Neil Osterweil

BOSTON – Both veterans and active-duty military are at significantly greater risk for suicide than is the general population, underscoring the critical need for identification of suicidal thoughts and prevention of suicidal actions, said clinicians who specialize in the mental health needs of current and former armed service members.

Of the 30,000-32,000 Americans annually who commit suicide, about one in five is a veteran – an average of 18 veteran suicides a day, according to the National Violent Death Reporting System of the Centers for Disease Control and Prevention.

From 1950 through 2005, despite four wars, seven recessions, and unprecedented advances in the diagnosis and treatment of mental illness, the overall American suicide rate has not changed, said Dr. Janet Kemp, Veterans Affairs national mental health director for suicide prevention at the VA Office of Mental Health in Washington.

"It’s not that people haven’t been paying attention to it, but to be perfectly honest, we’re not that far ahead in our ability to change the problem," she said at a symposium on the complexities and challenges of posttraumatic stress disorder (PTSD) and traumatic brain injury.

For active duty military, particularly those who are deployed to combat zones, a combination of "rage, guilt, and despair" and ready access to firearms can be a deadly combination, added Col. John Bradley, a physician who serves as chair of Integrated Health Services in the department of psychiatry at Walter Reed Army Medical Center, Washington, D.C.

"It’s not simply exposure to bad things, but it’s the emotional response to those things that really creates the distress for our returning veterans, and in particular, anger and survivor’s guilt are important themes," Dr. Bradley said.

Younger Vets, Women at Higher Risk

CDC data from 2008, the latest year available, suggest that younger veterans (aged 20-29 years), those 39 and older, and women vets are increased risk for suicide, compared with other veterans, although information on trends is hard to come by, Dr. Kemp noted.

Three of the most significant risk factors for suicide are PTSD, depression, and sleep disorders, Col. Bradley said. He cited a 2004 study of soldiers and Marines returning from combat in Iraq or Afghanistan that found that PTSD symptoms ranged from 9.5% among those with low levels of combat experience, to 18.5% among those with high levels of combat exposure. Rates of depression were 5.2% and 7.9%, respectively, and more than one-fourth of service members returning from war zones reported sleep problems: 25.6% and 37.2%, respectively (N. Engl. J. Med. 2004;351:13-22).

Additionally, the prevalence of PTSD and other mental health problems has been shown to increase during the first year after the end of a combat deployment, with PTSD levels increasing from 5% from 12.9% 3 months after deployment (during Operation Iraqi Freedom) to 17% at year, depression levels increasing from 7.9 to 12%, and anxiety rising from 7.9% to 11.5% (Arch. Gen. Psychiatry 2010;67:614-23).

Department of Defense studies have found that the rate of suicides among active duty military have begun to approximate those of the general public, Col. Bradley said.

"We used to believe that we were afforded some protection by our increased selection criteria for becoming a service member, access to health care, health and fitness, wellness, unit cohesion, etc., but now our rates are no better, and we have to ask the question ‘why?’ "

Data from the Post-Deployment Health Assessment, a universal screening instrument for returning service members, show that 25% of those who went on to commit suicide endorsed one of two depression items (hopelessness, loss of interest), 26% endorsed one of four PTSD items (nightmares, avoiding situations/thoughts, constantly on guard, and numb or detached), but only about 2% had reported suicidal thoughts. About 6% said they had sought mental health care in the past month, and 11% said they had been referred for mental health care.

Gunshot wounds are by far the most significant cause of death (from about 56% to 70%), followed by hanging/asphyxiation (18-20%), and drug, poisoning/carbon monoxide, exsanguination, or other causes (all below 10%).

Risk factors

The best predictor of a suicide attempt is presence of a current suicide plan or past attempt, the latter of which is associated with 100-fold risk for a second attempt within a year, but predictive ability is generally poor, Dr. Bradley said.

Other significant risk factors include:

• Family history of suicide.

• Family history of child maltreatment.

• History of mental disorders (particularly depression), alcohol, or substance abuse.

• Feelings of hopelessness or isolation from others.

• Impulsive or aggressive tendencies.

• Cultural and religious beliefs regarding acceptability of suicide.

• Local epidemics of suicide.

