2008 Salmonella Outbreak Illustrates Difficulty Identifying Source

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2008 Salmonella Outbreak Illustrates Difficulty Identifying Source

Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

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Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

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2008 Salmonella Outbreak Illustrates Difficulty Identifying Source

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2008 Salmonella Outbreak Illustrates Difficulty Identifying Source

Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

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Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

Tomatoes first got the blame for a nationwide outbreak of salmonella in 2008, but epidemiologic investigation and microbiologic analysis revealed that jalapeño and serrano peppers played a key role.

Photo credit: Flickr user Choose_Freewill (Creative Commons)
    Jalapeño peppers were implicated in a salmonella outbreak in 2008 that affected 1,500 individuals nationwide.

A team of national, state, and local investigators identified jalapeño peppers as the major vehicle for transmission of the Saintpaul serotype of Salmonella enterica that lasted from April to September 2008, according to a study published in the New England Journal of Medicine on Feb. 23 (doi: 10.1056/NEJMoa1005741). Serrano peppers were also identified as a vehicle of transmission.

"This outbreak of foodborne disease in the United States was one of the largest salmonella outbreaks ever identified," wrote Casey Barton Behravesh, D.V.M., Dr.P.H., on behalf of the Salmonella Saintpaul Outbreak Investigation Team. Dr. Behravesh is with the National Center for Emerging and Zoonotic Infectious Diseases, Atlanta.

In all, the investigators identified 1,500 individuals who were infected with the outbreak strain of the salmonella Saintpaul serotype in 43 states, the District of Columbia, and Canada. The greatest incidence rates occurred in New Mexico and Texas – 58.4 cases/million population and 24.5/million population, respectively. Illnesses peaked between mid-May and mid-June. Among case subjects, 21% were hospitalized, and the infection may have contributed to two deaths.

"This outbreak investigation highlights the recurring challenges of epidemiologic identification of ingredients in foods that are commonly consumed, rapid identification and investigation of local clusters, the need to continue exploring hypotheses during an outbreak, and produce tracing in the supply chain," the authors noted.

In an accompanying editorial, Michael T. Osterholm, Ph.D., pointed out the importance of considering all possible sources and the difficulty of identifying outbreaks related to raw produce. "Barton Behravesh et al. remind us that previously unrecognized vehicles for foodborne disease, such as jalapeño peppers can cause large nationwide outbreaks," he said (doi: 10.1056/NEJMp1010907). Dr. Osterholm is with the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Outbreaks associated with raw produce are among the most difficult ones for public health officials to identify and control, since produce from a single farm may be distributed widely and consumed rapidly because it is perishable," he noted.

The authors also noted that based on their experience with this outbreak, "improvements in product-tracing systems and the ability of the systems to work together are needed for more rapid tracing of implicated products through the supply chain."

The investigation began on May 22, when the New Mexico Department of Health notified the Centers for Disease Control and Prevention about 19 cases of salmonella infection. All seven isolates with complete serotyping were S. enterica serotype Saintpaul. The next day the CDC identified three additional isolates with the same pulsed-field gel electrophoresis (PFGE) pattern in Colorado and Texas.

Outbreaks were identified via clinical laboratories that sent salmonella strains from ill people to state public health laboratories for serotyping. State laboratories routinely submit PFGE patterns to the CDC’s PulseNet (a national molecular subtyping network).

For this outbreak, cases were defined as laboratory-confirmed infection with a specific PFGE XbaI pattern from April 1, 2008 through Sept. 4, 2008. Diarrhea was defined as at least three loose stools in a 24-hour period.

Three case-control epidemiologic studies were conducted to investigate cases that were not linked to restaurant clusters. The first study was conducted in May 2008 by the departments of health in New Mexico and Texas, the Navajo Nation, the Indian Health Service, and the CDC.

In this hypothesis-generating study, case individuals were interviewed about food consumption – particularly red and green bell peppers and other peppers. Raw tomatoes were the most commonly reported food consumed by ill individuals (84%). Roughly a quarter (26%) reported eating peppers other than red or green bell peppers.

In this study, 51 case subjects were matched with 106 control individuals. Illness was significantly associated with eating raw tomatoes (matched odds ratio 5.6) after adjustment for consumption of tortillas. However, illness was not significantly associated with eating salsa or any other food item.

In subsequent studies, investigators included all food items that were reported to have been consumed by more than half of case individuals in this first study (in addition to avocado and guacamole).

In June 2008, the CDC and state and local health departments in 29 states conducted a case-control study to better identify sources. In particular, data were collected on patterns of eating at Mexican-style restaurants and the consumption of raw produce.

