CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

CHICAGO – Donepezil proved no better than placebo at improving overall cognitive function among 198 patients who had undergone partial or whole brain irradiation for brain tumors, investigators reported at the annual meeting of the American Society of Clinical Oncology.

A randomized, double-blind, multicenter phase III trial found no significant differences between donepezil (Aricept) and placebo in either cognitive composite scores after 12 or 24 weeks of therapy – the study’s primary end point – or in domains of attention/concentration, motor speed/dexterity, learning, or memory, said Stephen R. Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest Baptist Medical Center in Winston-Salem, N.C.

Among patients with more cognitive problems at baseline, however, there was a significant benefit in verbal memory for patients on donepezil, compared with controls (P = .005), and a trend toward preservation of motor speed and dexterity, Dr. Rapp said.

"We have to continue looking for effective treatments for cognitive symptoms in this population. It has a big impact on patients," he said.

Previous studies indicated that more than half of patients who receive partial or whole brain irradiation for tumors will have cognitive deficits, and that about 12% will develop some form of dementia. Cognitive problems have a major impact on patient quality of life, and anything clinicians can do to preserve or improve patient mental faculties is important, Dr. Rapp said.

The study was designed to test whether donepezil, an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate cognitive decline from Alzheimer’s disease, could have a similar neuroprotective effect following whole brain irradiation.

Investigators enrolled 198 patients 6 months after they received at least 30 Gy of brain irradiation. Following a baseline evaluation, patients were randomized to receive either 5-10 mg daily of oral donepezil or placebo for 24 weeks, with an interim assessment performed at 12 weeks.

The study looked at the effect of the drug on cognitive functioning and on measures of fatigue, mood, and quality of life.

The patients were assessed at baseline for cognitive function, and at 12 and 24 weeks with the Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure-modified (a measure of visual spatial ability, memory, and planning ability), Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard (a measure of dexterity and motor control).

Both study arms showed significant improvement in cognitive composite scores over baseline (P less than .01 for both), but the degree of improvement did not differ significantly between arms. Similarly, there were no significant differences between the treatment arms in any of the test domains, Dr. Rapp said.

Among patients with greater baseline cognitive deficits, as measured by a score of less than 51 on the FACT Brain subscale, there was also significant improvement over baseline but no between-group difference, he reported.

Donepezil was significantly better than placebo control in this subgroup for improvement in performance on the recognition portion of the Hopkins Verbal Learning Test, which measures verbal memory, and donepezil danced on the edge of significance at preserving motor speed and dexterity as measured by the Grooved Pegboard-Dominant Hand test but never crossed the line (P = .06), he said.

Adverse events were similar between the groups, and the patients assigned to donepezil appeared to tolerate it well, Dr. Rapp said.

Dr. Robin Grant of the Center for Clinical Brain Sciences at the University of Edinburgh, the invited discussant, said that the study was very well designed. He noted, however, "that there was no specified level of cognitive deficit at the time of [study] entry, and I think if you look at moderate to severely affected patients then you’re more likely to be able to show a change there," he said.

He added that it would be interesting to see results from the Grooved Pegboard test performed with the contralateral rather than dominant hand.

The study was funded by the National Institutes of Health and by Eisai, maker of donepezil. Dr. Rapp disclosed receiving research funding from the company. Dr. Grant reported having no financial disclosures.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

Median progression-free survival reached 10.7 months in the bevacizumab arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the bevacizumab arm had significantly worse neurocognitive and overall symptom scores over time.

"We feel that bevacizumab remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment," he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the ASCO annual meeting.

The Avaglio investigators found that adding bevacizumab to radiotherapy and temozolomide "achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma," Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on bevacizumab, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, temozolomide, and bevacizumab arm, vs. 6.2 months in 463 patients in its radiation, temozolomide, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Bevacizumab misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with temozolomide for 3 weeks followed by chemoradiation with temozolomide and either bevacizumab or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on, bevacizumab. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that bevacizumab combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than temozolomide chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the bevacizumab-irinotecan combination.)

