Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.

CHICAGO – Vascular surgery trainees are increasingly turning to online texts for clinical information and seek more training on the business aspects of vascular surgery and noninvasive laboratory studies, according to a survey by the Association of Program Directors in Vascular Surgery.

The survey included 163 respondents, of which 46 were in an integrated (0-5) residency program and 117 were currently in or new graduates of an independent (5+2) program.

When asked how they obtained clinical information on the wards or prior to an operation, integrated program respondents said online text books were their go-to source, while independent responders preferred a traditional textbook. Asking a colleague came in second for both groups.

"You can certainly figure out why that might be," said Dr. Michael Dalsing who reported the findings at the annual meeting of the Peripheral Vascular Surgical Society. "If you’re a PGY 1 - 3, patient care is your primary concern. While for those with additional levels of training, specific vascular concerns and surgery are most important."

One-on-one instruction was the best way both groups of trainees reported learning new information. Integrated residents were less enthusiastic than independent residents about small group discussions, while simulation training ranked higher among integrated residents.

When asked to grade their overall program, both programs ranked their endovascular training as excellent.

"Less than a decade you would not have seen endovascular training as the best part of their program, and now nearly 70% said it’s excellent," said Dr. Dalsing, of Indiana University.

Other "excellent" ratings included involvement of teaching faculty, open abdominal and aortic/mesenteric/renal training, didactic teaching and responsiveness to resident stresses. Appropriate performance feedback and support in their job search received "good" marks.

When asked if training in a specific area was appropriate, the business aspects of vascular surgery were judged the most underserved among both integrated and independent (69% vs. 70%) trainees, followed by coding and billing (66% and 64%). The next closest area in need of more attention was formal clinical research training, with just 27% and 35% of trainees, respectively, expressing this opinion. Surgical training and vascular lab/venous training were judged "just right" by more than 75% of respondents.

The ability to actually perform noninvasive vascular laboratory studies requires more attention, with a whopping 49% of integrated program trainees and 59% of independent program trainees viewing training in this area as "fair or nonexistent." Training in vascular laboratory interpretation received the same marks by 29% and 34% of trainees, respectively. About 85% of all trainees, however, view noninvasive vascular lab training as essential in future practice.

Dr. Joseph Mills, of the University of Arizona, rose from the audience to express alarm at these findings and asked what is being done to standardize the curriculum in the vascular lab. Dr. Dalsing said that CDs are available to educators to standardize training, but added that educators will have to become more aggressive in quantifying that the educational experience at their institution has met expected standards.

The two groups of trainees were split over the 80-hour work week. Independent trainees were significantly more likely than integrated trainees to view the 80-hour work week as detrimental to the continuity of care (62% vs. 24%, P value = .0001), while integrated trainees were significantly more likely to view the rule as essential to avoid fatigue and errors (82% vs. 42%, P = .0001).

CHICAGO – Vascular surgery trainees are increasingly turning to online texts for clinical information and seek more training on the business aspects of vascular surgery and noninvasive laboratory studies, according to a survey by the Association of Program Directors in Vascular Surgery.

The survey included 163 respondents, of which 46 were in an integrated (0-5) residency program and 117 were currently in or new graduates of an independent (5+2) program.

When asked how they obtained clinical information on the wards or prior to an operation, integrated program respondents said online text books were their go-to source, while independent responders preferred a traditional textbook. Asking a colleague came in second for both groups.

"You can certainly figure out why that might be," said Dr. Michael Dalsing who reported the findings at the annual meeting of the Peripheral Vascular Surgical Society. "If you’re a PGY 1 - 3, patient care is your primary concern. While for those with additional levels of training, specific vascular concerns and surgery are most important."

One-on-one instruction was the best way both groups of trainees reported learning new information. Integrated residents were less enthusiastic than independent residents about small group discussions, while simulation training ranked higher among integrated residents.

When asked to grade their overall program, both programs ranked their endovascular training as excellent.

"Less than a decade you would not have seen endovascular training as the best part of their program, and now nearly 70% said it’s excellent," said Dr. Dalsing, of Indiana University.

Other "excellent" ratings included involvement of teaching faculty, open abdominal and aortic/mesenteric/renal training, didactic teaching and responsiveness to resident stresses. Appropriate performance feedback and support in their job search received "good" marks.

When asked if training in a specific area was appropriate, the business aspects of vascular surgery were judged the most underserved among both integrated and independent (69% vs. 70%) trainees, followed by coding and billing (66% and 64%). The next closest area in need of more attention was formal clinical research training, with just 27% and 35% of trainees, respectively, expressing this opinion. Surgical training and vascular lab/venous training were judged "just right" by more than 75% of respondents.

The ability to actually perform noninvasive vascular laboratory studies requires more attention, with a whopping 49% of integrated program trainees and 59% of independent program trainees viewing training in this area as "fair or nonexistent." Training in vascular laboratory interpretation received the same marks by 29% and 34% of trainees, respectively. About 85% of all trainees, however, view noninvasive vascular lab training as essential in future practice.

