors reported financial relationships with several pharmaceutical firms, including Onyx.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

SAN DIEGO – The combination of vorinostat and bortezomib produced mixed results for patients with relapsed or refractory multiple myeloma in two pivotal international trials.

Heavily pretreated patients achieved durable responses and an unprecedented survival advantage in the phase IIB Vantage 095 trial, whereas survival gains were less impressive among pretreated patients who remained sensitive to bortezomib (Velcade) in the phase III Vantage 088 trial. Findings from both trials were presented at the annual meeting of the American Society of Hematology.

"I think this kind of combination of the histone deacetylase [HDAC] inhibitor vorinostat and bortezomib offers a very important option in patients who really have no other conventional therapeutic alternatives," said Dr. David S. Siegel, lead author of the Vantage 095 trial and division chief for myeloma at the Hackensack (N.J.) University Medical Center.

Vorinostat (Zolinza) has been approved since 2006 for the treatment of cutaneous T-cell lymphoma, and is under investigation in a variety of other cancers. Phase II trials of vorinostat, lenalidomide (Revlimid), and dexamethasone are underway or planned in myeloma patients who are refractory to lenalidomide-containing regimens or have relapsed on lenalidomide maintenance therapy.

Dr. Siegel said in an interview that vorinostat does not have intrinsic activity, but that HDAC inhibitors resensitize patients by dampening the changes involved in drug resistance. Whether Merck will file for an additional indication for vorinostat based on the current Vantage data is unclear, but Dr. Siegel suggested that the drug could play a key role in overcoming resistance to lenalidomide, bortezomib, and pomalidomide (a promising investigational immunomodulatory drug, or IMiD) as the use of these agents increases.

"It [vorinostat] has sort of been reserved for the last-ditch effort, with extraordinary success ... and no drugs in the myeloma space work in that last-ditch effort better than vorinostat in my hands," he said.

Vantage 095: Refractory Patients

According to final results from the phase IIB Vantage 095 trial involving 142 patients whose disease was described as refractory to basically all available therapies, 17% achieved at least a partial response and 77% achieved disease control.

Responses to vorinostat and bortezomib were sustainable, and in some cases particularly durable, said Dr. Siegel. The median duration of response was 6.3 months. Applying the EBMT (European Group for Blood and Marrow Transplantation) criteria, the median duration was 7.0 months and the overall response rate 11%.

The 2-year overall survival rate was 32%, and median overall survival was 11.1 months. Dr. Siegel noted that a median of roughly 4.5 months occurred from the time when patients were considered refractory to prior bortezomib and an IMiD to the time when they came on trial. He said the survival benchmark for such dual-refractory patients is 8.8 months.

The doublet was described as generally well tolerated, with 27% of patients completing at least eight cycles. Serious adverse events were reported in 65% of patients, but only 11% of treatment discontinuations resulted from serious adverse events. Neuropathy and febrile neutropenia were reported in 2% and 4%, respectively. One patient died because of an adverse event that was considered possibly or probably drug related.

Patients received oral vorinostat 400 mg/day on days 1-14 plus bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease or no change after four cycles could receive oral dexamethasone 20 mg on the day of and day after each dose of bortezomib.

The trial enrolled patients with relapsed and refractory disease who had received at least two prior lines of therapy, and were refractory to bortezomib and ineligible for or refractory to at least one IMiD. Their median age was 63 years, and 69% had received at least four prior lines of therapy (range, 2-17 lines).

Subgroup analyses revealed that partial responses occurred in 18% of patients who were refractory to a bortezomib regimen and 22% who were refractory to up to two IMiDs. Overall survival was 11.7 months and 11.2 months, respectively. Progression-free survival for the entire cohort was 3.13 months.

