The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

[email protected]

On Twitter @aliciaault

The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

[email protected]

On Twitter @aliciaault

The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

[email protected]

On Twitter @aliciaault

Many hospitalists are anxious about looming changes to the American Board of Medicine’s (ABIM) Maintenance of Certification (MOC) process, but hospital medicine leaders say the effect will be positive.

In January, ABIM and the American Board of Medical Specialties (ABMS) will begin reporting on whether hospitalists and other physicians are meeting MOC requirements. To do so, physicians need to complete 20 ABIM MOC points by December 2015, and every two years after that. Physicians also need to earn 100 ABIM MOC points by December 2018, and every five years after that.

Previously, physicians had to amass a total of 100 points every 10 years between secure exams. The new rules are aimed at keeping “pace with the changes in the science of medicine and assessment,” ABIM says on its website.

“I think the anxiety is coming out of it being misunderstood,” says Jeff Wiese, MD, MHM, professor of medicine and associate dean for graduate medical education at Tulane University Health Sciences Center in New Orleans. “It’s not that big of a deal when you put it in the context of what you do for CME now.”

Dr. Wiese emphasizes the secure exam will still be taken every 10 years, but increasing the frequency of learning via practice-improvement modules (PIMs) and other vehicles should serve to improve hospitalists’ efficiency and care delivery.

Ethan Cumbler, MD, FACP, of the University of Colorado at Denver, an annual faculty member for the ABIM’s MOC pre-course at SHM’s annual meetings, says that codifying additional learning is a good thing for the specialty. “If the point of this is to actually improve how we’re practicing as doctors, then we do want to be practicing this in an ongoing fashion,” Dr. Cumbler says.

Visit our website for more information on CME.

Many hospitalists are anxious about looming changes to the American Board of Medicine’s (ABIM) Maintenance of Certification (MOC) process, but hospital medicine leaders say the effect will be positive.

In January, ABIM and the American Board of Medical Specialties (ABMS) will begin reporting on whether hospitalists and other physicians are meeting MOC requirements. To do so, physicians need to complete 20 ABIM MOC points by December 2015, and every two years after that. Physicians also need to earn 100 ABIM MOC points by December 2018, and every five years after that.

Previously, physicians had to amass a total of 100 points every 10 years between secure exams. The new rules are aimed at keeping “pace with the changes in the science of medicine and assessment,” ABIM says on its website.

“I think the anxiety is coming out of it being misunderstood,” says Jeff Wiese, MD, MHM, professor of medicine and associate dean for graduate medical education at Tulane University Health Sciences Center in New Orleans. “It’s not that big of a deal when you put it in the context of what you do for CME now.”

Dr. Wiese emphasizes the secure exam will still be taken every 10 years, but increasing the frequency of learning via practice-improvement modules (PIMs) and other vehicles should serve to improve hospitalists’ efficiency and care delivery.

Ethan Cumbler, MD, FACP, of the University of Colorado at Denver, an annual faculty member for the ABIM’s MOC pre-course at SHM’s annual meetings, says that codifying additional learning is a good thing for the specialty. “If the point of this is to actually improve how we’re practicing as doctors, then we do want to be practicing this in an ongoing fashion,” Dr. Cumbler says.

Visit our website for more information on CME.

Many hospitalists are anxious about looming changes to the American Board of Medicine’s (ABIM) Maintenance of Certification (MOC) process, but hospital medicine leaders say the effect will be positive.

In January, ABIM and the American Board of Medical Specialties (ABMS) will begin reporting on whether hospitalists and other physicians are meeting MOC requirements. To do so, physicians need to complete 20 ABIM MOC points by December 2015, and every two years after that. Physicians also need to earn 100 ABIM MOC points by December 2018, and every five years after that.

Previously, physicians had to amass a total of 100 points every 10 years between secure exams. The new rules are aimed at keeping “pace with the changes in the science of medicine and assessment,” ABIM says on its website.

“I think the anxiety is coming out of it being misunderstood,” says Jeff Wiese, MD, MHM, professor of medicine and associate dean for graduate medical education at Tulane University Health Sciences Center in New Orleans. “It’s not that big of a deal when you put it in the context of what you do for CME now.”