As noted, in RTOG 0825, patients in the bevacizumab arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on bevacizumab in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with bevacizumab is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as bevacizumab, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although bevacizumab has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of bevacizumab to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

"Despite these new data demonstrating its limitation, I feel very strongly that bevacizumab represents the single most important agent in glioblastoma since temozolomide, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options," Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

CHICAGO – The combination of bevacizumab and irinotecan far outshone tenozolomide in delaying disease progression among patients with MGMT-unmethylated glioblastoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

In the phase II GLARIUS trial, 79.6% of patients treated with bevacizumab (Avastin) and irinotecan (Camptosar) were free of progression at 6 months, compared with 41.3% of patients randomized to receive temozolmide (Temodar) (P less than .0001), reported Dr. Ulrich Herrlinger from the department of neurology at University Clinic of Bonn, Germany.

Progression-free survival at 6 months (PFS-6) was the study's primary endpoint.

Neil Osterweil/IMNG Medical Media

A preliminary analysis also hinted at a potential overall survival advantage for the bevacizumab-irinotecan (BEV/IRI) combination. After nearly 50% of patients in each arm had died, median overall survival was 16.6 months for the BEV/IRI group, compared with 14.8 months for the temozolomide group (hazard ratio, 0.60; P = .031).

"Obviously we did not harm our patients by omitting temozolomide and choosing something different, BEV/IRI, for treating these patients," Dr. Herrlinger said.

The combination is a promising alternative to temozolomide therapy in patients with with MGMT (O⁶-methylguanine-DNA methyltransferase)-unmethylated glioblastoma, he said. About 55%-65% of newly diagnosed glioblastomas are not methylated by MGMT, a DNA repair enzyme, and these have a worse prognosis than those in which MGMT promotes methylation, according to Dr. Herrlinger.

Investigators at 22 centers in Germany tested patients with glioblastoma for MGMT status, and randomized a total of 182 patients with newly diagnosed, histologically confirmed MGMT-unmethylated glioblastoma. Of these, 170 received at least one course of drug therapy and were evaluable for response; these patients were included in the analysis.

All patients received 60 Gy localized radiation in 30 fragments of 2 Gy each. They were randomized 2:1 to BEV-IRI (116 patients) or temozolomide (54 patients).

The experimental arm received bevacizumab 10 mg/kg every 2 weeks during radiotherapy followed by maintenance bevacizumab at the same dose and irinotecan 125 mg/m² every 2 weeks without or with enzyme-inducing antiepileptic drugs at a dose of 340 mg/m². The standard therapy arm was given temozolomide 75 mg/m² daily during radiotherapy, followed by 6 courses of temozolomide 150-200 mg/m² for 5 days every 4 weeks.

In addition to the advantage in progression-free survival at 6 months, median progression-free survival also was longer with BEV/IRI: 9.74 months vs. 6 months in patients treated with temozolomide (HR 0.30, P less than .0001).

In addition patients on the combination used fewer mean daily steroids than patients on temozolomide.

The safety analysis showed that grade 3 or 4 vascular disorders – including deep vein thrombosis, pulmonary embolism, and hypertension – occurred in 10.9% of patients on BEV/IRI, compared with 3.6% of those on temozolomide. The combination was also associated with more grade 3 or 4 diarrhea and nausea, wound infections, and proteinuria. However, hematotoxicity was higher among patients on temozolomide, occurring in 14.8%, compared with 1.7% of patients on BEV/IRI.

"I think it’s important to recognize that there is a [bevacizumab] toxicity signal," said Dr Albert Lai, a neuro-oncologist at the University of California, Los Angeles, who was the invited discussant.

Dr. Lai commented that the overall survival signal seen by the GLARIUS investigators may have been affected by an optional crossover to BEV/IRI after disease progression on temozolomide. Of the 54 patients in the temozolomide arm, 29 crossed over to BEV/IRI.

The GLARIUS trial was sponsored by Hoffman-La Roche. Dr. Herrlinger disclosed being a consultant and speaker and receiving research support from the company. Dr. Lai disclosed serving as a consultant and receiving research funding from Genentech/Roche.

Median hospitalist compensation has grown steadily over the past decade, but physicians aren’t immune to the sting of accelerated premiums, copays, and contributions imposed by health insurers.

According to the Hay Group’s 2011 Physician Compensation Survey, the number of physicians who contributing to health insurance premiums increased to 68% in 2011 from 58% in 2010. The survey showed only 9% of physicians did not pay anything for medical coverage, down from 19% in 2010.

Moreover, the expected physician contribution was between 1% and 25% of the premium.

Dan Fuller, president and cofounder of Alpharetta, Ga.-based IN Compass Health, has noticed an uptick in candidates’ interest in their health-care benefits. “Especially for physicians who have families, health benefits have become one of the top issues in recruiting,” the SHM Practice Analysis Committee (PAC) member says.

