Michele G. Sullivan

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Triple-negative breast cancer, which is often associated with aggressive presentation, seems moderately related to body mass index and exercise status – factors that could be modified to reduce a woman’s risk of developing the disease.

The associations were "modest in magnitude and not statistically significant," lead author Amanda I. Phipps, Ph.D., and associates wrote in the March issue of Cancer Epidemiology, Biomarkers, and Prevention. Only weight increase between age 35 and 50 years was significantly related with the tumor (hazard ratio [HR] 1.69 for a gain of more than 6 kg, compared with a gain of less than 2.5 kg).

"However, given the potentially modifiable nature of these exposures, the results suggest that there may be ways postmenopausal women can impact their risks of both estrogen receptor-positive and triple-negative breast cancer," the authors said (Canc. Epidem. Biom. Prev. 2011;20:1-10 [doi: 10.1158/1055-9965.EPI-10-0974]).

Neither hormone receptors nor HER2 are overexpressed in women with the triple-negative subtype. When compared with estrogen receptor–positive breast cancer, triple-negative cancers are more likely to present with high tumor grade, elevated Ki-67 and p53 expression, and a poorer prognosis. Triple-negative tumors also are more likely to occur in black women and BRCA1 carriers, and to be diagnosed at younger ages.

Dr. Phipps of the Fred Hutchinson Cancer Research Center, Seattle, and her coauthors extracted their data from the Women’s Health Initiative. From the total cohort of 162,000 women, their final analysis consisted of 3,116 cases with complete tumor marker data, of which 307 (10%) were triple-negative and 2,610 (84%) were ER-positive. The rest were ER-negative, PR-negative, and HER2-positive (154 cases); ER-negative, PR-positive, and HER2-negative (31 cases); or ER-negative, PR-positive, and HER2-positive (14 cases).

Triple-negative tumors were associated with body mass index, with the highest association (HR 1.35) occurring between the highest quartile (BMI 31 kg/m² or more) and the lowest quartile (less than 23.75 kg/m²). There was a similar association of BMI and ER-positive tumors compared with estrogen receptor-negative tumors (HR 1.39).

Waist-hip ratio was not significantly associated with any of the cancer subtypes, but waist and hip circumferences were nonsignificantly associated with the risk of ER-positive tumors. For triple-negative tumors, there were modest but nonsignificant associations between waist circumference (HR 0.66) and hip circumference (HR 0.88).

Women with increased BMI at age 50 (highest vs. lowest quartile) were most at risk for triple-negative breast cancer at age 50 (HR 1.93), but, again, this was not a significant finding.

The authors also found a modest but, again, not significant inverse association between the triple-negative subtype and physical activity. The association between the highest tertile of exercise (strenuous vs. none; HR 0.77) was not significant. "For both subtypes, there was some suggestion that these modest associations were limited to moderate to low-intensity activity," the authors noted.

"Despite substantial molecular and clinical differences between triple-negative and ER-positive breast cancers, these subtypes of disease appear similar in their associations with baseline BMI and recreational physical activity," the authors wrote. The finding of a modest positive association between waist circumference and ER-positive tumors is in line with prior studies, probably because excess abdominal fat influences hormone levels.

"On the contrary, triple-negative breast cancers are hormone-receptor negative by definition, yet we observed a similar positive association between BMI and breast cancer risk for both subtypes, suggesting that nonhormonal factors may also play a role in mediating associations with this aspect of body size."

There may be some biologic plausibility to this theory, they said. "In particular, obesity is associated with increased inflammation and with increased levels of insulin and insulin-like growth factors, which may impact breast cancer risk."

The results of the study point out a possible benefit to lifestyle modifications, especially in light of the more aggressive nature of triple-negative breast cancers, the authors said: "The risk of triple-negative breast cancer was reduced, albeit not to the extent of statistical significance, among women who were physically active and among women with lower BMI.

"These factors were similarly associated with the lower risk of ER-positive breast cancer, suggesting that the protective effects of these exposures are not breast cancer-subtype-specific and that there may be lifestyle modifications that postmenopausal women can make to reduce their risk of triple-negative and ER-positive breast cancer."

The authors disclosed no financial conflicts. The National Heart, Lung, and Blood Institute sponsored the Women’s Health Initiative; the National Cancer Institute sponsored the subanalysis.

Major Finding: In patients undergoing bariatric surgery who had a mean HbA_1c of 8%, all patients had an HbA_1c of 6% within 1 year of surgery.

Data Source: A review of 1,603 patients who underwent either gastric bypass (90%) or gastric banding, of whom 47% had elevated blood glucose and insulin, over 3 years.

Disclosures: Dr. Livingstone had no financial disclosures. Dr. Nestor F. De La Cruz-Munoz Jr., a coauthor, is a consultant and proctor for Ethicon.

PALM BEACH, FLA. – Bariatric surgery resulted in complete remission of type 2 diabetes and prediabetes in a group of mostly Hispanic and black patients.

Within 1 year of surgery, 100% of patients with those disorders experienced a normalization of fasting blood glucose and hemoglobin A_1c, and they lost a mean of 40 kg, Dr. Alan Livingstone said at the meeting.

By the end of the 3-year follow-up period, all patients still had normal levels of blood glucose and insulin, he said.

“Uncontrolled type 2 diabetes is highly prevalent among ethnic minorities,” said Dr. Livingstone, the Lucille and DeWitt Daughtry Professor and Chairman of Surgery, University of Miami Miller School of Medicine, and chief of surgery Jackson Memorial Hospital, Miami.

“Bariatric surgery helps to effectively treat these diverse minority groups and is a safe and effective option for permanent weight loss and chronic disease risk improvement in this population,” he added.

Dr. Livingstone reported on a cohort of 1,603 adult bariatric surgery patients. Sixty-six percent of the patients were Hispanic, 17% were black, and the rest were other ethnicities. They were prospectively entered into a research database and then retrospectively studied.

“Minorities are at a particularly high risk for type 2 diabetes and its associated complications,” Dr. Livingstone said. “While only 6% of whites have [the disorder], it's present in 10% of Hispanics and 12% of blacks – a huge burden of disease.”

The patients' mean age was 45 years; most (77%) were female. The mean preoperative weight was 130 kg; the mean body mass index, 47 kg/m

Most of the group already had some insulin abnormality; 377 had diagnosed type 2 diabetes, 107 had undiagnosed type 2 (fasting blood glucose of more than 126 mg/dL), and 276 had prediabetes (fasting blood glucose of 100–125 mg/dL). Among those with elevated blood glucose, the mean HbA_1c was 8%. The rest of the group had a normal insulin profile.

Most patients underwent gastric bypass (90%); the rest had gastric banding. “The amount of weight loss was profound in the first year, as expected,” Dr. Livingstone said. There was no significant difference in weight loss between the diagnostic groups. Body mass index also fell quickly, correlating with weight loss. By the end of the first 6 months, the mean BMI had dropped to 35 kg/m

Among the 57% of patients with full 3-year follow-up, there was no significant regain of weight, Dr. Livingstone reported.

Fasting blood glucose and HbA_1c also improved rapidly and significantly in all those with preoperatively elevated levels.

“It's important to note how quickly this happened,” Dr. Livingstone said. “Within the first year, all of these patients had normal fasting blood glucose and an HbA_1c of 6% or below.” Again, these values remained steady and in the normal range in the entire 3-year follow-up cohort. “This is a tremendous accomplishment,” he said.

However, Dr. Bruce Schirmer of the University of Virginia, Charlottesville, cautioned that a 3-year follow-up period may not be long enough to proclaim bariatric surgery as a cure for type 2 diabetes in any population.

“In mostly Caucasian populations, if you follow the patients for up to 5 years, you see that 15%–20%, at least, have some weight regain and with it, a return to diabetes,” Dr. Schirmer said. “So to make this statement that there is no weight regain and no return to the disorder is a little premature.”

Major Finding: In patients undergoing bariatric surgery who had a mean HbA_1c of 8%, all patients had an HbA_1c of 6% within 1 year of surgery.

Data Source: A review of 1,603 patients who underwent either gastric bypass (90%) or gastric banding, of whom 47% had elevated blood glucose and insulin, over 3 years.

Disclosures: Dr. Livingstone had no financial disclosures. Dr. Nestor F. De La Cruz-Munoz Jr., a coauthor, is a consultant and proctor for Ethicon.

PALM BEACH, FLA. – Bariatric surgery resulted in complete remission of type 2 diabetes and prediabetes in a group of mostly Hispanic and black patients.