Dr. Joseph Mills, of the University of Arizona, rose from the audience to express alarm at these findings and asked what is being done to standardize the curriculum in the vascular lab. Dr. Dalsing said that CDs are available to educators to standardize training, but added that educators will have to become more aggressive in quantifying that the educational experience at their institution has met expected standards.

The two groups of trainees were split over the 80-hour work week. Independent trainees were significantly more likely than integrated trainees to view the 80-hour work week as detrimental to the continuity of care (62% vs. 24%, P value = .0001), while integrated trainees were significantly more likely to view the rule as essential to avoid fatigue and errors (82% vs. 42%, P = .0001).

CHICAGO – Vascular surgery trainees are increasingly turning to online texts for clinical information and seek more training on the business aspects of vascular surgery and noninvasive laboratory studies, according to a survey by the Association of Program Directors in Vascular Surgery.

The survey included 163 respondents, of which 46 were in an integrated (0-5) residency program and 117 were currently in or new graduates of an independent (5+2) program.

When asked how they obtained clinical information on the wards or prior to an operation, integrated program respondents said online text books were their go-to source, while independent responders preferred a traditional textbook. Asking a colleague came in second for both groups.

"You can certainly figure out why that might be," said Dr. Michael Dalsing who reported the findings at the annual meeting of the Peripheral Vascular Surgical Society. "If you’re a PGY 1 - 3, patient care is your primary concern. While for those with additional levels of training, specific vascular concerns and surgery are most important."

One-on-one instruction was the best way both groups of trainees reported learning new information. Integrated residents were less enthusiastic than independent residents about small group discussions, while simulation training ranked higher among integrated residents.

When asked to grade their overall program, both programs ranked their endovascular training as excellent.

"Less than a decade you would not have seen endovascular training as the best part of their program, and now nearly 70% said it’s excellent," said Dr. Dalsing, of Indiana University.

Other "excellent" ratings included involvement of teaching faculty, open abdominal and aortic/mesenteric/renal training, didactic teaching and responsiveness to resident stresses. Appropriate performance feedback and support in their job search received "good" marks.

When asked if training in a specific area was appropriate, the business aspects of vascular surgery were judged the most underserved among both integrated and independent (69% vs. 70%) trainees, followed by coding and billing (66% and 64%). The next closest area in need of more attention was formal clinical research training, with just 27% and 35% of trainees, respectively, expressing this opinion. Surgical training and vascular lab/venous training were judged "just right" by more than 75% of respondents.

The ability to actually perform noninvasive vascular laboratory studies requires more attention, with a whopping 49% of integrated program trainees and 59% of independent program trainees viewing training in this area as "fair or nonexistent." Training in vascular laboratory interpretation received the same marks by 29% and 34% of trainees, respectively. About 85% of all trainees, however, view noninvasive vascular lab training as essential in future practice.

Dr. Joseph Mills, of the University of Arizona, rose from the audience to express alarm at these findings and asked what is being done to standardize the curriculum in the vascular lab. Dr. Dalsing said that CDs are available to educators to standardize training, but added that educators will have to become more aggressive in quantifying that the educational experience at their institution has met expected standards.

The two groups of trainees were split over the 80-hour work week. Independent trainees were significantly more likely than integrated trainees to view the 80-hour work week as detrimental to the continuity of care (62% vs. 24%, P value = .0001), while integrated trainees were significantly more likely to view the rule as essential to avoid fatigue and errors (82% vs. 42%, P = .0001).

Hospitalists might be able to save their institutions time and money by shuttling out patients who have a low risk for acute pulmonary embolism (PE), according to one researcher.

Donald Yealy, MD, chair of the Department of Emergency Medicine at the University of Pittsburgh School of Medicine, was among the authors of a new study that reported that in certain cases, "outpatient care can safely and effectively be used in place of inpatient care" (Lancet. 2011;378(9785):41-48).

Dr. Yealy says HM should pay close attention to the results, as patients moved to the outpatient setting clear bed space for more acute cases. "[Hospitalists] should identify low-risk patients and try as quickly as possible to return patients to the setting they prefer: their home," he says.

In a primary analysis, the international noninferiority trial reported that one of 171 outpatients (0.006%) developed recurrent VTE within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2.7%; P=0.011). Mean length of stay was 0.5 days for outpatients, compared with 3.9 days.

Dr. Yealy notes that the next step for research is to determine which treatment to use for PE cases, as his study focused just on where the treatment was rendered. He also notes that the review focused only on patients diagnosed by ED physicians as having a PE severity index risk class 1 or 2. He compares potential future treatment therapies to those for cancer patients, for which "not everyone who has cancer has a high risk for terrible outcomes."

"All pulmonary emboli are not the same," Dr. Yealy adds. "If you use a strategy that identifies the lowest-risk patients, you have a lot of options. … We need to right-size our approach."