 

 

In this study, 141 case subjects were matched with 281 control individuals. Illness was significantly associated with eating at a Mexican-style restaurant (matched odds ratio 4.6), eating pico de gallo (matched OR 4.0), corn tortillas (matched OR 2.3), and freshly prepared salsa (matched odds ratio 2.1), after adjustment for sex, Hispanic ethnic background, and age.

In July 2008, the departments of health in New Mexico and Arizona, the Navajo Nation, the Indian Health Service, and the CDC conducted a household-based study using personal interviews about possible sources of infection and preparation of food. A total of 41 case households and 107 control households were included. In particular, data were collected about how cilantro, jalapeño peppers, serrano peppers, and tomatoes were brought into, stored, prepared, and consumed in the home.

On univariate analysis, illness was associated with having a raw jalapeño pepper in the home (matched OR 2.9).

Epidemiologists also investigated clusters linked to restaurants or events, which were defined as a single location or event in which at least two people with the outbreak strain became ill within 7 days of their meal date and had meal dates within 10 days of each other. Nine of these epidemiologic studies were conducted.

State and local health departments in 14 states and the District of Columbia reported 37 clusters associated with restaurants or events.

Local and state health and agricultural departments, the Food and Drug Administration, and the CDC conducted traceback investigations of distribution pathways for implicated foods associated with ill individuals and restaurant clusters.

"The FDA collected food samples and conducted environmental investigations along the distribution chain, including at distribution centers, packing facilities, and farms, to determine possible sources of contamination," wrote the investigators."

"Salsa and guacamole, both foods typically containing tomatoes and hot peppers, were implicated repeatedly in cluster investigations; these foods may have provided a medium for salmonella growth. Cut or diced tomatoes require prompt refrigeration because of the potential for salmonella growth," the authors wrote. Both salsa and guacamole are often kept at room temperature for several hours in commercial settings.

"On the basis of the FDA investigations, pepper contamination probably occurred on the farm." The outbreak strain was traced back to and identified in jalapeño peppers collected in Texas and in serrano peppers (and agricultural water) on a Mexican farm. Tomato tracebacks did not converge.

The authors reported that they have no relevant financial relationships. Dr. Osterholm reported that he is a consultant to Fresh Express, Hormel, and Alex Lee Inc.

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New Imaging Agent Aids in Parkinson's Diagnosis

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The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

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The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

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New Imaging Agent Aids in Parkinson's Diagnosis

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New Imaging Agent Aids in Parkinson's Diagnosis

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

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The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

The Food and Drug Administration’s recent approval of the dopamine transporter radiotracer DaTscan (ioflupane I-123 injection) provides clinicians with a much-needed diagnostic tool for patients with questionable parkinsonian symptoms and could lead to earlier diagnosis of Parkinson’s disease and initiation of therapies to slow or halt disease progression.

GE Healthcare’s DaTscan is a radiolabeled compound that binds to dopamine transporter (DaT) protein, allowing for visualization of the distribution and relative amount of DaT in the striata using SPECT (single-photon emission computed tomography) imaging. The radiotracer allows neurologists to evaluate neurodegenerative movement disorders, such as idiopathic Parkinson’s disease (PD), and may be used as an adjunct to other diagnostic tools to help differentiate essential tremor from tremor resulting from parkinsonian syndromes. DaTscan is the first such imaging agent to be approved in the United States.

Dr. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Conn., said DaT imaging is an objective measure that can provide more evidence about whether a patient has a dopamine deficit in the brain. "There is a little bit of a leap from ‘yes, you have a dopamine deficit in your brain’ to ‘yes, you have Parkinson’s disease’ but it’s not a very [big] leap."

Dr. Kenneth Marek    

Neurologists already know how much DaT to expect in healthy individuals, depending on age. "Typically, if an individual has lost more than about a half of their [expected] dopamine transporters, that would be very consistent with Parkinson’s disease," said Dr. Marek. DaTscan will provide a visual analysis of the amount. "Nuclear medicine physicians, who are very familiar with this type of work, will simply look at the images and compare them with healthy images."

DaTscan might be of greater diagnostic value to subsets of patients. "Not everyone will require a test like this," Dr. Marek said in an interview. For example, DaT scanning would not be useful for a patient who has more advanced disease at presentation or those with very typical symptoms early on.

However, it can be helpful in patients who "have questionable symptoms or who are very early in their disease or who have intermittent symptoms. ... It’s really for individuals about whom there is substantial uncertainty of diagnosis," Dr. Marek explained.