Session comoderator Prof. Michele Cavo of the University of Bologna (Italy) said the most important message of the trial was the 11-month median overall survival. "This combination may offer a chance to patients heavily pretreated, almost 100% of them with prior refractoriness to bortezomib and lenalidomide and [other] IMiDs," he said in an interview. "This means that the combination of a histone deacetylase inhibitor with bortezomib may partially overcome prior refractoriness to a proteasome inhibitor or an IMiD."

Clinicians will need to figure out how best to use vorinostat, but Dr. Siegel and Dr. Cavo agreed that its oral administration is a big advantage, particularly for patients with advanced-stage disease, who are often elderly and in pain.

Vantage 088: In Bortezomib Sensitive

Dr. Meletios Dimopoulos presented data from the randomized phase III Vantage 088 trial involving 637 patients who had progressive disease after one to three prior treatments, but were bortezomib sensitive. Patients were randomized to the same combination regimen that was used in Vantage 095, or to vorinostat 400 mg/day on days 1-14 plus placebo.

The combination of bortezomib plus vorinostat increased the primary end point of progression-free survival from 6.83 months to 7.63 months (hazard ratio, 0.774; P = .01). Although the difference reached statistical significance, the audience questioned the clinical significance of a 25-day advantage, and pointed out that this was the very first salvage line for 45% of patients in the bortezomib/vorinostat arm vs. 40% in the control arm. In addition, median overall survival was not significantly different between the bortezomib/vorinostat and control arms.

Dr. Dimopoulos responded that Vantage 088 was indeed a positive trial because one in five patients benefited from the combination. "If vorinostat is approved for the use of myeloma, it is sure that we will find better ways to use it, as is the case with bortezomib today," he said.

Using EBMT criteria, the combination of vorinostat plus bortezomib significantly improved the overall response (56% vs. 41%) and clinical benefit rates (71% vs. 53%), compared with bortezomib alone (both P less than .0001). Duration of response by EBMT criteria was similar at 8.5 months and 8.4 months, respectively, reported Dr. Dimopoulos of the department of clinical therapeutics at the National and Kapodistrian University of Athens.

Subgroup analyses revealed no significant differences between the two arms in overall response or progression-free survival based on age, type of melanoma, number of previous lines of therapy, or prior exposure to IMiDs or bortezomib.

At baseline, 46% of the 317 patients in the bortezomib/vorinostat arm and 48% of the 320 patients in the bortezomib/placebo arm were nonresponsive to their last line of therapy.

Dr. Siegel reported receiving research funding and honoraria and serving as a speaker for Millennium Pharmaceuticals and honoraria from Merck. His coauthors reported financial relationships with several firms including Millennium, Merck, and Novartis. Dr. Dimopoulos reported consultancy and honoraria from Celgene and Ortho-Biotech. His coauthors reported relationships with multiple pharmaceutical firms.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

SAN DIEGO – Prophylaxis with rivaroxaban achieved significant reductions in venous thromboembolism, compared with two commonly used drugs when put to the test in 5,346 consecutive, unselected patients undergoing major orthopedic surgery.

The incidence of in-hospital symptomatic venous thromboembolism (VTE) was 2.4% with rivaroxaban (Xarelto), compared with 3.9% with low molecular weight heparin (LMWH), and 5.5% with fondaparinux (Arixtra). This corresponds to a relative risk reduction of 39%, compared with LMWH, and 57% compared with fondaparinux.

Rivaroxaban, an oral Factor Xa inhibitor, also has superior safety with regard to major bleeding and surgical complications, according to Dr. Jan Beyer-Westendorf, with the University Clinic at Dresden (Germany) Technical University.

"Patients in real-world major orthopedic surgery benefit from VTE-prophylaxis with rivaroxaban even more than could be expected from the phase III results of the RECORD trial," he said at the annual meeting of the American Society of Hematology.

The four phase III RECORD (REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials compared rivaroxaban with enoxaparin in more than 12,500 patients undergoing knee and hip replacement. The trials did not evaluate fondaparinux or LMWH, despite being the standard of care at many hospitals.