Hospitalists might be able to save their institutions time and money by shuttling out patients who have a low risk for acute pulmonary embolism (PE), according to one researcher.

Donald Yealy, MD, chair of the Department of Emergency Medicine at the University of Pittsburgh School of Medicine, was among the authors of a new study that reported that in certain cases, "outpatient care can safely and effectively be used in place of inpatient care" (Lancet. 2011;378(9785):41-48).

Dr. Yealy says HM should pay close attention to the results, as patients moved to the outpatient setting clear bed space for more acute cases. "[Hospitalists] should identify low-risk patients and try as quickly as possible to return patients to the setting they prefer: their home," he says.

In a primary analysis, the international noninferiority trial reported that one of 171 outpatients (0.006%) developed recurrent VTE within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2.7%; P=0.011). Mean length of stay was 0.5 days for outpatients, compared with 3.9 days.

Dr. Yealy notes that the next step for research is to determine which treatment to use for PE cases, as his study focused just on where the treatment was rendered. He also notes that the review focused only on patients diagnosed by ED physicians as having a PE severity index risk class 1 or 2. He compares potential future treatment therapies to those for cancer patients, for which "not everyone who has cancer has a high risk for terrible outcomes."

"All pulmonary emboli are not the same," Dr. Yealy adds. "If you use a strategy that identifies the lowest-risk patients, you have a lot of options. … We need to right-size our approach."

Hospitalists might be able to save their institutions time and money by shuttling out patients who have a low risk for acute pulmonary embolism (PE), according to one researcher.

Donald Yealy, MD, chair of the Department of Emergency Medicine at the University of Pittsburgh School of Medicine, was among the authors of a new study that reported that in certain cases, "outpatient care can safely and effectively be used in place of inpatient care" (Lancet. 2011;378(9785):41-48).

Dr. Yealy says HM should pay close attention to the results, as patients moved to the outpatient setting clear bed space for more acute cases. "[Hospitalists] should identify low-risk patients and try as quickly as possible to return patients to the setting they prefer: their home," he says.

In a primary analysis, the international noninferiority trial reported that one of 171 outpatients (0.006%) developed recurrent VTE within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2.7%; P=0.011). Mean length of stay was 0.5 days for outpatients, compared with 3.9 days.

Dr. Yealy notes that the next step for research is to determine which treatment to use for PE cases, as his study focused just on where the treatment was rendered. He also notes that the review focused only on patients diagnosed by ED physicians as having a PE severity index risk class 1 or 2. He compares potential future treatment therapies to those for cancer patients, for which "not everyone who has cancer has a high risk for terrible outcomes."

"All pulmonary emboli are not the same," Dr. Yealy adds. "If you use a strategy that identifies the lowest-risk patients, you have a lot of options. … We need to right-size our approach."

As part of its new hospital ratings, Consumer Reports has reported that some well-established teaching hospitals have higher rates of central-line-catheter-related bloodstream infections (CRBSIs) than the national average. Three Council of Teaching Hospitals members received the magazine's lowest rating, and 64 received its second-lowest rating for infection prevention.

The Association of Professionals in Infection Control and Epidemiology has challenged the findings as only a partial picture of a complex problem.

"We understand that the data are aggregated, but there are issues with the aggregation," says Carolyn Chrisman, BBA, vice president for quality integration and improvement at Carilion Clinic, whose Roanoke, Va.-based Carilion Medical Center was one of Consumer Reports' second-lowest-rated teaching hospitals, with a rate that it reported was 24% worse than national rates for its mix of ICUs in calendar year 2010. "One of the biggest issues is that the type of patients seen in Level One trauma centers such as ours is very different. We work hard to follow the guidelines, but some of these patients are just more compromised."

Checklists for preventing CRBSIs are widely used in U.S. hospitals and have been shown to reduce infection rates. "But that's only part of the story. What about care and maintenance of the central line after it is inserted, which we're trying to focus on here?" Chrisman says.

At Carilion, a quality team was chartered in 2007 to address BSIs, and that group is planning to reconvene. Having the right supplies readily available when needed for central-line insertions is another challenge, and Carilion has developed carts and kits to help make sure that they are, Chrisman adds. "We also have data from 2011 that show significant improvement" over the 2010 data reported by Consumer Reports, she says.

Bradley Flansbaum, DO, MPH, FACP, director of the hospitalist program at Lenox Hill Hospital in New York City, another teaching hospital on Consumer Reports' lower-performing list for BSIs, with a rate that was 75% worse than national rates for the hospital's mix of ICUs, notes the benchmark has been set high for hospitals. “Some institutions have shown zero bloodstream infections, so the question of what's acceptable has been established. We know what we need to do," he says.

But achieving zero infections is more than just following the checklists, he adds. Ultimately it requires a change of hospital culture, even around issues as mundane as poor hand hygiene, against which all hospitals struggle, he says.

For more information on preventing BSIs, visit the Institute for Healthcare Improvement's Five Million Lives Campaign.