Christopher Frost, MD, FHM, medical director of hospital medicine at the Hospital Corporation of America in Nashville, Tenn., reports that he is seeing an upward trend in employees’ contributions to premiums and out-of-pocket costs. He’s also observed colleagues becoming more selective when choosing their own health-care plans and how they use those plans.

Gretchen Henkel is a freelance writer in California.

Median hospitalist compensation has grown steadily over the past decade, but physicians aren’t immune to the sting of accelerated premiums, copays, and contributions imposed by health insurers.

According to the Hay Group’s 2011 Physician Compensation Survey, the number of physicians who contributing to health insurance premiums increased to 68% in 2011 from 58% in 2010. The survey showed only 9% of physicians did not pay anything for medical coverage, down from 19% in 2010.

Moreover, the expected physician contribution was between 1% and 25% of the premium.

Dan Fuller, president and cofounder of Alpharetta, Ga.-based IN Compass Health, has noticed an uptick in candidates’ interest in their health-care benefits. “Especially for physicians who have families, health benefits have become one of the top issues in recruiting,” the SHM Practice Analysis Committee (PAC) member says.

Christopher Frost, MD, FHM, medical director of hospital medicine at the Hospital Corporation of America in Nashville, Tenn., reports that he is seeing an upward trend in employees’ contributions to premiums and out-of-pocket costs. He’s also observed colleagues becoming more selective when choosing their own health-care plans and how they use those plans.

Gretchen Henkel is a freelance writer in California.

Median hospitalist compensation has grown steadily over the past decade, but physicians aren’t immune to the sting of accelerated premiums, copays, and contributions imposed by health insurers.

According to the Hay Group’s 2011 Physician Compensation Survey, the number of physicians who contributing to health insurance premiums increased to 68% in 2011 from 58% in 2010. The survey showed only 9% of physicians did not pay anything for medical coverage, down from 19% in 2010.

Moreover, the expected physician contribution was between 1% and 25% of the premium.

Dan Fuller, president and cofounder of Alpharetta, Ga.-based IN Compass Health, has noticed an uptick in candidates’ interest in their health-care benefits. “Especially for physicians who have families, health benefits have become one of the top issues in recruiting,” the SHM Practice Analysis Committee (PAC) member says.

Christopher Frost, MD, FHM, medical director of hospital medicine at the Hospital Corporation of America in Nashville, Tenn., reports that he is seeing an upward trend in employees’ contributions to premiums and out-of-pocket costs. He’s also observed colleagues becoming more selective when choosing their own health-care plans and how they use those plans.

Gretchen Henkel is a freelance writer in California.

Click here to listen to Dr. Frederickson's take on Medicare reimbursement

Click here to listen to Dr. Frederickson's take on Medicare reimbursement

Click here to listen to Dr. Frederickson's take on Medicare reimbursement

Click here to listen to new SHM President Eric Howell

Click here to listen to new SHM President Eric Howell

Click here to listen to new SHM President Eric Howell

The tiresome cycle of the sustainable growth rate (SGR) continues and, as a result, providers are facing a pay cut of approximately 25% at the end of 2013. With virtually universal agreement that something must be done to permanently repeal the SGR, the insurmountable barrier to a solution has been the cost, which is estimated at $245 billion.

However, a bright spot has emerged.

Several months ago, the Congressional Budget Office produced an anomalous, revised SGR repeal estimate of $138 billion. At nearly half the cost of previous estimates, this is a much less daunting budgetary hole to fill. Needless to say, this revised estimate has breathed new life into the potential to permanently fix the SGR this year. The only catch is that this low estimate is unlikely to persist, so a flurry of activity is expected to last throughout the summer months before the window of opportunity closes.

One of the earliest proposals to move away from fee-for-service to a payment system rooted in quality and value came from the reintroduction of legislation by U.S. Reps. Allyson Schwartz (D-Pa.) and Joe Heck (R-Nev.). SHM is actively supporting this legislation and will continue to do so, but it will give the same attention to other reasonable plans designed to move away from the SGR by incorporating the concepts of quality and value as laid out by Schwartz and Heck.