Although current clinical uses of brain imaging with DaTscan are reason enough for patients and neurologists to be excited about its approval, the real potential is in the research arena.

"By the time someone with symptoms ends up presenting to their physician, they’ve probably lost on the order of 50%-60% of their dopamine activity, as one would measure it using this imaging tool," Dr. Marek said.

It follows that early in PD, there is a time when a patient has lost some DaT but has no symptoms. "It turns out that this imaging technique is very robust in being able to distinguish between individuals who are normal and those who actually have early Parkinson’s disease."

There are already a number of studies underway to identify those individuals. One way to do this is to evaluate relatives of individuals with PD – particularly people who have a known genetic disorder. "You could theoretically follow these individuals before they have Parkinson’s symptoms; indeed, we are actually doing exactly that study," said Dr. Marek. The study is sponsored by the Michael Fox Foundation.

Another way to identify people before they develop Parkinson’s symptoms is through their loss of the sense of smell, which can appear even before more typical motor symptoms. In fact, Dr. Marek and his coinvestigators are conducting another study using a scratch and sniff test.

From this group, the researchers have identified individuals with poor sense of smell and those with a good sense of smell. Both groups have undergone imaging, so that the researchers can identify the participants who have a poor sense of smell and abnormal brain imaging but do not have any Parkinson’s symptoms.

"The idea is to follow those people to see if this [imaging] would help us ultimately screen for Parkinson’s disease, with the idea that eventually this would be the group that you’d want to identify for treatment," Dr. Marek said. "From a research perspective, this is the most exciting use of this imaging and it takes advantage of the fact that you can identify individuals before they have symptoms."

Of course, without disease-modifying drugs, the ability to identify patients before symptoms appear is of limited use. However, DaT imaging will likely play a big role in the development of such therapies.

The Parkinson Progression Marker Initiative (sponsored by the Michael J. Fox Foundation) is one such research initiative that is aimed at understanding how brain imaging and other types of biomarkers can be used in drug development.

 

 

"We look at Parkinson’s disease as a whole because we don’t know how to separate it, but it’s very likely that within Parkinson’s disease there are some individuals who respond to one drug and not another, and certainly there are individuals who progress more rapidly than others," said Dr. Marek.

"This would be another way to focus treatment more effectively on those who would be more likely to respond to it, if you could identify different biomarkers to identify these subgroups."

There have been other DaT-related tracers that have been used for research over the last 12-15 years in the United States, but it has been difficult to get FDA approval for such agents, because the bar for approval from the FDA’s perspective was to demonstrate that DaT agents were useful as diagnostic tools for Parkinson’s disease, Dr. Marek said in an interview.

However, the agency’s approach to imaging agents has changed in recent years. Manufacturers can now seek indications for imaging agents in four categories: delineation of structure; disease or pathology detection or assessment; functional, physiological, or biochemical assessment; and diagnostic or therapeutic patient management.

DaTscan is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. "That is to say that it is not necessarily a diagnostic tool for Parkinson’s disease, but that it measures dopamine transporter density in the brain and that’s its primary indication," said Dr. Marek. "That distinction enabled the FDA to move ahead more rapidly." DaTscan has been available in Europe since 2000.

Another problem related to its approval is that DaTscan is a derivative of cocaine, so it is classified in the United States as a schedule II drug under the Controlled Substances Act. Radiologists and nuclear medicine physicians working with the tracer will have to be licensed for schedule II drugs by the Drug Enforcement Administration.

Dr. Marek is a consultant for GE Healthcare.

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New Antidepressant May Cause Less Sexual Dysfunction

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New Antidepressant May Cause Less Sexual Dysfunction

The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

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The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

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Analysis: New Mammography Guidelines Will Cost Lives

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A new analysis of the data behind controversial new recommendations raising the age for women to start routine mammography screening supports older recommendations endorsed by the American Cancer Society.

In November 2009, the U.S. Preventive Services Task Force (USPSTF) released recommendations for breast cancer for women to begin routine screening biennially, beginning at age 50 and ending at age 74 years. Prior to that time, the USPSTF – and other organizations – recommended screening mammography every 1-2 years for women beginning at age 40. The ACS recommends annual screening mammography starting at age 40.

Photo credit: Courtesy Rhoda Baer/National Cancer Institute
The analysis found that annual mammography screening of women aged 40-84 years would reduce mortality by 39%.     