As part of its new hospital ratings, Consumer Reports has reported that some well-established teaching hospitals have higher rates of central-line-catheter-related bloodstream infections (CRBSIs) than the national average. Three Council of Teaching Hospitals members received the magazine's lowest rating, and 64 received its second-lowest rating for infection prevention.

The Association of Professionals in Infection Control and Epidemiology has challenged the findings as only a partial picture of a complex problem.

"We understand that the data are aggregated, but there are issues with the aggregation," says Carolyn Chrisman, BBA, vice president for quality integration and improvement at Carilion Clinic, whose Roanoke, Va.-based Carilion Medical Center was one of Consumer Reports' second-lowest-rated teaching hospitals, with a rate that it reported was 24% worse than national rates for its mix of ICUs in calendar year 2010. "One of the biggest issues is that the type of patients seen in Level One trauma centers such as ours is very different. We work hard to follow the guidelines, but some of these patients are just more compromised."

Checklists for preventing CRBSIs are widely used in U.S. hospitals and have been shown to reduce infection rates. "But that's only part of the story. What about care and maintenance of the central line after it is inserted, which we're trying to focus on here?" Chrisman says.

At Carilion, a quality team was chartered in 2007 to address BSIs, and that group is planning to reconvene. Having the right supplies readily available when needed for central-line insertions is another challenge, and Carilion has developed carts and kits to help make sure that they are, Chrisman adds. "We also have data from 2011 that show significant improvement" over the 2010 data reported by Consumer Reports, she says.

Bradley Flansbaum, DO, MPH, FACP, director of the hospitalist program at Lenox Hill Hospital in New York City, another teaching hospital on Consumer Reports' lower-performing list for BSIs, with a rate that was 75% worse than national rates for the hospital's mix of ICUs, notes the benchmark has been set high for hospitals. “Some institutions have shown zero bloodstream infections, so the question of what's acceptable has been established. We know what we need to do," he says.

But achieving zero infections is more than just following the checklists, he adds. Ultimately it requires a change of hospital culture, even around issues as mundane as poor hand hygiene, against which all hospitals struggle, he says.

For more information on preventing BSIs, visit the Institute for Healthcare Improvement's Five Million Lives Campaign.

As part of its new hospital ratings, Consumer Reports has reported that some well-established teaching hospitals have higher rates of central-line-catheter-related bloodstream infections (CRBSIs) than the national average. Three Council of Teaching Hospitals members received the magazine's lowest rating, and 64 received its second-lowest rating for infection prevention.

The Association of Professionals in Infection Control and Epidemiology has challenged the findings as only a partial picture of a complex problem.

"We understand that the data are aggregated, but there are issues with the aggregation," says Carolyn Chrisman, BBA, vice president for quality integration and improvement at Carilion Clinic, whose Roanoke, Va.-based Carilion Medical Center was one of Consumer Reports' second-lowest-rated teaching hospitals, with a rate that it reported was 24% worse than national rates for its mix of ICUs in calendar year 2010. "One of the biggest issues is that the type of patients seen in Level One trauma centers such as ours is very different. We work hard to follow the guidelines, but some of these patients are just more compromised."

Checklists for preventing CRBSIs are widely used in U.S. hospitals and have been shown to reduce infection rates. "But that's only part of the story. What about care and maintenance of the central line after it is inserted, which we're trying to focus on here?" Chrisman says.

At Carilion, a quality team was chartered in 2007 to address BSIs, and that group is planning to reconvene. Having the right supplies readily available when needed for central-line insertions is another challenge, and Carilion has developed carts and kits to help make sure that they are, Chrisman adds. "We also have data from 2011 that show significant improvement" over the 2010 data reported by Consumer Reports, she says.

Bradley Flansbaum, DO, MPH, FACP, director of the hospitalist program at Lenox Hill Hospital in New York City, another teaching hospital on Consumer Reports' lower-performing list for BSIs, with a rate that was 75% worse than national rates for the hospital's mix of ICUs, notes the benchmark has been set high for hospitals. “Some institutions have shown zero bloodstream infections, so the question of what's acceptable has been established. We know what we need to do," he says.

But achieving zero infections is more than just following the checklists, he adds. Ultimately it requires a change of hospital culture, even around issues as mundane as poor hand hygiene, against which all hospitals struggle, he says.

For more information on preventing BSIs, visit the Institute for Healthcare Improvement's Five Million Lives Campaign.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

SAN DIEGO – Adolescents and young adults with type 1 diabetes have thicker and stiffer carotid arteries, compared with their healthy peers, results from a multicenter study showed.

"Type 1 diabetes has an adverse effect on carotid thickness and stiffness, and we can measure this by the time patients reach young adulthood," Dr. Elaine M. Urbina said at the annual scientific sessions of the American Diabetes Association. "It’s independent of demographics, lipids, and blood pressure, but may be influenced by adiposity. We need to control risk factors, especially obesity, in these adolescents and young adults to improve cardiovascular outcomes in type 1 diabetes."