• Barriers to mental health treatment access.

• Loss (relational, social, work, or financial).

• Physical illness.

• Easy access to lethal methods (guns, knives, etc.).

• Unwillingness to seek help because of stigma attached to mental health/substance abuse or suicidal thoughts.

Prevention Recommendations

Col. Bradley served on a Defense Department suicide prevention task force that recommended key strategies to prevent suicide in the armed services in four domains:

• Organization and leadership.

• Wellness enhancement and training.

• Access to and delivery of high-quality care.

• Surveillance, investigations, and research.

"During our 19 site visits with military families at different installations across all four services, families and troops told us again and again and again that the major stressor in their lives is the repeated deployments and the lack of quality dwell time that they have in between those deployments to be able to reintegrate, reestablish a baseline, reestablish a support system in order to be successful," Col. Bradley said.

The task force recommended enhancing well-being, mental fitness, life skills, and resiliency of service members and families with programs such as financial management training, marriage and family relationship counseling, anger management, and conflict resolution skills.

Service members and their families also should have ready access to high quality behavioral health care, with continuity of care to ensure timely provision of services and seamless management. The task forces also called for standardized crisis intervention services and hotlines across all branches of the military.

Assessment and Management

The clinician should assess the degree of risk – acute or imminent – and ask the patient about current stressors and potential vulnerabilities over the long term. Col. Bradley and his colleagues employ the SAD PERSONS suicide assessment scale and the Beck Scale for Suicidal Ideation for evaluating patients.

Managing at-risk patients might include stabilizing medical conditions, taking steps to ensure the safety of both the patient and the clinician, and ruling out intoxication or withdrawal as possible causes of suicidal statements or actions. However, even retracted suicidal statements must still be evaluated, Dr. Bradley cautioned.

Treatment options include hospitalizing or committing to a care facility patients at imminent risk, although evidence to support this practice is limited. There is better evidence for suicide-specific therapies, psychosocial support, and medical therapies such as flupenthixol, clozapine, or electroconvulsive therapy.

Col. Bradley emphasized that there is no evidence to support the use of a "suicide contract," in which the clinician elicits a promise from the patient that he/she will not commit suicide.

"The only thing a suicide contract does is make a malpractice lawyer salivate when you’re being taken to court," he said.

The ongoing Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is the largest study of suicide and mental health among military personnel ever undertaken. It is designed to identify modifiable risk and protective factors related to mental health and suicide and will support the Army’s ongoing efforts to prevent suicide and improve soldiers’ overall well-being.

Data were presented at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital. Neither Dr. Kemp nor Col. Bradley had relevant financial disclosures.

BOSTON – Both veterans and active-duty military are at significantly greater risk for suicide than is the general population, underscoring the critical need for identification of suicidal thoughts and prevention of suicidal actions, said clinicians who specialize in the mental health needs of current and former armed service members.

Of the 30,000-32,000 Americans annually who commit suicide, about one in five is a veteran – an average of 18 veteran suicides a day, according to the National Violent Death Reporting System of the Centers for Disease Control and Prevention.

From 1950 through 2005, despite four wars, seven recessions, and unprecedented advances in the diagnosis and treatment of mental illness, the overall American suicide rate has not changed, said Dr. Janet Kemp, Veterans Affairs national mental health director for suicide prevention at the VA Office of Mental Health in Washington.

"It’s not that people haven’t been paying attention to it, but to be perfectly honest, we’re not that far ahead in our ability to change the problem," she said at a symposium on the complexities and challenges of posttraumatic stress disorder (PTSD) and traumatic brain injury.

For active duty military, particularly those who are deployed to combat zones, a combination of "rage, guilt, and despair" and ready access to firearms can be a deadly combination, added Col. John Bradley, a physician who serves as chair of Integrated Health Services in the department of psychiatry at Walter Reed Army Medical Center, Washington, D.C.

"It’s not simply exposure to bad things, but it’s the emotional response to those things that really creates the distress for our returning veterans, and in particular, anger and survivor’s guilt are important themes," Dr. Bradley said.