Along these lines, a joint effort by House Energy and Commerce Committee chairman

Fred Upton (R-Mich.) and House Ways and Means Committee chairman Dave Camp (R-Mich.) would repeal the SGR and replace it with a more sustainable payment system. The plan is being developed iteratively, with opportunities for specialty societies, such as SHM, to provide input along the way. Clear details have yet to emerge because the plan is still in its early stages, but broadly, it will repeal the SGR, replacing it with quality and resource use metrics coupled with value-based payment, and somehow incorporate alternative payment models, such as accountable-care organizations (ACOs). This may sound familiar

because much of it is.

The Centers for Medicare & Medicaid Services (CMS) is developing programs, guided by the Affordable Care Act (ACA), to meet many of these systemic needs in the absence of a repeal of the SGR. The Physician Quality Reporting System (PQRS) is transitioning into a mandatory program, and it’s coupling with Quality and Resource Use Reports (QRURs) brings value into the equation. Both of these programs are a part of the ACA-mandated Physician Value-Based Payment Modifier (VBPM), which implements a level of value-based payment to all physicians by 2017. Additionally, the Center for Medicare & Medicaid Innovation, along with Medicare itself, is developing and testing many alternative models, such as ACOs, bundled payments, and patient-centered medical homes, to name a few.

Upton and Camp have expressed that their goal is to not only repeal the SGR, but also to establish a system that pays for value and is less piecemeal and confusing than what is currently being implemented. For example, they are looking at ways to potentially unify the often disparate yet overlapping reporting requirements placed on physicians through such programs as PQRS, Meaningful Use, and VBPM. This is a great opportunity to take the knowledge and experience hospitalists have with these current CMS programs and advocate for aligning programs, ensuring the usefulness of quality measurement, and reducing administrative barriers and burdens.

Ultimately, the repeal of the SGR will take much thought and legislative will to accomplish. With a broad framework in place, the process has at least begun. It remains to be seen whether Congress will act now on the SGR “sale” and help the health-care system transition into something more sustainable and stable.

Josh Boswell is SHM’s senior manager of government relations

The tiresome cycle of the sustainable growth rate (SGR) continues and, as a result, providers are facing a pay cut of approximately 25% at the end of 2013. With virtually universal agreement that something must be done to permanently repeal the SGR, the insurmountable barrier to a solution has been the cost, which is estimated at $245 billion.

However, a bright spot has emerged.

Several months ago, the Congressional Budget Office produced an anomalous, revised SGR repeal estimate of $138 billion. At nearly half the cost of previous estimates, this is a much less daunting budgetary hole to fill. Needless to say, this revised estimate has breathed new life into the potential to permanently fix the SGR this year. The only catch is that this low estimate is unlikely to persist, so a flurry of activity is expected to last throughout the summer months before the window of opportunity closes.

One of the earliest proposals to move away from fee-for-service to a payment system rooted in quality and value came from the reintroduction of legislation by U.S. Reps. Allyson Schwartz (D-Pa.) and Joe Heck (R-Nev.). SHM is actively supporting this legislation and will continue to do so, but it will give the same attention to other reasonable plans designed to move away from the SGR by incorporating the concepts of quality and value as laid out by Schwartz and Heck.

Along these lines, a joint effort by House Energy and Commerce Committee chairman

Fred Upton (R-Mich.) and House Ways and Means Committee chairman Dave Camp (R-Mich.) would repeal the SGR and replace it with a more sustainable payment system. The plan is being developed iteratively, with opportunities for specialty societies, such as SHM, to provide input along the way. Clear details have yet to emerge because the plan is still in its early stages, but broadly, it will repeal the SGR, replacing it with quality and resource use metrics coupled with value-based payment, and somehow incorporate alternative payment models, such as accountable-care organizations (ACOs). This may sound familiar

because much of it is.

The Centers for Medicare & Medicaid Services (CMS) is developing programs, guided by the Affordable Care Act (ACA), to meet many of these systemic needs in the absence of a repeal of the SGR. The Physician Quality Reporting System (PQRS) is transitioning into a mandatory program, and it’s coupling with Quality and Resource Use Reports (QRURs) brings value into the equation. Both of these programs are a part of the ACA-mandated Physician Value-Based Payment Modifier (VBPM), which implements a level of value-based payment to all physicians by 2017. Additionally, the Center for Medicare & Medicaid Innovation, along with Medicare itself, is developing and testing many alternative models, such as ACOs, bundled payments, and patient-centered medical homes, to name a few.