Dr. Wiese emphasizes the secure exam will still be taken every 10 years, but increasing the frequency of learning via practice-improvement modules (PIMs) and other vehicles should serve to improve hospitalists’ efficiency and care delivery.

Ethan Cumbler, MD, FACP, of the University of Colorado at Denver, an annual faculty member for the ABIM’s MOC pre-course at SHM’s annual meetings, says that codifying additional learning is a good thing for the specialty. “If the point of this is to actually improve how we’re practicing as doctors, then we do want to be practicing this in an ongoing fashion,” Dr. Cumbler says.

Visit our website for more information on CME.

After a monstrous tornado roared through Moore, Okla., chewing up and spitting out everything in its path, hospitalist Joe R. Womble, MD, who was off that day, wondered what had become of his colleagues, his patients, and his hospital, Moore Medical Center.

The initial news was encouraging: Everyone who had been inside the hospital—roughly 200 to 300 people, including a few dozen patients—had survived. He thought that boded well for the hospital as well.

“When I was getting information back from people who were there and I was hearing that everyone was fine, all the patients and staff, and no one got injured, I was thinking that either the hospital was missed by the storm, or that it must not have really damaged it very significantly,” says Dr. Womble. “And then they started showing aerial shots [on TV] and I was just shocked. My jaw was just dropped. The main entrance that I would go in every day was literally stacked three or four cars deep with … about 30 cars.” Likewise, the storm ripped through patient rooms on the second floor, obliterating some and reducing others to their steel innards.

About a week after the storm, word came back that Moore Medical Center will have to be demolished.

“Nobody knows what will happen next, but a lot of us speculate that they will not rebuild an inpatient facility,” says Dr. Womble. “It’s the only hospital in that city of Moore, and it’s just me and my partner to take care of virtually everyone that comes in with any kind of medical problem.

“And so I definitely feel a tie to the community. … Now that it’s gone, it’s just hard to put into words,” he says. “I would just say devastating, I guess.”

After a monstrous tornado roared through Moore, Okla., chewing up and spitting out everything in its path, hospitalist Joe R. Womble, MD, who was off that day, wondered what had become of his colleagues, his patients, and his hospital, Moore Medical Center.

The initial news was encouraging: Everyone who had been inside the hospital—roughly 200 to 300 people, including a few dozen patients—had survived. He thought that boded well for the hospital as well.

“When I was getting information back from people who were there and I was hearing that everyone was fine, all the patients and staff, and no one got injured, I was thinking that either the hospital was missed by the storm, or that it must not have really damaged it very significantly,” says Dr. Womble. “And then they started showing aerial shots [on TV] and I was just shocked. My jaw was just dropped. The main entrance that I would go in every day was literally stacked three or four cars deep with … about 30 cars.” Likewise, the storm ripped through patient rooms on the second floor, obliterating some and reducing others to their steel innards.

About a week after the storm, word came back that Moore Medical Center will have to be demolished.

“Nobody knows what will happen next, but a lot of us speculate that they will not rebuild an inpatient facility,” says Dr. Womble. “It’s the only hospital in that city of Moore, and it’s just me and my partner to take care of virtually everyone that comes in with any kind of medical problem.

“And so I definitely feel a tie to the community. … Now that it’s gone, it’s just hard to put into words,” he says. “I would just say devastating, I guess.”

After a monstrous tornado roared through Moore, Okla., chewing up and spitting out everything in its path, hospitalist Joe R. Womble, MD, who was off that day, wondered what had become of his colleagues, his patients, and his hospital, Moore Medical Center.

The initial news was encouraging: Everyone who had been inside the hospital—roughly 200 to 300 people, including a few dozen patients—had survived. He thought that boded well for the hospital as well.

“When I was getting information back from people who were there and I was hearing that everyone was fine, all the patients and staff, and no one got injured, I was thinking that either the hospital was missed by the storm, or that it must not have really damaged it very significantly,” says Dr. Womble. “And then they started showing aerial shots [on TV] and I was just shocked. My jaw was just dropped. The main entrance that I would go in every day was literally stacked three or four cars deep with … about 30 cars.” Likewise, the storm ripped through patient rooms on the second floor, obliterating some and reducing others to their steel innards.

About a week after the storm, word came back that Moore Medical Center will have to be demolished.