As part of the SEARCH CVD study, a collaborative effort between investigators at the University of Colorado at Denver, the Colorado School of Public Health in Aurora, and Cincinnati Children’s Hospital Medical Center, Dr. Urbina and her associates set out to examine whether type 1 diabetes has a measurable effect on carotid arteries in adolescents and young adults. They studied 162 people aged 13-26 years, collecting data on demographics, anthropometrics, blood pressure, fasting lipid and hemoglobin A_1c levels, and carotid ultrasound to measure the common, bulb, and internal carotid intima-media thickness (cIMT), with M-mode for calculation of carotid stiffness by Peterson’s elastic modulus (PEM), Young’s elastic modulus (YEM), and the incremental elastic modulus (Einc).

Of the 162 study participants, 127 (78%) had type 1 diabetes and 35 were healthy controls who attended clinics at the two locations, said Dr. Urbina, director of preventive cardiology at Cincinnati Children’s Hospital Medical Center. Their mean age was 20 years, 51% were male, 81% were white, and their mean duration of diabetes was 10 years.

Dr. Urbina reported that there were significantly higher proportions of males and whites among cases, compared with controls (55% vs. 34% and 90% vs. 50%, respectively), but there were no significant differences between the two groups in anthropometric or lipid values.

After adjustment for age, sex, race, mean arterial pressure by mercury sphygmomanometry, and lipids, patients with type 1 diabetes had a significantly thicker internal cIMT, compared with controls (mean, 0.56 mm vs. 0.50 mm, respectively), with a trend for a thicker common cIMT (mean, 0.63 mm vs. 0.60 mm). Bulb cIMT was the same in both groups (mean, 0.61 mm).

Patients with type 1 diabetes also had significantly stiffer carotids, compared with controls (mean PEM, 193 mm Hg vs. 169 mm Hg, respectively; mean YEM, 204 mm Hg/mm vs. 182 mm Hg/mm; mean Einc, 963 mm Hg vs. 862 mm Hg).

After adjustment for body mass index, there was a trend only for significantly thicker internal cIMT, although PEM remained stiffer for the patients with type 1 diabetes who were at least 20 years old.

SEARCH CVD is funded by the National Institutes of Health and is an ancillary study of the SEARCH for Diabetes in Youth study, a multicenter study funded by the Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Urbina said that she had no relevant financial disclosures to make.

SAN DIEGO – Adolescents and young adults with type 1 diabetes have thicker and stiffer carotid arteries, compared with their healthy peers, results from a multicenter study showed.

"Type 1 diabetes has an adverse effect on carotid thickness and stiffness, and we can measure this by the time patients reach young adulthood," Dr. Elaine M. Urbina said at the annual scientific sessions of the American Diabetes Association. "It’s independent of demographics, lipids, and blood pressure, but may be influenced by adiposity. We need to control risk factors, especially obesity, in these adolescents and young adults to improve cardiovascular outcomes in type 1 diabetes."

As part of the SEARCH CVD study, a collaborative effort between investigators at the University of Colorado at Denver, the Colorado School of Public Health in Aurora, and Cincinnati Children’s Hospital Medical Center, Dr. Urbina and her associates set out to examine whether type 1 diabetes has a measurable effect on carotid arteries in adolescents and young adults. They studied 162 people aged 13-26 years, collecting data on demographics, anthropometrics, blood pressure, fasting lipid and hemoglobin A_1c levels, and carotid ultrasound to measure the common, bulb, and internal carotid intima-media thickness (cIMT), with M-mode for calculation of carotid stiffness by Peterson’s elastic modulus (PEM), Young’s elastic modulus (YEM), and the incremental elastic modulus (Einc).

Of the 162 study participants, 127 (78%) had type 1 diabetes and 35 were healthy controls who attended clinics at the two locations, said Dr. Urbina, director of preventive cardiology at Cincinnati Children’s Hospital Medical Center. Their mean age was 20 years, 51% were male, 81% were white, and their mean duration of diabetes was 10 years.

Dr. Urbina reported that there were significantly higher proportions of males and whites among cases, compared with controls (55% vs. 34% and 90% vs. 50%, respectively), but there were no significant differences between the two groups in anthropometric or lipid values.

After adjustment for age, sex, race, mean arterial pressure by mercury sphygmomanometry, and lipids, patients with type 1 diabetes had a significantly thicker internal cIMT, compared with controls (mean, 0.56 mm vs. 0.50 mm, respectively), with a trend for a thicker common cIMT (mean, 0.63 mm vs. 0.60 mm). Bulb cIMT was the same in both groups (mean, 0.61 mm).

Patients with type 1 diabetes also had significantly stiffer carotids, compared with controls (mean PEM, 193 mm Hg vs. 169 mm Hg, respectively; mean YEM, 204 mm Hg/mm vs. 182 mm Hg/mm; mean Einc, 963 mm Hg vs. 862 mm Hg).