Younger Vets, Women at Higher Risk

CDC data from 2008, the latest year available, suggest that younger veterans (aged 20-29 years), those 39 and older, and women vets are increased risk for suicide, compared with other veterans, although information on trends is hard to come by, Dr. Kemp noted.

Three of the most significant risk factors for suicide are PTSD, depression, and sleep disorders, Col. Bradley said. He cited a 2004 study of soldiers and Marines returning from combat in Iraq or Afghanistan that found that PTSD symptoms ranged from 9.5% among those with low levels of combat experience, to 18.5% among those with high levels of combat exposure. Rates of depression were 5.2% and 7.9%, respectively, and more than one-fourth of service members returning from war zones reported sleep problems: 25.6% and 37.2%, respectively (N. Engl. J. Med. 2004;351:13-22).

Additionally, the prevalence of PTSD and other mental health problems has been shown to increase during the first year after the end of a combat deployment, with PTSD levels increasing from 5% from 12.9% 3 months after deployment (during Operation Iraqi Freedom) to 17% at year, depression levels increasing from 7.9 to 12%, and anxiety rising from 7.9% to 11.5% (Arch. Gen. Psychiatry 2010;67:614-23).

Department of Defense studies have found that the rate of suicides among active duty military have begun to approximate those of the general public, Col. Bradley said.

"We used to believe that we were afforded some protection by our increased selection criteria for becoming a service member, access to health care, health and fitness, wellness, unit cohesion, etc., but now our rates are no better, and we have to ask the question ‘why?’ "

Data from the Post-Deployment Health Assessment, a universal screening instrument for returning service members, show that 25% of those who went on to commit suicide endorsed one of two depression items (hopelessness, loss of interest), 26% endorsed one of four PTSD items (nightmares, avoiding situations/thoughts, constantly on guard, and numb or detached), but only about 2% had reported suicidal thoughts. About 6% said they had sought mental health care in the past month, and 11% said they had been referred for mental health care.

Gunshot wounds are by far the most significant cause of death (from about 56% to 70%), followed by hanging/asphyxiation (18-20%), and drug, poisoning/carbon monoxide, exsanguination, or other causes (all below 10%).

Risk factors

The best predictor of a suicide attempt is presence of a current suicide plan or past attempt, the latter of which is associated with 100-fold risk for a second attempt within a year, but predictive ability is generally poor, Dr. Bradley said.

Other significant risk factors include:

• Family history of suicide.

• Family history of child maltreatment.

• History of mental disorders (particularly depression), alcohol, or substance abuse.

• Feelings of hopelessness or isolation from others.

• Impulsive or aggressive tendencies.

• Cultural and religious beliefs regarding acceptability of suicide.

• Local epidemics of suicide.

• Barriers to mental health treatment access.

• Loss (relational, social, work, or financial).

• Physical illness.

• Easy access to lethal methods (guns, knives, etc.).

• Unwillingness to seek help because of stigma attached to mental health/substance abuse or suicidal thoughts.

Prevention Recommendations

Col. Bradley served on a Defense Department suicide prevention task force that recommended key strategies to prevent suicide in the armed services in four domains:

• Organization and leadership.

• Wellness enhancement and training.

• Access to and delivery of high-quality care.

• Surveillance, investigations, and research.

"During our 19 site visits with military families at different installations across all four services, families and troops told us again and again and again that the major stressor in their lives is the repeated deployments and the lack of quality dwell time that they have in between those deployments to be able to reintegrate, reestablish a baseline, reestablish a support system in order to be successful," Col. Bradley said.

The task force recommended enhancing well-being, mental fitness, life skills, and resiliency of service members and families with programs such as financial management training, marriage and family relationship counseling, anger management, and conflict resolution skills.

Service members and their families also should have ready access to high quality behavioral health care, with continuity of care to ensure timely provision of services and seamless management. The task forces also called for standardized crisis intervention services and hotlines across all branches of the military.

Assessment and Management

The clinician should assess the degree of risk – acute or imminent – and ask the patient about current stressors and potential vulnerabilities over the long term. Col. Bradley and his colleagues employ the SAD PERSONS suicide assessment scale and the Beck Scale for Suicidal Ideation for evaluating patients.