Upton and Camp have expressed that their goal is to not only repeal the SGR, but also to establish a system that pays for value and is less piecemeal and confusing than what is currently being implemented. For example, they are looking at ways to potentially unify the often disparate yet overlapping reporting requirements placed on physicians through such programs as PQRS, Meaningful Use, and VBPM. This is a great opportunity to take the knowledge and experience hospitalists have with these current CMS programs and advocate for aligning programs, ensuring the usefulness of quality measurement, and reducing administrative barriers and burdens.

Ultimately, the repeal of the SGR will take much thought and legislative will to accomplish. With a broad framework in place, the process has at least begun. It remains to be seen whether Congress will act now on the SGR “sale” and help the health-care system transition into something more sustainable and stable.

Josh Boswell is SHM’s senior manager of government relations

The tiresome cycle of the sustainable growth rate (SGR) continues and, as a result, providers are facing a pay cut of approximately 25% at the end of 2013. With virtually universal agreement that something must be done to permanently repeal the SGR, the insurmountable barrier to a solution has been the cost, which is estimated at $245 billion.

However, a bright spot has emerged.

Several months ago, the Congressional Budget Office produced an anomalous, revised SGR repeal estimate of $138 billion. At nearly half the cost of previous estimates, this is a much less daunting budgetary hole to fill. Needless to say, this revised estimate has breathed new life into the potential to permanently fix the SGR this year. The only catch is that this low estimate is unlikely to persist, so a flurry of activity is expected to last throughout the summer months before the window of opportunity closes.

One of the earliest proposals to move away from fee-for-service to a payment system rooted in quality and value came from the reintroduction of legislation by U.S. Reps. Allyson Schwartz (D-Pa.) and Joe Heck (R-Nev.). SHM is actively supporting this legislation and will continue to do so, but it will give the same attention to other reasonable plans designed to move away from the SGR by incorporating the concepts of quality and value as laid out by Schwartz and Heck.

Along these lines, a joint effort by House Energy and Commerce Committee chairman

Fred Upton (R-Mich.) and House Ways and Means Committee chairman Dave Camp (R-Mich.) would repeal the SGR and replace it with a more sustainable payment system. The plan is being developed iteratively, with opportunities for specialty societies, such as SHM, to provide input along the way. Clear details have yet to emerge because the plan is still in its early stages, but broadly, it will repeal the SGR, replacing it with quality and resource use metrics coupled with value-based payment, and somehow incorporate alternative payment models, such as accountable-care organizations (ACOs). This may sound familiar

because much of it is.

The Centers for Medicare & Medicaid Services (CMS) is developing programs, guided by the Affordable Care Act (ACA), to meet many of these systemic needs in the absence of a repeal of the SGR. The Physician Quality Reporting System (PQRS) is transitioning into a mandatory program, and it’s coupling with Quality and Resource Use Reports (QRURs) brings value into the equation. Both of these programs are a part of the ACA-mandated Physician Value-Based Payment Modifier (VBPM), which implements a level of value-based payment to all physicians by 2017. Additionally, the Center for Medicare & Medicaid Innovation, along with Medicare itself, is developing and testing many alternative models, such as ACOs, bundled payments, and patient-centered medical homes, to name a few.

Upton and Camp have expressed that their goal is to not only repeal the SGR, but also to establish a system that pays for value and is less piecemeal and confusing than what is currently being implemented. For example, they are looking at ways to potentially unify the often disparate yet overlapping reporting requirements placed on physicians through such programs as PQRS, Meaningful Use, and VBPM. This is a great opportunity to take the knowledge and experience hospitalists have with these current CMS programs and advocate for aligning programs, ensuring the usefulness of quality measurement, and reducing administrative barriers and burdens.

Ultimately, the repeal of the SGR will take much thought and legislative will to accomplish. With a broad framework in place, the process has at least begun. It remains to be seen whether Congress will act now on the SGR “sale” and help the health-care system transition into something more sustainable and stable.

Josh Boswell is SHM’s senior manager of government relations

Launching this summer, SHM’s new Learning Portal will offer a better way to access and track online CME, with member discounts to a growing library of content. For more information, visit www.shmlearningportal.org.

Launching this summer, SHM’s new Learning Portal will offer a better way to access and track online CME, with member discounts to a growing library of content. For more information, visit www.shmlearningportal.org.

Launching this summer, SHM’s new Learning Portal will offer a better way to access and track online CME, with member discounts to a growing library of content. For more information, visit www.shmlearningportal.org.