“Nobody knows what will happen next, but a lot of us speculate that they will not rebuild an inpatient facility,” says Dr. Womble. “It’s the only hospital in that city of Moore, and it’s just me and my partner to take care of virtually everyone that comes in with any kind of medical problem.

“And so I definitely feel a tie to the community. … Now that it’s gone, it’s just hard to put into words,” he says. “I would just say devastating, I guess.”

Maybe it’s because spring is here and the flowers are blooming. Or it may be because my wife and I are marrying off our daughter this summer. (Why, thank you.) Whatever the reason, I thought I would share some of the ways my married patients met each other. When I ask couples how they got together, they are usually happy to tell me. Even after many years, most of them have no trouble remembering the particular circumstances of their introduction. They smile, and tell me a tale they have probably told many times. (Remember that this is a selected group – these couples are still together!)

Some of the stories are conventional – a mutual friend or family member fixed them up, or they met in high school or college. Nowadays, more and more are technological, though sometimes with a twist. ("I had so many bad experiences on EBliss4Ever.com that I was ready to give up. But then I decided to give it one more try – and got Stanley!") Sometimes, however, people share tales that sound too cute to be true, ones that even Hollywood script committees – lovers of the "cute-meet" – would reject as too schmaltzy and improbable to work in a romantic comedy. And yet, out here in real life, they somehow did.

"I met Lars in a bar," says Bridget. "My friend Susie and I were having a beer, and I decided to stand up and move to another table. Lars is a large person, and he was walking by just when I got up. I turned to my left- – and hit him right in the chest with my glass. The beer splashed all over him and made a real mess. It took a long time to clean up."

"Oh come on. Did that really happen?"

"Absolutely! We were married a year ago."

Then there is Shane Walsh, who tells me not about himself but about his sister. "We’re a close-knit Irish family," he says. "Five boys and a girl. We were very protective of our sister and made sure that the guys she went out with were the right sort. Then she met the man who’s now her husband, and we all agree that he’s terrific. His name is also Walsh."

"In fact, that’s how they met," Shane says. "They were both at a party, when a guy across the room called out, ‘Hey, Walshie!’ "

"Both of them turned around at the same time and saw each other. The rest is history."

The luck of the Irish, I guess.

My last tale concerns an older pair, Gregory and Kate, married 39 years. They remember their first meeting very fondly.

"We both belonged to an apple-picking club," recalls Kate. "That fall weekend the whole group traveled by bus up to Maine. It was raining and miserable. When we got to the farm, the lady handing out the collecting baskets said, ‘You’re not from around here, are you?’ She meant that anybody local would have too much sense to pick apples in the driving rain."

"We were standing near each other under the same tree," said Gregory. "It was just like ..."

"Wait a minute," I interrupt, "you don’t mean ..."

"Yes indeed," says Greg, with a twinkle. "She handed me an apple." Kate laughs in agreement.

There you have it – life imitating Scripture. Although there’s nothing in the Good Book about Adam and Eve hiding under the Tree of Knowledge to keep from getting wet.

Here’s to happy endings, however they start out.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected]. 

Maybe it’s because spring is here and the flowers are blooming. Or it may be because my wife and I are marrying off our daughter this summer. (Why, thank you.) Whatever the reason, I thought I would share some of the ways my married patients met each other. When I ask couples how they got together, they are usually happy to tell me. Even after many years, most of them have no trouble remembering the particular circumstances of their introduction. They smile, and tell me a tale they have probably told many times. (Remember that this is a selected group – these couples are still together!)

Some of the stories are conventional – a mutual friend or family member fixed them up, or they met in high school or college. Nowadays, more and more are technological, though sometimes with a twist. ("I had so many bad experiences on EBliss4Ever.com that I was ready to give up. But then I decided to give it one more try – and got Stanley!") Sometimes, however, people share tales that sound too cute to be true, ones that even Hollywood script committees – lovers of the "cute-meet" – would reject as too schmaltzy and improbable to work in a romantic comedy. And yet, out here in real life, they somehow did.

"I met Lars in a bar," says Bridget. "My friend Susie and I were having a beer, and I decided to stand up and move to another table. Lars is a large person, and he was walking by just when I got up. I turned to my left- – and hit him right in the chest with my glass. The beer splashed all over him and made a real mess. It took a long time to clean up."