Managing at-risk patients might include stabilizing medical conditions, taking steps to ensure the safety of both the patient and the clinician, and ruling out intoxication or withdrawal as possible causes of suicidal statements or actions. However, even retracted suicidal statements must still be evaluated, Dr. Bradley cautioned.

Treatment options include hospitalizing or committing to a care facility patients at imminent risk, although evidence to support this practice is limited. There is better evidence for suicide-specific therapies, psychosocial support, and medical therapies such as flupenthixol, clozapine, or electroconvulsive therapy.

Col. Bradley emphasized that there is no evidence to support the use of a "suicide contract," in which the clinician elicits a promise from the patient that he/she will not commit suicide.

"The only thing a suicide contract does is make a malpractice lawyer salivate when you’re being taken to court," he said.

The ongoing Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is the largest study of suicide and mental health among military personnel ever undertaken. It is designed to identify modifiable risk and protective factors related to mental health and suicide and will support the Army’s ongoing efforts to prevent suicide and improve soldiers’ overall well-being.

Data were presented at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital. Neither Dr. Kemp nor Col. Bradley had relevant financial disclosures.

BOSTON – Both veterans and active-duty military are at significantly greater risk for suicide than is the general population, underscoring the critical need for identification of suicidal thoughts and prevention of suicidal actions, said clinicians who specialize in the mental health needs of current and former armed service members.

Of the 30,000-32,000 Americans annually who commit suicide, about one in five is a veteran – an average of 18 veteran suicides a day, according to the National Violent Death Reporting System of the Centers for Disease Control and Prevention.

From 1950 through 2005, despite four wars, seven recessions, and unprecedented advances in the diagnosis and treatment of mental illness, the overall American suicide rate has not changed, said Dr. Janet Kemp, Veterans Affairs national mental health director for suicide prevention at the VA Office of Mental Health in Washington.

"It’s not that people haven’t been paying attention to it, but to be perfectly honest, we’re not that far ahead in our ability to change the problem," she said at a symposium on the complexities and challenges of posttraumatic stress disorder (PTSD) and traumatic brain injury.

For active duty military, particularly those who are deployed to combat zones, a combination of "rage, guilt, and despair" and ready access to firearms can be a deadly combination, added Col. John Bradley, a physician who serves as chair of Integrated Health Services in the department of psychiatry at Walter Reed Army Medical Center, Washington, D.C.

"It’s not simply exposure to bad things, but it’s the emotional response to those things that really creates the distress for our returning veterans, and in particular, anger and survivor’s guilt are important themes," Dr. Bradley said.

Younger Vets, Women at Higher Risk

CDC data from 2008, the latest year available, suggest that younger veterans (aged 20-29 years), those 39 and older, and women vets are increased risk for suicide, compared with other veterans, although information on trends is hard to come by, Dr. Kemp noted.

Three of the most significant risk factors for suicide are PTSD, depression, and sleep disorders, Col. Bradley said. He cited a 2004 study of soldiers and Marines returning from combat in Iraq or Afghanistan that found that PTSD symptoms ranged from 9.5% among those with low levels of combat experience, to 18.5% among those with high levels of combat exposure. Rates of depression were 5.2% and 7.9%, respectively, and more than one-fourth of service members returning from war zones reported sleep problems: 25.6% and 37.2%, respectively (N. Engl. J. Med. 2004;351:13-22).

Additionally, the prevalence of PTSD and other mental health problems has been shown to increase during the first year after the end of a combat deployment, with PTSD levels increasing from 5% from 12.9% 3 months after deployment (during Operation Iraqi Freedom) to 17% at year, depression levels increasing from 7.9 to 12%, and anxiety rising from 7.9% to 11.5% (Arch. Gen. Psychiatry 2010;67:614-23).

Department of Defense studies have found that the rate of suicides among active duty military have begun to approximate those of the general public, Col. Bradley said.

"We used to believe that we were afforded some protection by our increased selection criteria for becoming a service member, access to health care, health and fitness, wellness, unit cohesion, etc., but now our rates are no better, and we have to ask the question ‘why?’ "

Data from the Post-Deployment Health Assessment, a universal screening instrument for returning service members, show that 25% of those who went on to commit suicide endorsed one of two depression items (hopelessness, loss of interest), 26% endorsed one of four PTSD items (nightmares, avoiding situations/thoughts, constantly on guard, and numb or detached), but only about 2% had reported suicidal thoughts. About 6% said they had sought mental health care in the past month, and 11% said they had been referred for mental health care.