Within 1 year of surgery, 100% of patients with those disorders experienced a normalization of fasting blood glucose and hemoglobin A_1c, and they lost a mean of 40 kg, Dr. Alan Livingstone said at the meeting.

By the end of the 3-year follow-up period, all patients still had normal levels of blood glucose and insulin, he said.

“Uncontrolled type 2 diabetes is highly prevalent among ethnic minorities,” said Dr. Livingstone, the Lucille and DeWitt Daughtry Professor and Chairman of Surgery, University of Miami Miller School of Medicine, and chief of surgery Jackson Memorial Hospital, Miami.

“Bariatric surgery helps to effectively treat these diverse minority groups and is a safe and effective option for permanent weight loss and chronic disease risk improvement in this population,” he added.

Dr. Livingstone reported on a cohort of 1,603 adult bariatric surgery patients. Sixty-six percent of the patients were Hispanic, 17% were black, and the rest were other ethnicities. They were prospectively entered into a research database and then retrospectively studied.

“Minorities are at a particularly high risk for type 2 diabetes and its associated complications,” Dr. Livingstone said. “While only 6% of whites have [the disorder], it's present in 10% of Hispanics and 12% of blacks – a huge burden of disease.”

The patients' mean age was 45 years; most (77%) were female. The mean preoperative weight was 130 kg; the mean body mass index, 47 kg/m

Most of the group already had some insulin abnormality; 377 had diagnosed type 2 diabetes, 107 had undiagnosed type 2 (fasting blood glucose of more than 126 mg/dL), and 276 had prediabetes (fasting blood glucose of 100–125 mg/dL). Among those with elevated blood glucose, the mean HbA_1c was 8%. The rest of the group had a normal insulin profile.

Most patients underwent gastric bypass (90%); the rest had gastric banding. “The amount of weight loss was profound in the first year, as expected,” Dr. Livingstone said. There was no significant difference in weight loss between the diagnostic groups. Body mass index also fell quickly, correlating with weight loss. By the end of the first 6 months, the mean BMI had dropped to 35 kg/m

Among the 57% of patients with full 3-year follow-up, there was no significant regain of weight, Dr. Livingstone reported.

Fasting blood glucose and HbA_1c also improved rapidly and significantly in all those with preoperatively elevated levels.

“It's important to note how quickly this happened,” Dr. Livingstone said. “Within the first year, all of these patients had normal fasting blood glucose and an HbA_1c of 6% or below.” Again, these values remained steady and in the normal range in the entire 3-year follow-up cohort. “This is a tremendous accomplishment,” he said.

However, Dr. Bruce Schirmer of the University of Virginia, Charlottesville, cautioned that a 3-year follow-up period may not be long enough to proclaim bariatric surgery as a cure for type 2 diabetes in any population.

“In mostly Caucasian populations, if you follow the patients for up to 5 years, you see that 15%–20%, at least, have some weight regain and with it, a return to diabetes,” Dr. Schirmer said. “So to make this statement that there is no weight regain and no return to the disorder is a little premature.”

Major Finding: In patients undergoing bariatric surgery who had a mean HbA_1c of 8%, all patients had an HbA_1c of 6% within 1 year of surgery.

Data Source: A review of 1,603 patients who underwent either gastric bypass (90%) or gastric banding, of whom 47% had elevated blood glucose and insulin, over 3 years.

Disclosures: Dr. Livingstone had no financial disclosures. Dr. Nestor F. De La Cruz-Munoz Jr., a coauthor, is a consultant and proctor for Ethicon.

PALM BEACH, FLA. – Bariatric surgery resulted in complete remission of type 2 diabetes and prediabetes in a group of mostly Hispanic and black patients.

Within 1 year of surgery, 100% of patients with those disorders experienced a normalization of fasting blood glucose and hemoglobin A_1c, and they lost a mean of 40 kg, Dr. Alan Livingstone said at the meeting.

By the end of the 3-year follow-up period, all patients still had normal levels of blood glucose and insulin, he said.

“Uncontrolled type 2 diabetes is highly prevalent among ethnic minorities,” said Dr. Livingstone, the Lucille and DeWitt Daughtry Professor and Chairman of Surgery, University of Miami Miller School of Medicine, and chief of surgery Jackson Memorial Hospital, Miami.

“Bariatric surgery helps to effectively treat these diverse minority groups and is a safe and effective option for permanent weight loss and chronic disease risk improvement in this population,” he added.

Dr. Livingstone reported on a cohort of 1,603 adult bariatric surgery patients. Sixty-six percent of the patients were Hispanic, 17% were black, and the rest were other ethnicities. They were prospectively entered into a research database and then retrospectively studied.

“Minorities are at a particularly high risk for type 2 diabetes and its associated complications,” Dr. Livingstone said. “While only 6% of whites have [the disorder], it's present in 10% of Hispanics and 12% of blacks – a huge burden of disease.”

The patients' mean age was 45 years; most (77%) were female. The mean preoperative weight was 130 kg; the mean body mass index, 47 kg/m

Most of the group already had some insulin abnormality; 377 had diagnosed type 2 diabetes, 107 had undiagnosed type 2 (fasting blood glucose of more than 126 mg/dL), and 276 had prediabetes (fasting blood glucose of 100–125 mg/dL). Among those with elevated blood glucose, the mean HbA_1c was 8%. The rest of the group had a normal insulin profile.

Most patients underwent gastric bypass (90%); the rest had gastric banding. “The amount of weight loss was profound in the first year, as expected,” Dr. Livingstone said. There was no significant difference in weight loss between the diagnostic groups. Body mass index also fell quickly, correlating with weight loss. By the end of the first 6 months, the mean BMI had dropped to 35 kg/m

Among the 57% of patients with full 3-year follow-up, there was no significant regain of weight, Dr. Livingstone reported.

Fasting blood glucose and HbA_1c also improved rapidly and significantly in all those with preoperatively elevated levels.

“It's important to note how quickly this happened,” Dr. Livingstone said. “Within the first year, all of these patients had normal fasting blood glucose and an HbA_1c of 6% or below.” Again, these values remained steady and in the normal range in the entire 3-year follow-up cohort. “This is a tremendous accomplishment,” he said.

However, Dr. Bruce Schirmer of the University of Virginia, Charlottesville, cautioned that a 3-year follow-up period may not be long enough to proclaim bariatric surgery as a cure for type 2 diabetes in any population.

“In mostly Caucasian populations, if you follow the patients for up to 5 years, you see that 15%–20%, at least, have some weight regain and with it, a return to diabetes,” Dr. Schirmer said. “So to make this statement that there is no weight regain and no return to the disorder is a little premature.”

Major Finding: IL-10 in the first trimester seems to protect against low birth weight, while IL-6 seems to increase the risk. TNF-alpha exerts its influence in the third trimester, when higher levels also seem to protect against lower birth weights.

Data Source: A study of 302 pregnant women with rheumatoid arthritis and 33 controls.

Disclosures: The study was funded by the Dutch Arthritis Association. Dr. Dolhain did not disclose any pertinent financial relationships.

Circulating cytokines appear to influence fetal growth in pregnant women who have rheumatoid arthritis, results of a Dutch study suggest.

High levels of interleukin-10, IL-6, and TNF-alpha might all play a role, each acting independently – and at different stages of pregnancy – to increase the risk of low birth weight among infants born to these mothers, Dr. Radboud Dolhain and colleagues wrote (J. Reprod. Immunol. 2010 [doi: 10.1016/j.jri.2010.08.010]).

Dr. Dolhain of Erasmus University Medical Centre, Rotterdam, the Netherlands, and his coinvestigators examined circulating cytokines in 134 pregnant patients with rheumatoid arthritis during their first trimester, 168 in their third trimester, and 33 healthy controls. Birth weights were analyzed using standard deviation scores.

Disease activity in the women was based on the disease activity score for 28 joints (DAS28); the scale runs from 0–10, with higher numbers indicating greater disease activity.

Since IL-10, IL-6 and TNF-alpha generally decrease during pregnancy, the investigators sought to determine if any increasing gestational levels correlated with birth weight. Among the first trimester patients, 12 had detectable IL-10; all of these women had a higher disease activity score than did those with no IL-10 (mean DAS28 4.4 vs. 3.6).

Birth weights were compared between the two groups, which were matched with regard to disease activity, parity, and prednisone use.

The mean birth weight standard deviation was significantly greater in the IL-10 positive group (0.92) than in the matched negative group (0.15), Dr. Dolhain and his associates reported.

This association with IL-10 was not seen in the third trimester pregnancies.