Based on an average of six CISNET (Cancer Intervention and Surveillance Modeling Network) models of benefit, the authors of the new analysis concluded that the data show that annual screening of women aged 40-84 years would reduce mortality by 39%, producing the greatest benefit when compared with the new recommendation.

"A 71% improvement in mortality reduction and similar improvement in life-years gained is predicted for women who elect ACS guidelines over the USPSTF guidelines of biennial mammography between ages 50 and 74 years," R. Edward Hendrick, Ph.D., and Dr. Mark A. Helvie wrote in the February 2011 issue of the American Journal of Roentgenology.

The authors attribute this improvement in mortality reduction to cumulative smaller gains in three areas: screening women aged 40-49 years, annual vs. biennial screening in women aged 50-74 years, and screening beyond age 74 years.

The authors used an ending age of 84 years in the ACS screening regimen because that coincides with CISNET data (AJR 2011 February [doi:10.2214/AJR.10.5609]).

The release of the new USPSTF recommendations in 2009 caused confusion among both physicians and patients. The USPSTF analysis led some physicians and patients to conclude that "mammography is ineffective for women in their 40s and that there is no real difference between annual and biennial screening intervals for older women," the researchers noted.

In developing the new recommendations, the task force also highlighted the harms associated with screening mammography, such as false positives and unnecessary biopsies.

Dr. Helvie and Dr. Hendrick found that a woman aged 40-49 years who has an annual screening mammogram will have a false-positive screening mammogram once every 10 years on average. She may be called back for additional imaging once every 12 years, undergo a false-positive biopsy once every 149 years, and have a missed breast cancer once in 1,000 years.

"These analyses also show that the individual harms from the additional screening, including the risks of recall for additional testing, biopsy, and radiation-induced breast cancers, are minimal compared with the life-saving benefit of early detection for women electing screening."

Dr. Hendrick is a radiologist at the University of Colorado in Denver, and Dr. Helvie is the director of breast imaging at the University of Michigan Health System in Ann Arbor.

Dr. Hendrick disclosed that he is a consultant to GE Healthcare and serves on the medical advisory boards of Koning Corp. and Bracco Imaging. Dr. Helvie has received grant support from GE Healthcare. All three companies produce mammography equipment or software.

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A new analysis of the data behind controversial new recommendations raising the age for women to start routine mammography screening supports older recommendations endorsed by the American Cancer Society.

In November 2009, the U.S. Preventive Services Task Force (USPSTF) released recommendations for breast cancer for women to begin routine screening biennially, beginning at age 50 and ending at age 74 years. Prior to that time, the USPSTF – and other organizations – recommended screening mammography every 1-2 years for women beginning at age 40. The ACS recommends annual screening mammography starting at age 40.

Photo credit: Courtesy Rhoda Baer/National Cancer Institute
The analysis found that annual mammography screening of women aged 40-84 years would reduce mortality by 39%.     

Based on an average of six CISNET (Cancer Intervention and Surveillance Modeling Network) models of benefit, the authors of the new analysis concluded that the data show that annual screening of women aged 40-84 years would reduce mortality by 39%, producing the greatest benefit when compared with the new recommendation.

"A 71% improvement in mortality reduction and similar improvement in life-years gained is predicted for women who elect ACS guidelines over the USPSTF guidelines of biennial mammography between ages 50 and 74 years," R. Edward Hendrick, Ph.D., and Dr. Mark A. Helvie wrote in the February 2011 issue of the American Journal of Roentgenology.

The authors attribute this improvement in mortality reduction to cumulative smaller gains in three areas: screening women aged 40-49 years, annual vs. biennial screening in women aged 50-74 years, and screening beyond age 74 years.

The authors used an ending age of 84 years in the ACS screening regimen because that coincides with CISNET data (AJR 2011 February [doi:10.2214/AJR.10.5609]).

The release of the new USPSTF recommendations in 2009 caused confusion among both physicians and patients. The USPSTF analysis led some physicians and patients to conclude that "mammography is ineffective for women in their 40s and that there is no real difference between annual and biennial screening intervals for older women," the researchers noted.

In developing the new recommendations, the task force also highlighted the harms associated with screening mammography, such as false positives and unnecessary biopsies.

Dr. Helvie and Dr. Hendrick found that a woman aged 40-49 years who has an annual screening mammogram will have a false-positive screening mammogram once every 10 years on average. She may be called back for additional imaging once every 12 years, undergo a false-positive biopsy once every 149 years, and have a missed breast cancer once in 1,000 years.

"These analyses also show that the individual harms from the additional screening, including the risks of recall for additional testing, biopsy, and radiation-induced breast cancers, are minimal compared with the life-saving benefit of early detection for women electing screening."