After adjustment for body mass index, there was a trend only for significantly thicker internal cIMT, although PEM remained stiffer for the patients with type 1 diabetes who were at least 20 years old.

SEARCH CVD is funded by the National Institutes of Health and is an ancillary study of the SEARCH for Diabetes in Youth study, a multicenter study funded by the Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Urbina said that she had no relevant financial disclosures to make.

SAN DIEGO – Adolescents and young adults with type 1 diabetes have thicker and stiffer carotid arteries, compared with their healthy peers, results from a multicenter study showed.

"Type 1 diabetes has an adverse effect on carotid thickness and stiffness, and we can measure this by the time patients reach young adulthood," Dr. Elaine M. Urbina said at the annual scientific sessions of the American Diabetes Association. "It’s independent of demographics, lipids, and blood pressure, but may be influenced by adiposity. We need to control risk factors, especially obesity, in these adolescents and young adults to improve cardiovascular outcomes in type 1 diabetes."

As part of the SEARCH CVD study, a collaborative effort between investigators at the University of Colorado at Denver, the Colorado School of Public Health in Aurora, and Cincinnati Children’s Hospital Medical Center, Dr. Urbina and her associates set out to examine whether type 1 diabetes has a measurable effect on carotid arteries in adolescents and young adults. They studied 162 people aged 13-26 years, collecting data on demographics, anthropometrics, blood pressure, fasting lipid and hemoglobin A_1c levels, and carotid ultrasound to measure the common, bulb, and internal carotid intima-media thickness (cIMT), with M-mode for calculation of carotid stiffness by Peterson’s elastic modulus (PEM), Young’s elastic modulus (YEM), and the incremental elastic modulus (Einc).

Of the 162 study participants, 127 (78%) had type 1 diabetes and 35 were healthy controls who attended clinics at the two locations, said Dr. Urbina, director of preventive cardiology at Cincinnati Children’s Hospital Medical Center. Their mean age was 20 years, 51% were male, 81% were white, and their mean duration of diabetes was 10 years.

Dr. Urbina reported that there were significantly higher proportions of males and whites among cases, compared with controls (55% vs. 34% and 90% vs. 50%, respectively), but there were no significant differences between the two groups in anthropometric or lipid values.

After adjustment for age, sex, race, mean arterial pressure by mercury sphygmomanometry, and lipids, patients with type 1 diabetes had a significantly thicker internal cIMT, compared with controls (mean, 0.56 mm vs. 0.50 mm, respectively), with a trend for a thicker common cIMT (mean, 0.63 mm vs. 0.60 mm). Bulb cIMT was the same in both groups (mean, 0.61 mm).

Patients with type 1 diabetes also had significantly stiffer carotids, compared with controls (mean PEM, 193 mm Hg vs. 169 mm Hg, respectively; mean YEM, 204 mm Hg/mm vs. 182 mm Hg/mm; mean Einc, 963 mm Hg vs. 862 mm Hg).

After adjustment for body mass index, there was a trend only for significantly thicker internal cIMT, although PEM remained stiffer for the patients with type 1 diabetes who were at least 20 years old.

SEARCH CVD is funded by the National Institutes of Health and is an ancillary study of the SEARCH for Diabetes in Youth study, a multicenter study funded by the Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Urbina said that she had no relevant financial disclosures to make.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

AMSTERDAM – Crizotinib treatment boosted overall survival of selected patients with advanced non–small cell lung cancer by about a year compared with patients on standard chemotherapy in a historical control analysis, adding to the growing body of evidence for the efficacy of this novel targeted therapy.

"Crizotinib may prolong overall survival and fundamentally alter the natural history" of NSCLC that features alterations in the anaplastic lymphoma kinase (ALK) gene, Dr. Alice T. Shaw said at the World Conference on Lung Cancer. Results from several recent studies indicated that about 7% of patients with advanced NSCLC have ALK-positive tumors in which the gene is rearranged.

Results from Dr. Shaw’s new analysis also indicated that the overall survival of patients with ALK-positive NSCLC closely tracked the survival rate of patients with normal ALK genes and advanced NSCLC, suggesting that the presence of ALK mutation does not change prognosis.

"ALK-positive patients do not intrinsically do better on their own, but you can make them live a lot longer if you give them this targeted therapy, crizotinib," said Dr. Shaw, an oncologist at Harvard Medical School and Massachusetts General Hospital, both in Boston.

In May, the Food and Drug Administration began a priority review of crizotinib, an ALK inhibitor, for an indication to treat patients with advanced, ALK-positive NSCLC.

"For regulatory approval, people look at overall survival, but you’ll never get [overall survival] from the large randomized studies because it would be unethical not to let patients [who were initially randomized to not receive crizotinib] cross over. That’s why this analysis is important, even with its flaws, because it shows – or at least strongly suggests – that this drug improves overall survival, that we are really making a difference for these patients," Dr. Shaw said in an interview. Prior reports from crizotinib studies in ALK-positive patients documented a response rate of 50%-60%, and a median progression-free survival of 10 months.