The investigators then examined the effect of IL-6 by stratifying IL-6 levels and disease activity scores in the first and third trimester.

In the two groups with high disease activity (DAS28 3.8 or higher), birth weight standard deviation was significantly lower in mothers with high IL-6.

In the high IL-6 group, the birth weight standard deviation was −0.19, compared with 0.36 in the low IL-6 group.

Again, the authors found no such association in the third trimester.

“In the first trimester, elevated IL-10 seems to protect against the negative influence of RA disease activity on birth weight, [while] IL-6 seems to amplify this negative influence,” the investigators wrote.

“Both cytokines create a birth weight standard deviation of more than 0.50, which is considered clinically relevant. In the third trimester, there is no influence, suggesting an early critical window.”

TNF-alpha, however, did exert an influence in the third trimester of pregnancy, Dr. Dolhain and his colleagues noted. Stratifying TNF-alpha in the same way, they concluded that the birth weight standard deviation was lower in the group with low TNF-alpha (0.05) than in the group with high TNF-alpha (0.52).

This association was not present in the first trimester.

The finding that increased TNF-alpha is associated with better birth weights may require a rethinking of anti–TNF-alpha therapy for pregnant women, they suggested.

This implies that “TNF blockers, which are more and more prescribed during pregnancy to treat rheumatoid arthritis, should be used with caution,” Dr. Dolhain and his associates said.

Major Finding: IL-10 in the first trimester seems to protect against low birth weight, while IL-6 seems to increase the risk. TNF-alpha exerts its influence in the third trimester, when higher levels also seem to protect against lower birth weights.

Data Source: A study of 302 pregnant women with rheumatoid arthritis and 33 controls.

Disclosures: The study was funded by the Dutch Arthritis Association. Dr. Dolhain did not disclose any pertinent financial relationships.

Circulating cytokines appear to influence fetal growth in pregnant women who have rheumatoid arthritis, results of a Dutch study suggest.

High levels of interleukin-10, IL-6, and TNF-alpha might all play a role, each acting independently – and at different stages of pregnancy – to increase the risk of low birth weight among infants born to these mothers, Dr. Radboud Dolhain and colleagues wrote (J. Reprod. Immunol. 2010 [doi: 10.1016/j.jri.2010.08.010]).

Dr. Dolhain of Erasmus University Medical Centre, Rotterdam, the Netherlands, and his coinvestigators examined circulating cytokines in 134 pregnant patients with rheumatoid arthritis during their first trimester, 168 in their third trimester, and 33 healthy controls. Birth weights were analyzed using standard deviation scores.

Disease activity in the women was based on the disease activity score for 28 joints (DAS28); the scale runs from 0–10, with higher numbers indicating greater disease activity.

Since IL-10, IL-6 and TNF-alpha generally decrease during pregnancy, the investigators sought to determine if any increasing gestational levels correlated with birth weight. Among the first trimester patients, 12 had detectable IL-10; all of these women had a higher disease activity score than did those with no IL-10 (mean DAS28 4.4 vs. 3.6).

Birth weights were compared between the two groups, which were matched with regard to disease activity, parity, and prednisone use.

The mean birth weight standard deviation was significantly greater in the IL-10 positive group (0.92) than in the matched negative group (0.15), Dr. Dolhain and his associates reported.

This association with IL-10 was not seen in the third trimester pregnancies.

The investigators then examined the effect of IL-6 by stratifying IL-6 levels and disease activity scores in the first and third trimester.

In the two groups with high disease activity (DAS28 3.8 or higher), birth weight standard deviation was significantly lower in mothers with high IL-6.

In the high IL-6 group, the birth weight standard deviation was −0.19, compared with 0.36 in the low IL-6 group.

Again, the authors found no such association in the third trimester.

“In the first trimester, elevated IL-10 seems to protect against the negative influence of RA disease activity on birth weight, [while] IL-6 seems to amplify this negative influence,” the investigators wrote.

“Both cytokines create a birth weight standard deviation of more than 0.50, which is considered clinically relevant. In the third trimester, there is no influence, suggesting an early critical window.”

TNF-alpha, however, did exert an influence in the third trimester of pregnancy, Dr. Dolhain and his colleagues noted. Stratifying TNF-alpha in the same way, they concluded that the birth weight standard deviation was lower in the group with low TNF-alpha (0.05) than in the group with high TNF-alpha (0.52).

This association was not present in the first trimester.

The finding that increased TNF-alpha is associated with better birth weights may require a rethinking of anti–TNF-alpha therapy for pregnant women, they suggested.

This implies that “TNF blockers, which are more and more prescribed during pregnancy to treat rheumatoid arthritis, should be used with caution,” Dr. Dolhain and his associates said.

Major Finding: IL-10 in the first trimester seems to protect against low birth weight, while IL-6 seems to increase the risk. TNF-alpha exerts its influence in the third trimester, when higher levels also seem to protect against lower birth weights.

Data Source: A study of 302 pregnant women with rheumatoid arthritis and 33 controls.

Disclosures: The study was funded by the Dutch Arthritis Association. Dr. Dolhain did not disclose any pertinent financial relationships.

Circulating cytokines appear to influence fetal growth in pregnant women who have rheumatoid arthritis, results of a Dutch study suggest.

High levels of interleukin-10, IL-6, and TNF-alpha might all play a role, each acting independently – and at different stages of pregnancy – to increase the risk of low birth weight among infants born to these mothers, Dr. Radboud Dolhain and colleagues wrote (J. Reprod. Immunol. 2010 [doi: 10.1016/j.jri.2010.08.010]).

Dr. Dolhain of Erasmus University Medical Centre, Rotterdam, the Netherlands, and his coinvestigators examined circulating cytokines in 134 pregnant patients with rheumatoid arthritis during their first trimester, 168 in their third trimester, and 33 healthy controls. Birth weights were analyzed using standard deviation scores.

Disease activity in the women was based on the disease activity score for 28 joints (DAS28); the scale runs from 0–10, with higher numbers indicating greater disease activity.

Since IL-10, IL-6 and TNF-alpha generally decrease during pregnancy, the investigators sought to determine if any increasing gestational levels correlated with birth weight. Among the first trimester patients, 12 had detectable IL-10; all of these women had a higher disease activity score than did those with no IL-10 (mean DAS28 4.4 vs. 3.6).

Birth weights were compared between the two groups, which were matched with regard to disease activity, parity, and prednisone use.

The mean birth weight standard deviation was significantly greater in the IL-10 positive group (0.92) than in the matched negative group (0.15), Dr. Dolhain and his associates reported.

This association with IL-10 was not seen in the third trimester pregnancies.

The investigators then examined the effect of IL-6 by stratifying IL-6 levels and disease activity scores in the first and third trimester.

In the two groups with high disease activity (DAS28 3.8 or higher), birth weight standard deviation was significantly lower in mothers with high IL-6.

In the high IL-6 group, the birth weight standard deviation was −0.19, compared with 0.36 in the low IL-6 group.

Again, the authors found no such association in the third trimester.

“In the first trimester, elevated IL-10 seems to protect against the negative influence of RA disease activity on birth weight, [while] IL-6 seems to amplify this negative influence,” the investigators wrote.

“Both cytokines create a birth weight standard deviation of more than 0.50, which is considered clinically relevant. In the third trimester, there is no influence, suggesting an early critical window.”

TNF-alpha, however, did exert an influence in the third trimester of pregnancy, Dr. Dolhain and his colleagues noted. Stratifying TNF-alpha in the same way, they concluded that the birth weight standard deviation was lower in the group with low TNF-alpha (0.05) than in the group with high TNF-alpha (0.52).

This association was not present in the first trimester.

The finding that increased TNF-alpha is associated with better birth weights may require a rethinking of anti–TNF-alpha therapy for pregnant women, they suggested.

This implies that “TNF blockers, which are more and more prescribed during pregnancy to treat rheumatoid arthritis, should be used with caution,” Dr. Dolhain and his associates said.

Major Finding: Treating mild stroke with tPA could save almost 4,000 patients from long-term disability and save $200 million each year in associated health care costs.

Data Source: An epidemiologic study of 247 patients with mild stroke, extrapolated to the entire U.S. population.

Disclosures: The study was sponsored by the National Institutes of Health; neither Dr. Khatri nor any co-authors had any financial disclosures.

LOS ANGELES — The use of tissue plasminogen activator in patients with mild stroke could save thousands of them from long-term disability, and about $200 million each year in stroke-related health care costs.