Rivaroxaban was approved in the United States in July 2011 for DVT prophylaxis in adults undergoing hip and knee replacement surgery, and gained a second indication in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation.

Dr. Beyer-Westendorf and his colleagues analyzed 5,346 consecutive patients who underwent major orthopedic surgery at the university clinic during three periods: 2005-2007 when LMWH was the standard prophylaxis; 2008-2009 when fondaparinux was the standard; and finally from 2010 to June 2011 when rivaroxaban became the clinic’s standard prophylaxis.

In all, 1,055 patients were treated with rivaroxaban, 1,683 with LMWH, and 2,069 with fondaparinux. Of note, previous VTE was more common at baseline in the rivaroxaban group at 4% vs. 1.4% in the LMWH group, and 1.1% in the fondaparinux group, he said.

Rivaroxaban reduced the relative risk of the composite of proximal DVT, pulmonary embolism, and VTE-related death by 29%, compared with LMWH, and 42% compared with fondaparinux, but the difference between the three groups did not achieve statistical significance (1.0% vs. 1.4% vs. 1.7%), Dr. Beyer-Westendorf said.

In a pooled analysis of RECORD 1, 2, and 3, rivaroxaban significantly reduced the composite of symptomatic VTE and all-cause mortality during the 2-week period after surgery, compared with enoxaparin (0.4% vs. 0.8%), according to the Bayer HealthCare website.

In the current analysis, severe bleeding was significantly lower with rivaroxaban at 7.4% vs. 14.9% with LMWH, and 11.1% with fondaparinux.

Bleeding leading to surgical revisions was also significantly lower at 0.4% vs. 1.7% with LMWH, and 1.1% with fondaparinux.

Dr. Beyer-Westendorf pointed out that severe bleeding rates were less than 1% in the RECORD 1-4 trials using a more narrow definition of severe bleeding as overt bleeding outside of the surgical site. Their analysis used the International Society on Thrombosis and Hemostasis criteria for severe bleeding.

Finally, the reduction in VTE events, bleeding, and surgical revisions was correlated with a significantly shorter median hospital stay in patients given rivaroxaban prophylaxis vs. LMWH or fondaparinux (8.3 days vs. 11.6 days vs. 9.3 days).

Dr. Beyer-Westendorf said it was unlikely that changes in anesthesia or surgical practice over the study period could have attenuated the results. In addition, the researchers conducted a matched-pair analysis to evaluate whether the benefits of rivaroxaban were due to selection or detection bias. Outcomes remained superior for rivaroxaban after matching patients according to age, gender, type of surgery, and history of VTE. Complete compression ultrasound testing also remained constant at about 13% from 2005 to 2010 before falling to 8.2% in 2011 due to fewer complete compression ultrasound–positive findings, Dr. Beyer-Westendorf noted.

"These findings in a large real-world surgery cohort are robust and not significantly influenced by a selection or detection bias," he said.

Dr. Beyer-Westendorf disclosed research grants from and serving as a speaker for Bayer HealthCare, which markets Xarelto.

SAN DIEGO – Prophylaxis with rivaroxaban achieved significant reductions in venous thromboembolism, compared with two commonly used drugs when put to the test in 5,346 consecutive, unselected patients undergoing major orthopedic surgery.

The incidence of in-hospital symptomatic venous thromboembolism (VTE) was 2.4% with rivaroxaban (Xarelto), compared with 3.9% with low molecular weight heparin (LMWH), and 5.5% with fondaparinux (Arixtra). This corresponds to a relative risk reduction of 39%, compared with LMWH, and 57% compared with fondaparinux.

Rivaroxaban, an oral Factor Xa inhibitor, also has superior safety with regard to major bleeding and surgical complications, according to Dr. Jan Beyer-Westendorf, with the University Clinic at Dresden (Germany) Technical University.

"Patients in real-world major orthopedic surgery benefit from VTE-prophylaxis with rivaroxaban even more than could be expected from the phase III results of the RECORD trial," he said at the annual meeting of the American Society of Hematology.