Dr. Shaw and her associates used data on patients who were treated with crizotinib from the first, phase I study of the drug, because those patients have had the longest follow-up on the drug, a median of 18 months for those who remained alive (N. Engl. J. Med. 2010;363:1693-703).

The phase I crizotinib study included 82 ALK-positive patients who received the drug. To better match these patients with a control group of ALK-positive patients who never got crizotinib, the researchers focused on the 56 patients who came from study centers in the United States and Australia, and specifically on the 30 patients within this subgroup who received crizotinib as their second or third chemotherapy agent.

They compared overall survival of these 30 patients with 21 ALK-positive patients from the United States or Australia who had been assessed for potential enrollment in the phase I study but never received crizotinib. In addition, during follow-up all of these control patients remained on second-line chemotherapy.

The new analysis showed that the 30 crizotinib-treated patients had an overall 1-year survival rate of 74%, and a 2-year rate of 54%, with median survival not yet reached during the median 18-month follow-up. The 21 matched control patients had a 1-year survival rate of 44% and a 2-year rate of 12%, and median survival duration of 6 months. Calculations showed a hazard ratio for overall survival of 0.36 for the patients who did not get crizotinib compared with those who did (P = .004).

"These results suggest that crizotinib may significantly improve survival outcomes in patients with advanced ALK-positive NSCLC," Dr. Shaw said.

To confirm that ALK positivity itself played no role in overall survival, Dr. Shaw and her associates compared overall survival in the 21 control patients who never received crizotinib vs. 48 patients who had advanced NSCLC without any ALK mutations, who never received crizotinib, and who had been treated with standard, second-line chemotherapy. In addition, all 48 control patients and all 21 ALK-positive patients had tumors with adenocarcinoma histology, and they all had a history of being never or light smokers. The two groups had virtually identical overall survival rates, Dr. Shaw reported at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

The crizotinib study that provided much of the data used in this analysis was funded by Pfizer, the company developing the drug. Dr. Shaw said that she has been a consultant to Pfizer, Ariad, Chugai, and Millennium. She has received research support from Novartis and AstraZeneca.

AMSTERDAM – Crizotinib treatment boosted overall survival of selected patients with advanced non–small cell lung cancer by about a year compared with patients on standard chemotherapy in a historical control analysis, adding to the growing body of evidence for the efficacy of this novel targeted therapy.

"Crizotinib may prolong overall survival and fundamentally alter the natural history" of NSCLC that features alterations in the anaplastic lymphoma kinase (ALK) gene, Dr. Alice T. Shaw said at the World Conference on Lung Cancer. Results from several recent studies indicated that about 7% of patients with advanced NSCLC have ALK-positive tumors in which the gene is rearranged.

Results from Dr. Shaw’s new analysis also indicated that the overall survival of patients with ALK-positive NSCLC closely tracked the survival rate of patients with normal ALK genes and advanced NSCLC, suggesting that the presence of ALK mutation does not change prognosis.

"ALK-positive patients do not intrinsically do better on their own, but you can make them live a lot longer if you give them this targeted therapy, crizotinib," said Dr. Shaw, an oncologist at Harvard Medical School and Massachusetts General Hospital, both in Boston.

In May, the Food and Drug Administration began a priority review of crizotinib, an ALK inhibitor, for an indication to treat patients with advanced, ALK-positive NSCLC.

"For regulatory approval, people look at overall survival, but you’ll never get [overall survival] from the large randomized studies because it would be unethical not to let patients [who were initially randomized to not receive crizotinib] cross over. That’s why this analysis is important, even with its flaws, because it shows – or at least strongly suggests – that this drug improves overall survival, that we are really making a difference for these patients," Dr. Shaw said in an interview. Prior reports from crizotinib studies in ALK-positive patients documented a response rate of 50%-60%, and a median progression-free survival of 10 months.

Dr. Shaw and her associates used data on patients who were treated with crizotinib from the first, phase I study of the drug, because those patients have had the longest follow-up on the drug, a median of 18 months for those who remained alive (N. Engl. J. Med. 2010;363:1693-703).

The phase I crizotinib study included 82 ALK-positive patients who received the drug. To better match these patients with a control group of ALK-positive patients who never got crizotinib, the researchers focused on the 56 patients who came from study centers in the United States and Australia, and specifically on the 30 patients within this subgroup who received crizotinib as their second or third chemotherapy agent.

They compared overall survival of these 30 patients with 21 ALK-positive patients from the United States or Australia who had been assessed for potential enrollment in the phase I study but never received crizotinib. In addition, during follow-up all of these control patients remained on second-line chemotherapy.