The decision to administer tPA to patients with mild stroke is a difficult one, balancing the possible benefits with the risk of further bleeding, Dr. Pooja Khatri said at the meeting. But her epidemiologic study of 150 mild strokes suggests that administering the drug could prevent the disability that affects up to one-third of these patients.

Her retrospective study drew its data from the Greater Cincinnati/Northern Kentucky Stroke Study. The database included 441 patients who were treated for ischemic stroke during 2005. Of those, 56% (247) had strokes that were considered mild, with a baseline modified Rankin Scale score of 2–6. And, of those patients, 62% (150) were considered eligible for tPA treatment; however, only 1% (4) received the drug.

Dr. Khatri, director of acute stroke at the University of Cincinnati Academic Health Center, did not follow the patients to compare clinical outcomes over time. However, she said, based on two extant studies, about 30% of mild stroke patients do experience deficits that affect their lives. “These tend to be on the milder end of the spectrum, but it's still disability.”

She extrapolated her findings to the entire U.S. population in 2010, estimating that mild strokes would have occurred in 27,203 patients without baseline disability. If all of the these patients had received an effective treatment, up to 13% (3,761) could have been saved from stroke-related disability.

The estimated annual cost savings could be immense, she said. “We could see a savings of $200 million across the country,” an estimate that includes the potential costs of adverse events associated with widening the treated population.

But her data don't directly address the day-to-day decisions clinicians have to make when faced with a mild stroke patient. Very few mild stroke patients receive tPA treatment, she said, because the potential gains are regarded as small against the risk of hemorrhage. Most of the time, things go well when treating mild stroke patients, because the risk of bleeding lessens with stroke severity. “But sometimes we get burned,” Dr. Khatri said. “That [untreated] patient may end up being paralyzed on one side or having cognitive problems that we didn't recognize. … On the other hand, we may treat and that patient can bleed and perhaps even die.” The dilemma can be answered only by a large, randomized trial, she said – something she and her colleagues at the University of Cincinnati are trying to get started.

View on the News

A Balancing Act That Could Pay Off

This study is a wake-up call, from the standpoints of both cost and the patient's daily life. From it, we can argue that every stroke is significant, so we must take all mild strokes very seriously when deciding treatment.

It's difficult to balance the risks of tPA treatment with the benefits in patients with mild stroke. It's true that the potential gain of treatment is smaller than that with a more severe stroke. On the other hand, tPA-related bleeding is less of a risk with mild stroke because the area of brain injury is smaller.

Treating mild stroke also may have some preventive role. We have a series of interventions we can use that lower the risk of subsequent stroke for people whose quality of life may not be seriously impaired after a mild stroke, but will be if they have another and another.

STEVEN GREENBERG, M.D., is professor of neurology at Harvard Medical School and director of hemorrhagic stroke research at Massachusetts General Hospital, both in Boston. He said he has no relevant conflicts of interest.

Major Finding: Treating mild stroke with tPA could save almost 4,000 patients from long-term disability and save $200 million each year in associated health care costs.

Data Source: An epidemiologic study of 247 patients with mild stroke, extrapolated to the entire U.S. population.

Disclosures: The study was sponsored by the National Institutes of Health; neither Dr. Khatri nor any co-authors had any financial disclosures.

LOS ANGELES — The use of tissue plasminogen activator in patients with mild stroke could save thousands of them from long-term disability, and about $200 million each year in stroke-related health care costs.

The decision to administer tPA to patients with mild stroke is a difficult one, balancing the possible benefits with the risk of further bleeding, Dr. Pooja Khatri said at the meeting. But her epidemiologic study of 150 mild strokes suggests that administering the drug could prevent the disability that affects up to one-third of these patients.

Her retrospective study drew its data from the Greater Cincinnati/Northern Kentucky Stroke Study. The database included 441 patients who were treated for ischemic stroke during 2005. Of those, 56% (247) had strokes that were considered mild, with a baseline modified Rankin Scale score of 2–6. And, of those patients, 62% (150) were considered eligible for tPA treatment; however, only 1% (4) received the drug.

Dr. Khatri, director of acute stroke at the University of Cincinnati Academic Health Center, did not follow the patients to compare clinical outcomes over time. However, she said, based on two extant studies, about 30% of mild stroke patients do experience deficits that affect their lives. “These tend to be on the milder end of the spectrum, but it's still disability.”

She extrapolated her findings to the entire U.S. population in 2010, estimating that mild strokes would have occurred in 27,203 patients without baseline disability. If all of the these patients had received an effective treatment, up to 13% (3,761) could have been saved from stroke-related disability.

The estimated annual cost savings could be immense, she said. “We could see a savings of $200 million across the country,” an estimate that includes the potential costs of adverse events associated with widening the treated population.

But her data don't directly address the day-to-day decisions clinicians have to make when faced with a mild stroke patient. Very few mild stroke patients receive tPA treatment, she said, because the potential gains are regarded as small against the risk of hemorrhage. Most of the time, things go well when treating mild stroke patients, because the risk of bleeding lessens with stroke severity. “But sometimes we get burned,” Dr. Khatri said. “That [untreated] patient may end up being paralyzed on one side or having cognitive problems that we didn't recognize. … On the other hand, we may treat and that patient can bleed and perhaps even die.” The dilemma can be answered only by a large, randomized trial, she said – something she and her colleagues at the University of Cincinnati are trying to get started.

View on the News

A Balancing Act That Could Pay Off

This study is a wake-up call, from the standpoints of both cost and the patient's daily life. From it, we can argue that every stroke is significant, so we must take all mild strokes very seriously when deciding treatment.

It's difficult to balance the risks of tPA treatment with the benefits in patients with mild stroke. It's true that the potential gain of treatment is smaller than that with a more severe stroke. On the other hand, tPA-related bleeding is less of a risk with mild stroke because the area of brain injury is smaller.

Treating mild stroke also may have some preventive role. We have a series of interventions we can use that lower the risk of subsequent stroke for people whose quality of life may not be seriously impaired after a mild stroke, but will be if they have another and another.

STEVEN GREENBERG, M.D., is professor of neurology at Harvard Medical School and director of hemorrhagic stroke research at Massachusetts General Hospital, both in Boston. He said he has no relevant conflicts of interest.

Major Finding: Treating mild stroke with tPA could save almost 4,000 patients from long-term disability and save $200 million each year in associated health care costs.

Data Source: An epidemiologic study of 247 patients with mild stroke, extrapolated to the entire U.S. population.

Disclosures: The study was sponsored by the National Institutes of Health; neither Dr. Khatri nor any co-authors had any financial disclosures.

LOS ANGELES — The use of tissue plasminogen activator in patients with mild stroke could save thousands of them from long-term disability, and about $200 million each year in stroke-related health care costs.

The decision to administer tPA to patients with mild stroke is a difficult one, balancing the possible benefits with the risk of further bleeding, Dr. Pooja Khatri said at the meeting. But her epidemiologic study of 150 mild strokes suggests that administering the drug could prevent the disability that affects up to one-third of these patients.

Her retrospective study drew its data from the Greater Cincinnati/Northern Kentucky Stroke Study. The database included 441 patients who were treated for ischemic stroke during 2005. Of those, 56% (247) had strokes that were considered mild, with a baseline modified Rankin Scale score of 2–6. And, of those patients, 62% (150) were considered eligible for tPA treatment; however, only 1% (4) received the drug.

Dr. Khatri, director of acute stroke at the University of Cincinnati Academic Health Center, did not follow the patients to compare clinical outcomes over time. However, she said, based on two extant studies, about 30% of mild stroke patients do experience deficits that affect their lives. “These tend to be on the milder end of the spectrum, but it's still disability.”

She extrapolated her findings to the entire U.S. population in 2010, estimating that mild strokes would have occurred in 27,203 patients without baseline disability. If all of the these patients had received an effective treatment, up to 13% (3,761) could have been saved from stroke-related disability.

The estimated annual cost savings could be immense, she said. “We could see a savings of $200 million across the country,” an estimate that includes the potential costs of adverse events associated with widening the treated population.

But her data don't directly address the day-to-day decisions clinicians have to make when faced with a mild stroke patient. Very few mild stroke patients receive tPA treatment, she said, because the potential gains are regarded as small against the risk of hemorrhage. Most of the time, things go well when treating mild stroke patients, because the risk of bleeding lessens with stroke severity. “But sometimes we get burned,” Dr. Khatri said. “That [untreated] patient may end up being paralyzed on one side or having cognitive problems that we didn't recognize. … On the other hand, we may treat and that patient can bleed and perhaps even die.” The dilemma can be answered only by a large, randomized trial, she said – something she and her colleagues at the University of Cincinnati are trying to get started.