Dr. Hendrick is a radiologist at the University of Colorado in Denver, and Dr. Helvie is the director of breast imaging at the University of Michigan Health System in Ann Arbor.

Dr. Hendrick disclosed that he is a consultant to GE Healthcare and serves on the medical advisory boards of Koning Corp. and Bracco Imaging. Dr. Helvie has received grant support from GE Healthcare. All three companies produce mammography equipment or software.

A new analysis of the data behind controversial new recommendations raising the age for women to start routine mammography screening supports older recommendations endorsed by the American Cancer Society.

In November 2009, the U.S. Preventive Services Task Force (USPSTF) released recommendations for breast cancer for women to begin routine screening biennially, beginning at age 50 and ending at age 74 years. Prior to that time, the USPSTF – and other organizations – recommended screening mammography every 1-2 years for women beginning at age 40. The ACS recommends annual screening mammography starting at age 40.

Photo credit: Courtesy Rhoda Baer/National Cancer Institute
The analysis found that annual mammography screening of women aged 40-84 years would reduce mortality by 39%.     

Based on an average of six CISNET (Cancer Intervention and Surveillance Modeling Network) models of benefit, the authors of the new analysis concluded that the data show that annual screening of women aged 40-84 years would reduce mortality by 39%, producing the greatest benefit when compared with the new recommendation.

"A 71% improvement in mortality reduction and similar improvement in life-years gained is predicted for women who elect ACS guidelines over the USPSTF guidelines of biennial mammography between ages 50 and 74 years," R. Edward Hendrick, Ph.D., and Dr. Mark A. Helvie wrote in the February 2011 issue of the American Journal of Roentgenology.

The authors attribute this improvement in mortality reduction to cumulative smaller gains in three areas: screening women aged 40-49 years, annual vs. biennial screening in women aged 50-74 years, and screening beyond age 74 years.

The authors used an ending age of 84 years in the ACS screening regimen because that coincides with CISNET data (AJR 2011 February [doi:10.2214/AJR.10.5609]).

The release of the new USPSTF recommendations in 2009 caused confusion among both physicians and patients. The USPSTF analysis led some physicians and patients to conclude that "mammography is ineffective for women in their 40s and that there is no real difference between annual and biennial screening intervals for older women," the researchers noted.

In developing the new recommendations, the task force also highlighted the harms associated with screening mammography, such as false positives and unnecessary biopsies.

Dr. Helvie and Dr. Hendrick found that a woman aged 40-49 years who has an annual screening mammogram will have a false-positive screening mammogram once every 10 years on average. She may be called back for additional imaging once every 12 years, undergo a false-positive biopsy once every 149 years, and have a missed breast cancer once in 1,000 years.

"These analyses also show that the individual harms from the additional screening, including the risks of recall for additional testing, biopsy, and radiation-induced breast cancers, are minimal compared with the life-saving benefit of early detection for women electing screening."

Dr. Hendrick is a radiologist at the University of Colorado in Denver, and Dr. Helvie is the director of breast imaging at the University of Michigan Health System in Ann Arbor.

Dr. Hendrick disclosed that he is a consultant to GE Healthcare and serves on the medical advisory boards of Koning Corp. and Bracco Imaging. Dr. Helvie has received grant support from GE Healthcare. All three companies produce mammography equipment or software.

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Major Finding: Yearly screening mammography starting at age 40 saves 71% more lives vs. biennial mammography between ages 50 and 74 years, as recommended by the USPSTF.

Data Source: A new analysis of six CISNET models of the data used by the USPSTF in making its recommendations.

Disclosures: Dr. Hendrick is a consultant to GE Healthcare and serves on the medical advisory boards of Koning Corp. and Bracco Imaging. Dr. Helvie has received grant support from GE Healthcare. All three companies produce mammography equipment or software.

New Antidepressant May Cause Less Sexual Dysfunction

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The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

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The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

The Food and Drug Administration’s approval of vilazodone hydrochloride on Jan. 21 for the treatment of major depressive disorder in adults adds another drug to the already large group of antidepressants, though this one could offer a better side effect profile through a novel combined mechanism of action.

"Unlike other antidepressants, Viibryd [vilazodone hydrochloride] is the first and only drug that is both a potent selective serotonin reuptake inhibitor and serotonin 1A [5-HT1A] receptor partial agonist in one single molecule," said Clinical Data Inc.’s CEO Drew Fromkin during a call with analysts and investors on Jan. 24. Clinical Data’s PGxHealth division acquired the rights to develop Viibryd from Merck KGaA. The drug will be marketed under the trade name Viibryd.