The new analysis showed that the 30 crizotinib-treated patients had an overall 1-year survival rate of 74%, and a 2-year rate of 54%, with median survival not yet reached during the median 18-month follow-up. The 21 matched control patients had a 1-year survival rate of 44% and a 2-year rate of 12%, and median survival duration of 6 months. Calculations showed a hazard ratio for overall survival of 0.36 for the patients who did not get crizotinib compared with those who did (P = .004).

"These results suggest that crizotinib may significantly improve survival outcomes in patients with advanced ALK-positive NSCLC," Dr. Shaw said.

To confirm that ALK positivity itself played no role in overall survival, Dr. Shaw and her associates compared overall survival in the 21 control patients who never received crizotinib vs. 48 patients who had advanced NSCLC without any ALK mutations, who never received crizotinib, and who had been treated with standard, second-line chemotherapy. In addition, all 48 control patients and all 21 ALK-positive patients had tumors with adenocarcinoma histology, and they all had a history of being never or light smokers. The two groups had virtually identical overall survival rates, Dr. Shaw reported at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

The crizotinib study that provided much of the data used in this analysis was funded by Pfizer, the company developing the drug. Dr. Shaw said that she has been a consultant to Pfizer, Ariad, Chugai, and Millennium. She has received research support from Novartis and AstraZeneca.

AMSTERDAM – Crizotinib treatment boosted overall survival of selected patients with advanced non–small cell lung cancer by about a year compared with patients on standard chemotherapy in a historical control analysis, adding to the growing body of evidence for the efficacy of this novel targeted therapy.

"Crizotinib may prolong overall survival and fundamentally alter the natural history" of NSCLC that features alterations in the anaplastic lymphoma kinase (ALK) gene, Dr. Alice T. Shaw said at the World Conference on Lung Cancer. Results from several recent studies indicated that about 7% of patients with advanced NSCLC have ALK-positive tumors in which the gene is rearranged.

Results from Dr. Shaw’s new analysis also indicated that the overall survival of patients with ALK-positive NSCLC closely tracked the survival rate of patients with normal ALK genes and advanced NSCLC, suggesting that the presence of ALK mutation does not change prognosis.

"ALK-positive patients do not intrinsically do better on their own, but you can make them live a lot longer if you give them this targeted therapy, crizotinib," said Dr. Shaw, an oncologist at Harvard Medical School and Massachusetts General Hospital, both in Boston.

In May, the Food and Drug Administration began a priority review of crizotinib, an ALK inhibitor, for an indication to treat patients with advanced, ALK-positive NSCLC.

"For regulatory approval, people look at overall survival, but you’ll never get [overall survival] from the large randomized studies because it would be unethical not to let patients [who were initially randomized to not receive crizotinib] cross over. That’s why this analysis is important, even with its flaws, because it shows – or at least strongly suggests – that this drug improves overall survival, that we are really making a difference for these patients," Dr. Shaw said in an interview. Prior reports from crizotinib studies in ALK-positive patients documented a response rate of 50%-60%, and a median progression-free survival of 10 months.

Dr. Shaw and her associates used data on patients who were treated with crizotinib from the first, phase I study of the drug, because those patients have had the longest follow-up on the drug, a median of 18 months for those who remained alive (N. Engl. J. Med. 2010;363:1693-703).

The phase I crizotinib study included 82 ALK-positive patients who received the drug. To better match these patients with a control group of ALK-positive patients who never got crizotinib, the researchers focused on the 56 patients who came from study centers in the United States and Australia, and specifically on the 30 patients within this subgroup who received crizotinib as their second or third chemotherapy agent.

They compared overall survival of these 30 patients with 21 ALK-positive patients from the United States or Australia who had been assessed for potential enrollment in the phase I study but never received crizotinib. In addition, during follow-up all of these control patients remained on second-line chemotherapy.

The new analysis showed that the 30 crizotinib-treated patients had an overall 1-year survival rate of 74%, and a 2-year rate of 54%, with median survival not yet reached during the median 18-month follow-up. The 21 matched control patients had a 1-year survival rate of 44% and a 2-year rate of 12%, and median survival duration of 6 months. Calculations showed a hazard ratio for overall survival of 0.36 for the patients who did not get crizotinib compared with those who did (P = .004).

"These results suggest that crizotinib may significantly improve survival outcomes in patients with advanced ALK-positive NSCLC," Dr. Shaw said.

To confirm that ALK positivity itself played no role in overall survival, Dr. Shaw and her associates compared overall survival in the 21 control patients who never received crizotinib vs. 48 patients who had advanced NSCLC without any ALK mutations, who never received crizotinib, and who had been treated with standard, second-line chemotherapy. In addition, all 48 control patients and all 21 ALK-positive patients had tumors with adenocarcinoma histology, and they all had a history of being never or light smokers. The two groups had virtually identical overall survival rates, Dr. Shaw reported at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

The crizotinib study that provided much of the data used in this analysis was funded by Pfizer, the company developing the drug. Dr. Shaw said that she has been a consultant to Pfizer, Ariad, Chugai, and Millennium. She has received research support from Novartis and AstraZeneca.