"Oh come on. Did that really happen?"

"Absolutely! We were married a year ago."

Then there is Shane Walsh, who tells me not about himself but about his sister. "We’re a close-knit Irish family," he says. "Five boys and a girl. We were very protective of our sister and made sure that the guys she went out with were the right sort. Then she met the man who’s now her husband, and we all agree that he’s terrific. His name is also Walsh."

"In fact, that’s how they met," Shane says. "They were both at a party, when a guy across the room called out, ‘Hey, Walshie!’ "

"Both of them turned around at the same time and saw each other. The rest is history."

The luck of the Irish, I guess.

My last tale concerns an older pair, Gregory and Kate, married 39 years. They remember their first meeting very fondly.

"We both belonged to an apple-picking club," recalls Kate. "That fall weekend the whole group traveled by bus up to Maine. It was raining and miserable. When we got to the farm, the lady handing out the collecting baskets said, ‘You’re not from around here, are you?’ She meant that anybody local would have too much sense to pick apples in the driving rain."

"We were standing near each other under the same tree," said Gregory. "It was just like ..."

"Wait a minute," I interrupt, "you don’t mean ..."

"Yes indeed," says Greg, with a twinkle. "She handed me an apple." Kate laughs in agreement.

There you have it – life imitating Scripture. Although there’s nothing in the Good Book about Adam and Eve hiding under the Tree of Knowledge to keep from getting wet.

Here’s to happy endings, however they start out.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected]. 

Maybe it’s because spring is here and the flowers are blooming. Or it may be because my wife and I are marrying off our daughter this summer. (Why, thank you.) Whatever the reason, I thought I would share some of the ways my married patients met each other. When I ask couples how they got together, they are usually happy to tell me. Even after many years, most of them have no trouble remembering the particular circumstances of their introduction. They smile, and tell me a tale they have probably told many times. (Remember that this is a selected group – these couples are still together!)

Some of the stories are conventional – a mutual friend or family member fixed them up, or they met in high school or college. Nowadays, more and more are technological, though sometimes with a twist. ("I had so many bad experiences on EBliss4Ever.com that I was ready to give up. But then I decided to give it one more try – and got Stanley!") Sometimes, however, people share tales that sound too cute to be true, ones that even Hollywood script committees – lovers of the "cute-meet" – would reject as too schmaltzy and improbable to work in a romantic comedy. And yet, out here in real life, they somehow did.

"I met Lars in a bar," says Bridget. "My friend Susie and I were having a beer, and I decided to stand up and move to another table. Lars is a large person, and he was walking by just when I got up. I turned to my left- – and hit him right in the chest with my glass. The beer splashed all over him and made a real mess. It took a long time to clean up."

"Oh come on. Did that really happen?"

"Absolutely! We were married a year ago."

Then there is Shane Walsh, who tells me not about himself but about his sister. "We’re a close-knit Irish family," he says. "Five boys and a girl. We were very protective of our sister and made sure that the guys she went out with were the right sort. Then she met the man who’s now her husband, and we all agree that he’s terrific. His name is also Walsh."

"In fact, that’s how they met," Shane says. "They were both at a party, when a guy across the room called out, ‘Hey, Walshie!’ "

"Both of them turned around at the same time and saw each other. The rest is history."

The luck of the Irish, I guess.

My last tale concerns an older pair, Gregory and Kate, married 39 years. They remember their first meeting very fondly.

"We both belonged to an apple-picking club," recalls Kate. "That fall weekend the whole group traveled by bus up to Maine. It was raining and miserable. When we got to the farm, the lady handing out the collecting baskets said, ‘You’re not from around here, are you?’ She meant that anybody local would have too much sense to pick apples in the driving rain."

"We were standing near each other under the same tree," said Gregory. "It was just like ..."

"Wait a minute," I interrupt, "you don’t mean ..."

"Yes indeed," says Greg, with a twinkle. "She handed me an apple." Kate laughs in agreement.

There you have it – life imitating Scripture. Although there’s nothing in the Good Book about Adam and Eve hiding under the Tree of Knowledge to keep from getting wet.

Here’s to happy endings, however they start out.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected]. 

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.