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A Balancing Act That Could Pay Off

This study is a wake-up call, from the standpoints of both cost and the patient's daily life. From it, we can argue that every stroke is significant, so we must take all mild strokes very seriously when deciding treatment.

It's difficult to balance the risks of tPA treatment with the benefits in patients with mild stroke. It's true that the potential gain of treatment is smaller than that with a more severe stroke. On the other hand, tPA-related bleeding is less of a risk with mild stroke because the area of brain injury is smaller.

Treating mild stroke also may have some preventive role. We have a series of interventions we can use that lower the risk of subsequent stroke for people whose quality of life may not be seriously impaired after a mild stroke, but will be if they have another and another.

STEVEN GREENBERG, M.D., is professor of neurology at Harvard Medical School and director of hemorrhagic stroke research at Massachusetts General Hospital, both in Boston. He said he has no relevant conflicts of interest.

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted Jan. 20 against immediate approval of the beta-amyloid imaging agent florbetapir, saying that inter-reader variability and lack of a single reading technique in the existing data must still be addressed.

But after voting 13 to 3 to deny approval, the Peripheral and Central Nervous System Drugs Advisory Committee – in an unusual motion – took an additional stance on the compound. The committee voted unanimously to approve florbetapir if Avid Radiopharmaceuticals Inc., the company developing the compound, would train readers in a consistent technique, and then re-evaluate scans from both a recent phase III and a previous phase II trial. Eli Lilly & Co. acquired Avid in November 2010.

"What we need as the underpinning for approval is a re-read and re-study of these scans based on a training program," said committee member Dr. Peter Herscovitch. "[Without that] we cannot say there is consistency in the reading" of patients with mild cognitive impairment – the population seen as the most likely to utilize florbetapir-PET imaging.

The action of a second vote surprised Capt. Rafel Rieves, director of FDA’s Division of Medical Imaging Products. But he said there was no prohibition against the committee voting on a motion of its own making, as long as it answered FDA’s primary question – whether or not to approve florbetapir based on the existing data.

The committee based its decision partially on Avid’s latest trial, published Jan. 19 (JAMA 2011;305:275-83). The study comprised 35 end-of-life patients, whose brains were also examined at autopsy, and 74 young, healthy controls. It found that florbetapir-PET imaging was 93% sensitive and 100% specific for identifying beta-amyloid plaques in the brain – a finding necessary for a diagnosis of Alzheimer’s disease.

But committee members pointed out that different readers examined the cohorts and used different techniques for each one. The autopsy cohort, read by three radiologists, rated amyloid burden on a scale of 1 to 5. The control cohort, read by three other radiologists, used a binary rating of positive or negative.

Reproducibility seemed good in these patients, who appeared to represent two ends of the amyloid spectrum – young adults almost universally expected to have negative results, and elderly patients close to death, who were much more likely to have positive results. None of the patients in the trial had a "moderate’ amyloid load, although the committee said that these patients would represent the bulk of those evaluated in clinical practice.

Avid’s phase II trial comprised 79 healthy controls, 45 patients with Alzheimer’s disease, and 60 with mild cognitive impairment (MCI). Among this MCI group, reader variability was high, indicating readers’ difficulty in judging the visual cut point of a clinically significant amyloid burden, the committee members said.

Re-evaluating the scans in both groups, with more readers specifically trained in florbetapir imaging techniques, would provide the definitive answers needed for approval, the committee agreed.

Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally the FDA grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted Jan. 20 against immediate approval of the beta-amyloid imaging agent florbetapir, saying that inter-reader variability and lack of a single reading technique in the existing data must still be addressed.

But after voting 13 to 3 to deny approval, the Peripheral and Central Nervous System Drugs Advisory Committee – in an unusual motion – took an additional stance on the compound. The committee voted unanimously to approve florbetapir if Avid Radiopharmaceuticals Inc., the company developing the compound, would train readers in a consistent technique, and then re-evaluate scans from both a recent phase III and a previous phase II trial. Eli Lilly & Co. acquired Avid in November 2010.

"What we need as the underpinning for approval is a re-read and re-study of these scans based on a training program," said committee member Dr. Peter Herscovitch. "[Without that] we cannot say there is consistency in the reading" of patients with mild cognitive impairment – the population seen as the most likely to utilize florbetapir-PET imaging.

The action of a second vote surprised Capt. Rafel Rieves, director of FDA’s Division of Medical Imaging Products. But he said there was no prohibition against the committee voting on a motion of its own making, as long as it answered FDA’s primary question – whether or not to approve florbetapir based on the existing data.

The committee based its decision partially on Avid’s latest trial, published Jan. 19 (JAMA 2011;305:275-83). The study comprised 35 end-of-life patients, whose brains were also examined at autopsy, and 74 young, healthy controls. It found that florbetapir-PET imaging was 93% sensitive and 100% specific for identifying beta-amyloid plaques in the brain – a finding necessary for a diagnosis of Alzheimer’s disease.

But committee members pointed out that different readers examined the cohorts and used different techniques for each one. The autopsy cohort, read by three radiologists, rated amyloid burden on a scale of 1 to 5. The control cohort, read by three other radiologists, used a binary rating of positive or negative.

Reproducibility seemed good in these patients, who appeared to represent two ends of the amyloid spectrum – young adults almost universally expected to have negative results, and elderly patients close to death, who were much more likely to have positive results. None of the patients in the trial had a "moderate’ amyloid load, although the committee said that these patients would represent the bulk of those evaluated in clinical practice.

Avid’s phase II trial comprised 79 healthy controls, 45 patients with Alzheimer’s disease, and 60 with mild cognitive impairment (MCI). Among this MCI group, reader variability was high, indicating readers’ difficulty in judging the visual cut point of a clinically significant amyloid burden, the committee members said.

Re-evaluating the scans in both groups, with more readers specifically trained in florbetapir imaging techniques, would provide the definitive answers needed for approval, the committee agreed.

Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally the FDA grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted Jan. 20 against immediate approval of the beta-amyloid imaging agent florbetapir, saying that inter-reader variability and lack of a single reading technique in the existing data must still be addressed.

But after voting 13 to 3 to deny approval, the Peripheral and Central Nervous System Drugs Advisory Committee – in an unusual motion – took an additional stance on the compound. The committee voted unanimously to approve florbetapir if Avid Radiopharmaceuticals Inc., the company developing the compound, would train readers in a consistent technique, and then re-evaluate scans from both a recent phase III and a previous phase II trial. Eli Lilly & Co. acquired Avid in November 2010.

"What we need as the underpinning for approval is a re-read and re-study of these scans based on a training program," said committee member Dr. Peter Herscovitch. "[Without that] we cannot say there is consistency in the reading" of patients with mild cognitive impairment – the population seen as the most likely to utilize florbetapir-PET imaging.

The action of a second vote surprised Capt. Rafel Rieves, director of FDA’s Division of Medical Imaging Products. But he said there was no prohibition against the committee voting on a motion of its own making, as long as it answered FDA’s primary question – whether or not to approve florbetapir based on the existing data.

The committee based its decision partially on Avid’s latest trial, published Jan. 19 (JAMA 2011;305:275-83). The study comprised 35 end-of-life patients, whose brains were also examined at autopsy, and 74 young, healthy controls. It found that florbetapir-PET imaging was 93% sensitive and 100% specific for identifying beta-amyloid plaques in the brain – a finding necessary for a diagnosis of Alzheimer’s disease.

But committee members pointed out that different readers examined the cohorts and used different techniques for each one. The autopsy cohort, read by three radiologists, rated amyloid burden on a scale of 1 to 5. The control cohort, read by three other radiologists, used a binary rating of positive or negative.

Reproducibility seemed good in these patients, who appeared to represent two ends of the amyloid spectrum – young adults almost universally expected to have negative results, and elderly patients close to death, who were much more likely to have positive results. None of the patients in the trial had a "moderate’ amyloid load, although the committee said that these patients would represent the bulk of those evaluated in clinical practice.

Avid’s phase II trial comprised 79 healthy controls, 45 patients with Alzheimer’s disease, and 60 with mild cognitive impairment (MCI). Among this MCI group, reader variability was high, indicating readers’ difficulty in judging the visual cut point of a clinically significant amyloid burden, the committee members said.

Re-evaluating the scans in both groups, with more readers specifically trained in florbetapir imaging techniques, would provide the definitive answers needed for approval, the committee agreed.

Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally the FDA grants a waiver to a panelist with a conflict of interest.

LOS ANGELES – Routinely lowering blood pressure in patients with acute ischemic or hemorrhagic stroke results in no apparent long-term benefits.

Patients who received candesartan – an angiotensin receptor blocker – or placebo within the first week after a stroke had virtually the same cardiovascular, clinical, and functional outcomes 6 months later, Dr. Eivind Berge reported at a Feb. 11 press briefing during the International Stroke Conference.

In fact, said Dr. Berge, patients taking the drug experienced slightly – though not significantly – increased rates of poor outcomes. "When we looked at the secondary end points, we found a slight difference in favor of placebo," in most cardiovascular outcomes, he said, with placebo significantly better in the finding of stroke progression within 2 days.

"This was statistically significant with a P value of .04," said Dr. Berge, principal investigator of the Scandinavian Candesartan Acute Stroke Trial (SCAST).

Other trials have examined the effect of different antihypertensives on stroke outcome, but SCAST is the largest to date and the only one that has studied candesartan, said Dr. Berge, who is also an internist at the Oslo University Hospital. The study enrolled 2,029 patients with ischemic or hemorrhagic stroke.

All patients in the SCAST trial had a systolic blood pressure of at least 140 mm Hg within 30 hours of symptom onset. They were randomized to either candesartan (1,017) or placebo (1,012) and treated for 7 days. Patients taking the study drug began treatment at 4 mg and progressed to 16 mg on days 3-7.

The patients’ mean age was 71 years; at baseline, their mean systolic blood pressure was 171 mm Hg, and their mean diastolic pressure was 90 mm Hg. About 85% had suffered an ischemic stroke, while 14% had hemorrhagic strokes; the remaining patients had a transient ischemic attack.

The study had two primary end points: the combination of death or major disability according to the modified Rankin Scale (mRS) by 6 months, and the combination of vascular death, heart attack, or another stroke within 6 months.

Secondary end points were all-cause death, and additional cardiovascular outcomes, including another stroke, heart attack, stroke progression, symptomatic hypotension, renal failure, and symptomatic venous thromboembolism.

Candesartan lowered blood pressure almost immediately, Dr. Berge said. By the end of the treatment period, blood pressures in the active group dropped to a mean of 147/82, compared with 152/84 in the placebo group. "Blood pressure was lowered by a statistically significant amount [compared with placebo] by day 2. From day 4 onward, we saw more modest blood pressure reduction."

But, at 6 months, none of the primary composite end points were significantly different between the two groups. The adjusted analysis showed that the composite vascular end point occurred in 12% of the active group and 11% of the placebo group; the adjusted hazard ratio in both groups was 1.09.

There were similar numbers of patients in each of the seven mRS levels. The most frequent mRS level at 6 months was 1 (290 active and 317 placebo patients). An mRS of 0 was achieved by 175 active patients and 192 placebo patients, while 84 active and 78 placebo patents had died.

Nor were there any statistically significant differences in any of the secondary end points, with the exception of stroke progression within 2 days. This occurred in 6% of the candesartan patients and 4% of the placebo patients (risk ratio 1.47; P = .04).

Dr. Berge said the findings were in accord with 10 previous studies, none of which found a significant advantage to lowering blood pressure in acute stroke. "All of these previous studies were small trials of different blood pressure–lowering agents with 100 or fewer patients," Dr. Berge said. Therefore he says he believes further investigations are still warranted.

"There are two ongoing trials that we hope will clarify whether there are subgroups of patients or different approaches to blood pressure–lowering management where a treatment benefit can be obtained," he said.

The study was published simultaneously to Dr. Berge’s presentation at a press conference in the Feb. 11 issue of the Lancet (doi:10.1016/S0140-6736[11]60104-9).

The study was sponsored by the Southeastern Norway Regional Health Authority and Oslo University. Dr. Berge disclosed that he and some of the other authors had received speaker fees and other remuneration from AstraZeneca and Takeda but that none of these were related to candesartan.

LOS ANGELES – Routinely lowering blood pressure in patients with acute ischemic or hemorrhagic stroke results in no apparent long-term benefits.

Patients who received candesartan – an angiotensin receptor blocker – or placebo within the first week after a stroke had virtually the same cardiovascular, clinical, and functional outcomes 6 months later, Dr. Eivind Berge reported at a Feb. 11 press briefing during the International Stroke Conference.

In fact, said Dr. Berge, patients taking the drug experienced slightly – though not significantly – increased rates of poor outcomes. "When we looked at the secondary end points, we found a slight difference in favor of placebo," in most cardiovascular outcomes, he said, with placebo significantly better in the finding of stroke progression within 2 days.

"This was statistically significant with a P value of .04," said Dr. Berge, principal investigator of the Scandinavian Candesartan Acute Stroke Trial (SCAST).

Other trials have examined the effect of different antihypertensives on stroke outcome, but SCAST is the largest to date and the only one that has studied candesartan, said Dr. Berge, who is also an internist at the Oslo University Hospital. The study enrolled 2,029 patients with ischemic or hemorrhagic stroke.

All patients in the SCAST trial had a systolic blood pressure of at least 140 mm Hg within 30 hours of symptom onset. They were randomized to either candesartan (1,017) or placebo (1,012) and treated for 7 days. Patients taking the study drug began treatment at 4 mg and progressed to 16 mg on days 3-7.

The patients’ mean age was 71 years; at baseline, their mean systolic blood pressure was 171 mm Hg, and their mean diastolic pressure was 90 mm Hg. About 85% had suffered an ischemic stroke, while 14% had hemorrhagic strokes; the remaining patients had a transient ischemic attack.

The study had two primary end points: the combination of death or major disability according to the modified Rankin Scale (mRS) by 6 months, and the combination of vascular death, heart attack, or another stroke within 6 months.

Secondary end points were all-cause death, and additional cardiovascular outcomes, including another stroke, heart attack, stroke progression, symptomatic hypotension, renal failure, and symptomatic venous thromboembolism.

Candesartan lowered blood pressure almost immediately, Dr. Berge said. By the end of the treatment period, blood pressures in the active group dropped to a mean of 147/82, compared with 152/84 in the placebo group. "Blood pressure was lowered by a statistically significant amount [compared with placebo] by day 2. From day 4 onward, we saw more modest blood pressure reduction."

But, at 6 months, none of the primary composite end points were significantly different between the two groups. The adjusted analysis showed that the composite vascular end point occurred in 12% of the active group and 11% of the placebo group; the adjusted hazard ratio in both groups was 1.09.

There were similar numbers of patients in each of the seven mRS levels. The most frequent mRS level at 6 months was 1 (290 active and 317 placebo patients). An mRS of 0 was achieved by 175 active patients and 192 placebo patients, while 84 active and 78 placebo patents had died.

Nor were there any statistically significant differences in any of the secondary end points, with the exception of stroke progression within 2 days. This occurred in 6% of the candesartan patients and 4% of the placebo patients (risk ratio 1.47; P = .04).

Dr. Berge said the findings were in accord with 10 previous studies, none of which found a significant advantage to lowering blood pressure in acute stroke. "All of these previous studies were small trials of different blood pressure–lowering agents with 100 or fewer patients," Dr. Berge said. Therefore he says he believes further investigations are still warranted.

"There are two ongoing trials that we hope will clarify whether there are subgroups of patients or different approaches to blood pressure–lowering management where a treatment benefit can be obtained," he said.

The study was published simultaneously to Dr. Berge’s presentation at a press conference in the Feb. 11 issue of the Lancet (doi:10.1016/S0140-6736[11]60104-9).

The study was sponsored by the Southeastern Norway Regional Health Authority and Oslo University. Dr. Berge disclosed that he and some of the other authors had received speaker fees and other remuneration from AstraZeneca and Takeda but that none of these were related to candesartan.

LOS ANGELES – Routinely lowering blood pressure in patients with acute ischemic or hemorrhagic stroke results in no apparent long-term benefits.

Patients who received candesartan – an angiotensin receptor blocker – or placebo within the first week after a stroke had virtually the same cardiovascular, clinical, and functional outcomes 6 months later, Dr. Eivind Berge reported at a Feb. 11 press briefing during the International Stroke Conference.

In fact, said Dr. Berge, patients taking the drug experienced slightly – though not significantly – increased rates of poor outcomes. "When we looked at the secondary end points, we found a slight difference in favor of placebo," in most cardiovascular outcomes, he said, with placebo significantly better in the finding of stroke progression within 2 days.