The four phase III RECORD (REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials compared rivaroxaban with enoxaparin in more than 12,500 patients undergoing knee and hip replacement. The trials did not evaluate fondaparinux or LMWH, despite being the standard of care at many hospitals.

Rivaroxaban was approved in the United States in July 2011 for DVT prophylaxis in adults undergoing hip and knee replacement surgery, and gained a second indication in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation.

Dr. Beyer-Westendorf and his colleagues analyzed 5,346 consecutive patients who underwent major orthopedic surgery at the university clinic during three periods: 2005-2007 when LMWH was the standard prophylaxis; 2008-2009 when fondaparinux was the standard; and finally from 2010 to June 2011 when rivaroxaban became the clinic’s standard prophylaxis.

In all, 1,055 patients were treated with rivaroxaban, 1,683 with LMWH, and 2,069 with fondaparinux. Of note, previous VTE was more common at baseline in the rivaroxaban group at 4% vs. 1.4% in the LMWH group, and 1.1% in the fondaparinux group, he said.

Rivaroxaban reduced the relative risk of the composite of proximal DVT, pulmonary embolism, and VTE-related death by 29%, compared with LMWH, and 42% compared with fondaparinux, but the difference between the three groups did not achieve statistical significance (1.0% vs. 1.4% vs. 1.7%), Dr. Beyer-Westendorf said.

In a pooled analysis of RECORD 1, 2, and 3, rivaroxaban significantly reduced the composite of symptomatic VTE and all-cause mortality during the 2-week period after surgery, compared with enoxaparin (0.4% vs. 0.8%), according to the Bayer HealthCare website.

In the current analysis, severe bleeding was significantly lower with rivaroxaban at 7.4% vs. 14.9% with LMWH, and 11.1% with fondaparinux.

Bleeding leading to surgical revisions was also significantly lower at 0.4% vs. 1.7% with LMWH, and 1.1% with fondaparinux.

Dr. Beyer-Westendorf pointed out that severe bleeding rates were less than 1% in the RECORD 1-4 trials using a more narrow definition of severe bleeding as overt bleeding outside of the surgical site. Their analysis used the International Society on Thrombosis and Hemostasis criteria for severe bleeding.

Finally, the reduction in VTE events, bleeding, and surgical revisions was correlated with a significantly shorter median hospital stay in patients given rivaroxaban prophylaxis vs. LMWH or fondaparinux (8.3 days vs. 11.6 days vs. 9.3 days).

Dr. Beyer-Westendorf said it was unlikely that changes in anesthesia or surgical practice over the study period could have attenuated the results. In addition, the researchers conducted a matched-pair analysis to evaluate whether the benefits of rivaroxaban were due to selection or detection bias. Outcomes remained superior for rivaroxaban after matching patients according to age, gender, type of surgery, and history of VTE. Complete compression ultrasound testing also remained constant at about 13% from 2005 to 2010 before falling to 8.2% in 2011 due to fewer complete compression ultrasound–positive findings, Dr. Beyer-Westendorf noted.

"These findings in a large real-world surgery cohort are robust and not significantly influenced by a selection or detection bias," he said.

Dr. Beyer-Westendorf disclosed research grants from and serving as a speaker for Bayer HealthCare, which markets Xarelto.

SAN DIEGO – Prophylaxis with rivaroxaban achieved significant reductions in venous thromboembolism, compared with two commonly used drugs when put to the test in 5,346 consecutive, unselected patients undergoing major orthopedic surgery.

The incidence of in-hospital symptomatic venous thromboembolism (VTE) was 2.4% with rivaroxaban (Xarelto), compared with 3.9% with low molecular weight heparin (LMWH), and 5.5% with fondaparinux (Arixtra). This corresponds to a relative risk reduction of 39%, compared with LMWH, and 57% compared with fondaparinux.