"The net effect [of vilazodone] is that it’s boosting serotonin ... so it’s enhancing serotonin and, at the same time, boosting the serotonin signal for one of the receptors," Dr. Norman Sussman, a professor of psychiatry at the New York University’s Langone Medical Center, said in an interview.

Vilazodone will be available in 10-, 20- and 40-mg tablets, and the company expects the drug to be available in the second quarter of 2011. As with all other antidepressants, Viibryd will have a boxed warning on the label and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults aged 18-24 during initial treatment.

Based on the result of two 8-week placebo-controlled studies including 861 patients with MDD and a 52-week open-label study including 599 patients, the company believes that the drug is associated with decreased sexual dysfunction, which is something of an Achilles’ heel for selective serotonin reuptake inhibitors (SSRIs).

"The problem that you have with serotonin reuptake inhibitors ... is that there are certain quality of life side effects that are associated, like sexual dysfunction and weight gain, that have mitigated the benefits provided in the treatment of anxiety and depression," Dr. Sussman said.

"From my reading, it has most of the same side effects as the SSRIs. It causes nausea and diarrhea. It causes insomnia ... the only thing that didn’t come up in the 8-week studies was sexual dysfunction," he said. If the decreased effect on sexual dysfunction seen in the trials bears out, the drug could be a boon to clinicians and patients.

"As a clinician, that would be relevant to me. If it worked as well as the SSRIs – without any other side effects – but didn’t cause sexual dysfunction, that in itself would make it useful."

The first patients who will be treated with these drugs are likely to be those who have already been on trials of many other antidepressants without adequate relief of symptoms, he noted. "I think you might have another group of people who are doing well on SSRIs who are having sexual dysfunction. They may be candidates for it."

In part, the drug acts as a partial agonist at serotonergic 5HT1A receptors, which play a role in serotonergic transmission. "There seems to be a nuanced difference between this drug and the SSRIs and it’s probably because the 5-HT1A receptor may damp down whatever causes sexual dysfunction," Dr. Sussman said.

There is some history to support the efficacy of 5-HT1A receptor partial agonists. Buspirone also worked on the 5-HT1A receptor, said Dr. Sussman. The drug was approved in 1986 under the name BuSpar for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Though never proven, "buspirone was one of the things that people claimed that some patients – not most – but some patients would be able to add to an SSRI to mitigate the sexual side effects," he said.

Dr. Sussman expressed concern, however, that the approval was based on two 8-week placebo-controlled studies including 861 patients with MDD. Those randomized to vilazodone were titrated up to 40 mg daily. It’s unclear how the drug would fare against other antidepressants currently available in terms of efficacy.

Based on the trial data, its maker believes that vilazodone also might minimize the weight gain that can accompany treatment with SSRIs. Dr. Sussman also cautioned that claims that weight gain is not associated with the drug might be premature. "They say that there was no weight gain in the 8-week studies but with the SSRIs in the 8-week studies, generally there was no weight gain either."

Dr. Sussman reported that he has no significant financial relationships.

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Sunitinib Improves Survival in Advanced Pancreatic Neuroendocrine Tumors

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The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

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The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

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The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

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The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

 

 

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

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Major Finding: Sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months.

Data Source: A randomized, placebo-controlled, phase III trial of 171 patients.

Disclosures: The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer.

ASCO: Discuss Palliative Care, Symptom Relief With Cancer Patients Early

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Oncologists should initiate difficult discussions about palliative care and symptom relief throughout the course of an illness, and not wait until the end stage to discuss these options with patients who have advanced cancers, according to a new policy statement self-described as a "clarion call" from the American Society of Clinical Oncology.

"There is a need to change the paradigm for advanced cancer care to include an earlier and more thorough assessment of patients’ options, goals, and preferences, and to tailor the care that we deliver to these individual needs throughout the continuum of care," Dr. Jeffrey M. Peppercorn of Duke University Medical Center in Durham, N.C., and his coauthors wrote in the statement published online in the Journal of Clinical Oncology.

Too often the transition from a focus on disease-directed treatment to an emphasis on palliative care comes within days of the end of life, they noted (J. Clin. Oncol. 2011 Jan. 24 [doi:10.1200/JCO.2010.33.1744]). "This is a clarion call for oncologists as individual practitioners, and for our profession in general, to take the lead in curtailing the use of ineffective therapy and ensuring a focus on palliative care and relief of symptoms throughout the course of illness."