"This was statistically significant with a P value of .04," said Dr. Berge, principal investigator of the Scandinavian Candesartan Acute Stroke Trial (SCAST).

Other trials have examined the effect of different antihypertensives on stroke outcome, but SCAST is the largest to date and the only one that has studied candesartan, said Dr. Berge, who is also an internist at the Oslo University Hospital. The study enrolled 2,029 patients with ischemic or hemorrhagic stroke.

All patients in the SCAST trial had a systolic blood pressure of at least 140 mm Hg within 30 hours of symptom onset. They were randomized to either candesartan (1,017) or placebo (1,012) and treated for 7 days. Patients taking the study drug began treatment at 4 mg and progressed to 16 mg on days 3-7.

The patients’ mean age was 71 years; at baseline, their mean systolic blood pressure was 171 mm Hg, and their mean diastolic pressure was 90 mm Hg. About 85% had suffered an ischemic stroke, while 14% had hemorrhagic strokes; the remaining patients had a transient ischemic attack.

The study had two primary end points: the combination of death or major disability according to the modified Rankin Scale (mRS) by 6 months, and the combination of vascular death, heart attack, or another stroke within 6 months.

Secondary end points were all-cause death, and additional cardiovascular outcomes, including another stroke, heart attack, stroke progression, symptomatic hypotension, renal failure, and symptomatic venous thromboembolism.

Candesartan lowered blood pressure almost immediately, Dr. Berge said. By the end of the treatment period, blood pressures in the active group dropped to a mean of 147/82, compared with 152/84 in the placebo group. "Blood pressure was lowered by a statistically significant amount [compared with placebo] by day 2. From day 4 onward, we saw more modest blood pressure reduction."

But, at 6 months, none of the primary composite end points were significantly different between the two groups. The adjusted analysis showed that the composite vascular end point occurred in 12% of the active group and 11% of the placebo group; the adjusted hazard ratio in both groups was 1.09.

There were similar numbers of patients in each of the seven mRS levels. The most frequent mRS level at 6 months was 1 (290 active and 317 placebo patients). An mRS of 0 was achieved by 175 active patients and 192 placebo patients, while 84 active and 78 placebo patents had died.

Nor were there any statistically significant differences in any of the secondary end points, with the exception of stroke progression within 2 days. This occurred in 6% of the candesartan patients and 4% of the placebo patients (risk ratio 1.47; P = .04).

Dr. Berge said the findings were in accord with 10 previous studies, none of which found a significant advantage to lowering blood pressure in acute stroke. "All of these previous studies were small trials of different blood pressure–lowering agents with 100 or fewer patients," Dr. Berge said. Therefore he says he believes further investigations are still warranted.

"There are two ongoing trials that we hope will clarify whether there are subgroups of patients or different approaches to blood pressure–lowering management where a treatment benefit can be obtained," he said.

The study was published simultaneously to Dr. Berge’s presentation at a press conference in the Feb. 11 issue of the Lancet (doi:10.1016/S0140-6736[11]60104-9).

The study was sponsored by the Southeastern Norway Regional Health Authority and Oslo University. Dr. Berge disclosed that he and some of the other authors had received speaker fees and other remuneration from AstraZeneca and Takeda but that none of these were related to candesartan.

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.

LOS ANGELES – A robotic device combined with standard occupational* therapy helped stroke patients with hemiplegia gain significantly more function in their affected arm, compared with similar patients who received physical therapy and an at-home exercise program.

The Japanese ReoGo robot was especially effective in patients with moderate to severe hemiplegia, Kayoko Takahashi, Sc.D., reported at the International Stroke Conference.

The difference in response between more and less severely affected patients might have been related to their baseline physical abilities, Dr. Takahashi said during a Feb. 10 press briefing at the meeting. "It could be that the patients with lower function had difficulty performing their self-training exercises correctly. Those with severe hemiplegia could use their nonaffected arm to help with exercise, so perhaps the unaffected arm helped too much and the affected arm did not get enough exercise."

With the robot, she added, the affected arm must do all its own work.

Dr. Takahashi reported the results of a randomized, open-label trial of the robotic training device, which is manufactured by Teijin Pharma Ltd. The robot consists of two interconnected platforms: a seat with an armrest that accommodates the affected arm, and a computer screen with targets toward which the armrest reaches. The targets lead the arm though a series of movements that replicate the normal ranges of motion in the elbow and shoulder joints.

The device can be programmed in five levels, depending on the patient’s baseline physical ability. The highest assist level is completely automatic; the lowest is completely patient guided. As the patient progresses through recovery, the machine allows for more and more self-directed movement, said Dr. Takahashi, an occupational therapist at the Kitasato University East Hospital in Kanagawa, Japan.

Her study group comprised 56 patients (mean age, 65 years) who were treated at any of six Japanese hospitals. All of the patients had suffered a stroke within the previous 4-6 weeks, with a mean time after onset of 47 days. All of them had experienced upper extremity hemiplegia of varying degrees. The baseline Fugl-Meyer Assessment (FMA) score of motor function after stroke was an average of 30 for the upper extremity total, 19 for the shoulder/forearm synergy, and 7 for the flexor synergy. (The scoring system ranges from 0-100, with 0 indicating hemiplegia and 100 indicating normal motor performance. The range for the lower extremity is 0-34, and for the upper extremity – which is used in this study – is 0-66.) Patients in this study with a score lower than 30 were considered to have moderate disability. "For example, they may be able to hold a cup still [on the table], but not raise it to their mouth."

The patients were randomized to one of two rehabilitation routines. Each day for 6 weeks, the experimental group underwent 40 minutes of standard occupation/physical therapy plus 40 minutes of self-directed exercises conducted at home. The control group received the standard 40-minute occupational/physical therapy plus 40 minutes of therapy on the robot. The primary outcome measure was change in the FMA score.

Overall, there was no significant between-group difference in total FMA score, although the robotic therapy group significantly improved its upper extremity synergy movement score, compared with the control group.

The groups were then further divided into functional categories, using a score of 30 as the cut-off point. Those with a score higher than 30 were considered to have mild impairment, and those with a score of 30 or lower were deemed to have moderate to severe impairment.

In this subcomparison, the lower-functioning group that used the robot achieved a significantly better overall score than did the lower-functioning control group. There was also a significant difference between the treatment groups, with the lower-functioning patients improving significantly more than the higher-functioning group. "This shows that patients with moderate to severe hemiplegia may benefit the most from robotic therapy," Dr. Takahashi said at the meeting, which was sponsored by the American Heart Association.

Those patients with low and high proprioception both benefited from the device. "They are reaching for the monitor image, so this can give them feedback about where the arm is and how it’s moving." Dr Takahashi said. Sensory perception is not required to benefit from the training, she added.

Although the device is still in its research phase, Dr. Takahashi said it has a financial as well as clinical benefit. "This is considered a cost-saving device because now what we, as therapists, do is spend most of the session focusing on improving impairment, and not as much time focusing on function. With the robot now working on impairment, therapists can focus completely on activities of daily living and the functional area, which is a great benefit to the client."

In Japan, she added, robotic devices are considered clinical tools that are included in the coverage of occupational or physical therapy, so the patient does not pay extra for the training.

The way in which robotic therapy improves impairment is not entirely known, but appears to be related to brain plasticity after insult, Dr. Takahashi said. "We did not capture how the brain is working in our study, but there is some research with functional [MRI] that shows how the brain is recovering. We believe the repetitive exercise is helping to reeducate the brain about how the arm works."

In the United States, a number of similar trials with different robotic platforms are ongoing, and either have been completed or are recruiting patients.

Teijin Pharma Ltd. sponsored the study; Dr. Takahashi reported no financial relationship with the company.

* CORRECTION, 2/25/2011: An earlier version of this story did not correctly identify the type of therapy as occupational therapy. The error has been corrected.

LOS ANGELES – A robotic device combined with standard occupational* therapy helped stroke patients with hemiplegia gain significantly more function in their affected arm, compared with similar patients who received physical therapy and an at-home exercise program.

The Japanese ReoGo robot was especially effective in patients with moderate to severe hemiplegia, Kayoko Takahashi, Sc.D., reported at the International Stroke Conference.

The difference in response between more and less severely affected patients might have been related to their baseline physical abilities, Dr. Takahashi said during a Feb. 10 press briefing at the meeting. "It could be that the patients with lower function had difficulty performing their self-training exercises correctly. Those with severe hemiplegia could use their nonaffected arm to help with exercise, so perhaps the unaffected arm helped too much and the affected arm did not get enough exercise."