Rivaroxaban, an oral Factor Xa inhibitor, also has superior safety with regard to major bleeding and surgical complications, according to Dr. Jan Beyer-Westendorf, with the University Clinic at Dresden (Germany) Technical University.

"Patients in real-world major orthopedic surgery benefit from VTE-prophylaxis with rivaroxaban even more than could be expected from the phase III results of the RECORD trial," he said at the annual meeting of the American Society of Hematology.

The four phase III RECORD (REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials compared rivaroxaban with enoxaparin in more than 12,500 patients undergoing knee and hip replacement. The trials did not evaluate fondaparinux or LMWH, despite being the standard of care at many hospitals.

Rivaroxaban was approved in the United States in July 2011 for DVT prophylaxis in adults undergoing hip and knee replacement surgery, and gained a second indication in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation.

Dr. Beyer-Westendorf and his colleagues analyzed 5,346 consecutive patients who underwent major orthopedic surgery at the university clinic during three periods: 2005-2007 when LMWH was the standard prophylaxis; 2008-2009 when fondaparinux was the standard; and finally from 2010 to June 2011 when rivaroxaban became the clinic’s standard prophylaxis.

In all, 1,055 patients were treated with rivaroxaban, 1,683 with LMWH, and 2,069 with fondaparinux. Of note, previous VTE was more common at baseline in the rivaroxaban group at 4% vs. 1.4% in the LMWH group, and 1.1% in the fondaparinux group, he said.

Rivaroxaban reduced the relative risk of the composite of proximal DVT, pulmonary embolism, and VTE-related death by 29%, compared with LMWH, and 42% compared with fondaparinux, but the difference between the three groups did not achieve statistical significance (1.0% vs. 1.4% vs. 1.7%), Dr. Beyer-Westendorf said.

In a pooled analysis of RECORD 1, 2, and 3, rivaroxaban significantly reduced the composite of symptomatic VTE and all-cause mortality during the 2-week period after surgery, compared with enoxaparin (0.4% vs. 0.8%), according to the Bayer HealthCare website.

In the current analysis, severe bleeding was significantly lower with rivaroxaban at 7.4% vs. 14.9% with LMWH, and 11.1% with fondaparinux.

Bleeding leading to surgical revisions was also significantly lower at 0.4% vs. 1.7% with LMWH, and 1.1% with fondaparinux.

Dr. Beyer-Westendorf pointed out that severe bleeding rates were less than 1% in the RECORD 1-4 trials using a more narrow definition of severe bleeding as overt bleeding outside of the surgical site. Their analysis used the International Society on Thrombosis and Hemostasis criteria for severe bleeding.

Finally, the reduction in VTE events, bleeding, and surgical revisions was correlated with a significantly shorter median hospital stay in patients given rivaroxaban prophylaxis vs. LMWH or fondaparinux (8.3 days vs. 11.6 days vs. 9.3 days).

Dr. Beyer-Westendorf said it was unlikely that changes in anesthesia or surgical practice over the study period could have attenuated the results. In addition, the researchers conducted a matched-pair analysis to evaluate whether the benefits of rivaroxaban were due to selection or detection bias. Outcomes remained superior for rivaroxaban after matching patients according to age, gender, type of surgery, and history of VTE. Complete compression ultrasound testing also remained constant at about 13% from 2005 to 2010 before falling to 8.2% in 2011 due to fewer complete compression ultrasound–positive findings, Dr. Beyer-Westendorf noted.

"These findings in a large real-world surgery cohort are robust and not significantly influenced by a selection or detection bias," he said.

Dr. Beyer-Westendorf disclosed research grants from and serving as a speaker for Bayer HealthCare, which markets Xarelto.

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram. When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the meeting.

“Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose,” she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a “C” cup or larger, to 27% of screening patients with small breasts imaged with a large detector. A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

“The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer,” Dr. Wells said.

“Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched.”

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts.

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy.

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said. “It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose,” she said. “We hope to analyze the data again, to answer this question.”