ASCO has also released a new guide to help start difficult discussions about end-of-life care with advanced cancer patients. "Central to all of these goals is the need for realistic conversations about options and alternatives that should occur throughout the course of the patient’s illness." Such conversations may currently occur in fewer than 40% of patients with advanced cancer, the authors observed.

"This statement is also a call to action to clinical researchers and funding sources to support research into physician- and patient-based barriers to individualized advanced cancer care and to support evaluation of interventions to overcome barriers to this care," they added, calling for improved training in communication issues and in palliative care, reimbursement for advanced care planning, and increased support for relevant research.

The statement is an important move toward changing care patterns for patients with advanced disease, Dr. Diane E. Meier, director of the Center to Advance Palliative Care, commented in an interview. "It’s a big step in the right direction because this is the prestigious oncology physician organization, which is drawing a line in the sand to its membership and saying that we’ve got to do better," she said. "The data suggest that in many types of cancer, people referred to hospice live substantially longer" than do those who are not referred.

There is a "virtual absence of undergraduate and graduate medical education in the core primary competencies of palliative medicine, including the basics of pain and symptom management, the identification and treatment of depression and other mood disorders, and the identification of and intervention for distressed family caregivers," said Dr. Meier. "Those things are simply absent from curriculum. So I do think that it’s odd that we expect doctors to do things that they’ve never been taught."

The pool of palliative care physicians currently in practice is small and overworked, she added. "It’s easy to say that every patient should get comanagement with palliative care. The problem is ... there are very few palliative care specialists around. Those who are around are overwhelmingly busy in the hospital," Dr. Meier said, adding that "the question of how to actually implement this approach to care of comanagement and concurrent management by oncologists and palliative care specialists is vexing, and not really addressed in the ASCO report or anywhere else."

In particular, reimbursement will have change in order to better integrate palliative care into the management of patients. "Quite logically, doctors and other providers do what they get paid to do and really cannot afford to sustain a practice doing things that are essentially nonreimbursed," said Dr. Meier, a professor of geriatrics and palliative medicine at the Mount Sinai School of Medicine in New York.

"If we continue to move toward these new delivery and payment models [accountable care, medical homes, and bundling], there will be strong financial incentives to integrate palliative care in all settings" because it will be too costly not to, she noted.

The statement authors and Dr. Meier reported that they have no relevant financial relationships.

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Oncologists should initiate difficult discussions about palliative care and symptom relief throughout the course of an illness, and not wait until the end stage to discuss these options with patients who have advanced cancers, according to a new policy statement self-described as a "clarion call" from the American Society of Clinical Oncology.

"There is a need to change the paradigm for advanced cancer care to include an earlier and more thorough assessment of patients’ options, goals, and preferences, and to tailor the care that we deliver to these individual needs throughout the continuum of care," Dr. Jeffrey M. Peppercorn of Duke University Medical Center in Durham, N.C., and his coauthors wrote in the statement published online in the Journal of Clinical Oncology.

Too often the transition from a focus on disease-directed treatment to an emphasis on palliative care comes within days of the end of life, they noted (J. Clin. Oncol. 2011 Jan. 24 [doi:10.1200/JCO.2010.33.1744]). "This is a clarion call for oncologists as individual practitioners, and for our profession in general, to take the lead in curtailing the use of ineffective therapy and ensuring a focus on palliative care and relief of symptoms throughout the course of illness."

ASCO has also released a new guide to help start difficult discussions about end-of-life care with advanced cancer patients. "Central to all of these goals is the need for realistic conversations about options and alternatives that should occur throughout the course of the patient’s illness." Such conversations may currently occur in fewer than 40% of patients with advanced cancer, the authors observed.

"This statement is also a call to action to clinical researchers and funding sources to support research into physician- and patient-based barriers to individualized advanced cancer care and to support evaluation of interventions to overcome barriers to this care," they added, calling for improved training in communication issues and in palliative care, reimbursement for advanced care planning, and increased support for relevant research.

The statement is an important move toward changing care patterns for patients with advanced disease, Dr. Diane E. Meier, director of the Center to Advance Palliative Care, commented in an interview. "It’s a big step in the right direction because this is the prestigious oncology physician organization, which is drawing a line in the sand to its membership and saying that we’ve got to do better," she said. "The data suggest that in many types of cancer, people referred to hospice live substantially longer" than do those who are not referred.

There is a "virtual absence of undergraduate and graduate medical education in the core primary competencies of palliative medicine, including the basics of pain and symptom management, the identification and treatment of depression and other mood disorders, and the identification of and intervention for distressed family caregivers," said Dr. Meier. "Those things are simply absent from curriculum. So I do think that it’s odd that we expect doctors to do things that they’ve never been taught."