With the robot, she added, the affected arm must do all its own work.

Dr. Takahashi reported the results of a randomized, open-label trial of the robotic training device, which is manufactured by Teijin Pharma Ltd. The robot consists of two interconnected platforms: a seat with an armrest that accommodates the affected arm, and a computer screen with targets toward which the armrest reaches. The targets lead the arm though a series of movements that replicate the normal ranges of motion in the elbow and shoulder joints.

The device can be programmed in five levels, depending on the patient’s baseline physical ability. The highest assist level is completely automatic; the lowest is completely patient guided. As the patient progresses through recovery, the machine allows for more and more self-directed movement, said Dr. Takahashi, an occupational therapist at the Kitasato University East Hospital in Kanagawa, Japan.

Her study group comprised 56 patients (mean age, 65 years) who were treated at any of six Japanese hospitals. All of the patients had suffered a stroke within the previous 4-6 weeks, with a mean time after onset of 47 days. All of them had experienced upper extremity hemiplegia of varying degrees. The baseline Fugl-Meyer Assessment (FMA) score of motor function after stroke was an average of 30 for the upper extremity total, 19 for the shoulder/forearm synergy, and 7 for the flexor synergy. (The scoring system ranges from 0-100, with 0 indicating hemiplegia and 100 indicating normal motor performance. The range for the lower extremity is 0-34, and for the upper extremity – which is used in this study – is 0-66.) Patients in this study with a score lower than 30 were considered to have moderate disability. "For example, they may be able to hold a cup still [on the table], but not raise it to their mouth."

The patients were randomized to one of two rehabilitation routines. Each day for 6 weeks, the experimental group underwent 40 minutes of standard occupation/physical therapy plus 40 minutes of self-directed exercises conducted at home. The control group received the standard 40-minute occupational/physical therapy plus 40 minutes of therapy on the robot. The primary outcome measure was change in the FMA score.

Overall, there was no significant between-group difference in total FMA score, although the robotic therapy group significantly improved its upper extremity synergy movement score, compared with the control group.

The groups were then further divided into functional categories, using a score of 30 as the cut-off point. Those with a score higher than 30 were considered to have mild impairment, and those with a score of 30 or lower were deemed to have moderate to severe impairment.

In this subcomparison, the lower-functioning group that used the robot achieved a significantly better overall score than did the lower-functioning control group. There was also a significant difference between the treatment groups, with the lower-functioning patients improving significantly more than the higher-functioning group. "This shows that patients with moderate to severe hemiplegia may benefit the most from robotic therapy," Dr. Takahashi said at the meeting, which was sponsored by the American Heart Association.

Those patients with low and high proprioception both benefited from the device. "They are reaching for the monitor image, so this can give them feedback about where the arm is and how it’s moving." Dr Takahashi said. Sensory perception is not required to benefit from the training, she added.

Although the device is still in its research phase, Dr. Takahashi said it has a financial as well as clinical benefit. "This is considered a cost-saving device because now what we, as therapists, do is spend most of the session focusing on improving impairment, and not as much time focusing on function. With the robot now working on impairment, therapists can focus completely on activities of daily living and the functional area, which is a great benefit to the client."

In Japan, she added, robotic devices are considered clinical tools that are included in the coverage of occupational or physical therapy, so the patient does not pay extra for the training.

The way in which robotic therapy improves impairment is not entirely known, but appears to be related to brain plasticity after insult, Dr. Takahashi said. "We did not capture how the brain is working in our study, but there is some research with functional [MRI] that shows how the brain is recovering. We believe the repetitive exercise is helping to reeducate the brain about how the arm works."

In the United States, a number of similar trials with different robotic platforms are ongoing, and either have been completed or are recruiting patients.

Teijin Pharma Ltd. sponsored the study; Dr. Takahashi reported no financial relationship with the company.

* CORRECTION, 2/25/2011: An earlier version of this story did not correctly identify the type of therapy as occupational therapy. The error has been corrected.

LOS ANGELES – A robotic device combined with standard occupational* therapy helped stroke patients with hemiplegia gain significantly more function in their affected arm, compared with similar patients who received physical therapy and an at-home exercise program.

The Japanese ReoGo robot was especially effective in patients with moderate to severe hemiplegia, Kayoko Takahashi, Sc.D., reported at the International Stroke Conference.

The difference in response between more and less severely affected patients might have been related to their baseline physical abilities, Dr. Takahashi said during a Feb. 10 press briefing at the meeting. "It could be that the patients with lower function had difficulty performing their self-training exercises correctly. Those with severe hemiplegia could use their nonaffected arm to help with exercise, so perhaps the unaffected arm helped too much and the affected arm did not get enough exercise."

With the robot, she added, the affected arm must do all its own work.

Dr. Takahashi reported the results of a randomized, open-label trial of the robotic training device, which is manufactured by Teijin Pharma Ltd. The robot consists of two interconnected platforms: a seat with an armrest that accommodates the affected arm, and a computer screen with targets toward which the armrest reaches. The targets lead the arm though a series of movements that replicate the normal ranges of motion in the elbow and shoulder joints.

The device can be programmed in five levels, depending on the patient’s baseline physical ability. The highest assist level is completely automatic; the lowest is completely patient guided. As the patient progresses through recovery, the machine allows for more and more self-directed movement, said Dr. Takahashi, an occupational therapist at the Kitasato University East Hospital in Kanagawa, Japan.

Her study group comprised 56 patients (mean age, 65 years) who were treated at any of six Japanese hospitals. All of the patients had suffered a stroke within the previous 4-6 weeks, with a mean time after onset of 47 days. All of them had experienced upper extremity hemiplegia of varying degrees. The baseline Fugl-Meyer Assessment (FMA) score of motor function after stroke was an average of 30 for the upper extremity total, 19 for the shoulder/forearm synergy, and 7 for the flexor synergy. (The scoring system ranges from 0-100, with 0 indicating hemiplegia and 100 indicating normal motor performance. The range for the lower extremity is 0-34, and for the upper extremity – which is used in this study – is 0-66.) Patients in this study with a score lower than 30 were considered to have moderate disability. "For example, they may be able to hold a cup still [on the table], but not raise it to their mouth."

The patients were randomized to one of two rehabilitation routines. Each day for 6 weeks, the experimental group underwent 40 minutes of standard occupation/physical therapy plus 40 minutes of self-directed exercises conducted at home. The control group received the standard 40-minute occupational/physical therapy plus 40 minutes of therapy on the robot. The primary outcome measure was change in the FMA score.

Overall, there was no significant between-group difference in total FMA score, although the robotic therapy group significantly improved its upper extremity synergy movement score, compared with the control group.

The groups were then further divided into functional categories, using a score of 30 as the cut-off point. Those with a score higher than 30 were considered to have mild impairment, and those with a score of 30 or lower were deemed to have moderate to severe impairment.

In this subcomparison, the lower-functioning group that used the robot achieved a significantly better overall score than did the lower-functioning control group. There was also a significant difference between the treatment groups, with the lower-functioning patients improving significantly more than the higher-functioning group. "This shows that patients with moderate to severe hemiplegia may benefit the most from robotic therapy," Dr. Takahashi said at the meeting, which was sponsored by the American Heart Association.

Those patients with low and high proprioception both benefited from the device. "They are reaching for the monitor image, so this can give them feedback about where the arm is and how it’s moving." Dr Takahashi said. Sensory perception is not required to benefit from the training, she added.

Although the device is still in its research phase, Dr. Takahashi said it has a financial as well as clinical benefit. "This is considered a cost-saving device because now what we, as therapists, do is spend most of the session focusing on improving impairment, and not as much time focusing on function. With the robot now working on impairment, therapists can focus completely on activities of daily living and the functional area, which is a great benefit to the client."

In Japan, she added, robotic devices are considered clinical tools that are included in the coverage of occupational or physical therapy, so the patient does not pay extra for the training.

The way in which robotic therapy improves impairment is not entirely known, but appears to be related to brain plasticity after insult, Dr. Takahashi said. "We did not capture how the brain is working in our study, but there is some research with functional [MRI] that shows how the brain is recovering. We believe the repetitive exercise is helping to reeducate the brain about how the arm works."

In the United States, a number of similar trials with different robotic platforms are ongoing, and either have been completed or are recruiting patients.

Teijin Pharma Ltd. sponsored the study; Dr. Takahashi reported no financial relationship with the company.

* CORRECTION, 2/25/2011: An earlier version of this story did not correctly identify the type of therapy as occupational therapy. The error has been corrected.