The pool of palliative care physicians currently in practice is small and overworked, she added. "It’s easy to say that every patient should get comanagement with palliative care. The problem is ... there are very few palliative care specialists around. Those who are around are overwhelmingly busy in the hospital," Dr. Meier said, adding that "the question of how to actually implement this approach to care of comanagement and concurrent management by oncologists and palliative care specialists is vexing, and not really addressed in the ASCO report or anywhere else."

In particular, reimbursement will have change in order to better integrate palliative care into the management of patients. "Quite logically, doctors and other providers do what they get paid to do and really cannot afford to sustain a practice doing things that are essentially nonreimbursed," said Dr. Meier, a professor of geriatrics and palliative medicine at the Mount Sinai School of Medicine in New York.

"If we continue to move toward these new delivery and payment models [accountable care, medical homes, and bundling], there will be strong financial incentives to integrate palliative care in all settings" because it will be too costly not to, she noted.

The statement authors and Dr. Meier reported that they have no relevant financial relationships.

Oncologists should initiate difficult discussions about palliative care and symptom relief throughout the course of an illness, and not wait until the end stage to discuss these options with patients who have advanced cancers, according to a new policy statement self-described as a "clarion call" from the American Society of Clinical Oncology.

"There is a need to change the paradigm for advanced cancer care to include an earlier and more thorough assessment of patients’ options, goals, and preferences, and to tailor the care that we deliver to these individual needs throughout the continuum of care," Dr. Jeffrey M. Peppercorn of Duke University Medical Center in Durham, N.C., and his coauthors wrote in the statement published online in the Journal of Clinical Oncology.

Too often the transition from a focus on disease-directed treatment to an emphasis on palliative care comes within days of the end of life, they noted (J. Clin. Oncol. 2011 Jan. 24 [doi:10.1200/JCO.2010.33.1744]). "This is a clarion call for oncologists as individual practitioners, and for our profession in general, to take the lead in curtailing the use of ineffective therapy and ensuring a focus on palliative care and relief of symptoms throughout the course of illness."

ASCO has also released a new guide to help start difficult discussions about end-of-life care with advanced cancer patients. "Central to all of these goals is the need for realistic conversations about options and alternatives that should occur throughout the course of the patient’s illness." Such conversations may currently occur in fewer than 40% of patients with advanced cancer, the authors observed.

"This statement is also a call to action to clinical researchers and funding sources to support research into physician- and patient-based barriers to individualized advanced cancer care and to support evaluation of interventions to overcome barriers to this care," they added, calling for improved training in communication issues and in palliative care, reimbursement for advanced care planning, and increased support for relevant research.

The statement is an important move toward changing care patterns for patients with advanced disease, Dr. Diane E. Meier, director of the Center to Advance Palliative Care, commented in an interview. "It’s a big step in the right direction because this is the prestigious oncology physician organization, which is drawing a line in the sand to its membership and saying that we’ve got to do better," she said. "The data suggest that in many types of cancer, people referred to hospice live substantially longer" than do those who are not referred.

There is a "virtual absence of undergraduate and graduate medical education in the core primary competencies of palliative medicine, including the basics of pain and symptom management, the identification and treatment of depression and other mood disorders, and the identification of and intervention for distressed family caregivers," said Dr. Meier. "Those things are simply absent from curriculum. So I do think that it’s odd that we expect doctors to do things that they’ve never been taught."

The pool of palliative care physicians currently in practice is small and overworked, she added. "It’s easy to say that every patient should get comanagement with palliative care. The problem is ... there are very few palliative care specialists around. Those who are around are overwhelmingly busy in the hospital," Dr. Meier said, adding that "the question of how to actually implement this approach to care of comanagement and concurrent management by oncologists and palliative care specialists is vexing, and not really addressed in the ASCO report or anywhere else."

In particular, reimbursement will have change in order to better integrate palliative care into the management of patients. "Quite logically, doctors and other providers do what they get paid to do and really cannot afford to sustain a practice doing things that are essentially nonreimbursed," said Dr. Meier, a professor of geriatrics and palliative medicine at the Mount Sinai School of Medicine in New York.

"If we continue to move toward these new delivery and payment models [accountable care, medical homes, and bundling], there will be strong financial incentives to integrate palliative care in all settings" because it will be too costly not to, she noted.

The statement authors and Dr. Meier reported that they have no relevant financial relationships.

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