Gunshot wounds are by far the most significant cause of death (from about 56% to 70%), followed by hanging/asphyxiation (18-20%), and drug, poisoning/carbon monoxide, exsanguination, or other causes (all below 10%).

Risk factors

The best predictor of a suicide attempt is presence of a current suicide plan or past attempt, the latter of which is associated with 100-fold risk for a second attempt within a year, but predictive ability is generally poor, Dr. Bradley said.

Other significant risk factors include:

• Family history of suicide.

• Family history of child maltreatment.

• History of mental disorders (particularly depression), alcohol, or substance abuse.

• Feelings of hopelessness or isolation from others.

• Impulsive or aggressive tendencies.

• Cultural and religious beliefs regarding acceptability of suicide.

• Local epidemics of suicide.

• Barriers to mental health treatment access.

• Loss (relational, social, work, or financial).

• Physical illness.

• Easy access to lethal methods (guns, knives, etc.).

• Unwillingness to seek help because of stigma attached to mental health/substance abuse or suicidal thoughts.

Prevention Recommendations

Col. Bradley served on a Defense Department suicide prevention task force that recommended key strategies to prevent suicide in the armed services in four domains:

• Organization and leadership.

• Wellness enhancement and training.

• Access to and delivery of high-quality care.

• Surveillance, investigations, and research.

"During our 19 site visits with military families at different installations across all four services, families and troops told us again and again and again that the major stressor in their lives is the repeated deployments and the lack of quality dwell time that they have in between those deployments to be able to reintegrate, reestablish a baseline, reestablish a support system in order to be successful," Col. Bradley said.

The task force recommended enhancing well-being, mental fitness, life skills, and resiliency of service members and families with programs such as financial management training, marriage and family relationship counseling, anger management, and conflict resolution skills.

Service members and their families also should have ready access to high quality behavioral health care, with continuity of care to ensure timely provision of services and seamless management. The task forces also called for standardized crisis intervention services and hotlines across all branches of the military.

Assessment and Management

The clinician should assess the degree of risk – acute or imminent – and ask the patient about current stressors and potential vulnerabilities over the long term. Col. Bradley and his colleagues employ the SAD PERSONS suicide assessment scale and the Beck Scale for Suicidal Ideation for evaluating patients.

Managing at-risk patients might include stabilizing medical conditions, taking steps to ensure the safety of both the patient and the clinician, and ruling out intoxication or withdrawal as possible causes of suicidal statements or actions. However, even retracted suicidal statements must still be evaluated, Dr. Bradley cautioned.

Treatment options include hospitalizing or committing to a care facility patients at imminent risk, although evidence to support this practice is limited. There is better evidence for suicide-specific therapies, psychosocial support, and medical therapies such as flupenthixol, clozapine, or electroconvulsive therapy.

Col. Bradley emphasized that there is no evidence to support the use of a "suicide contract," in which the clinician elicits a promise from the patient that he/she will not commit suicide.

"The only thing a suicide contract does is make a malpractice lawyer salivate when you’re being taken to court," he said.

The ongoing Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is the largest study of suicide and mental health among military personnel ever undertaken. It is designed to identify modifiable risk and protective factors related to mental health and suicide and will support the Army’s ongoing efforts to prevent suicide and improve soldiers’ overall well-being.

Data were presented at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital. Neither Dr. Kemp nor Col. Bradley had relevant financial disclosures.

BOSTON – Exposure to trauma is ephemeral, but its effects in the form of posttraumatic stress disorder can linger for decades. However, a handful of psychosocial therapies and at least one class of drugs can be effective at reducing the invisible scars of PTSD, investigators reported at a conference on the complexities and challenges of PTSD and traumatic brain injury.

Interventions such as exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing can help PTSD sufferers direct their thoughts away from traumatic events, often with durable results, said Terence M. Keane, Ph.D., director of the behavioral science division of the National Center for Posttraumatic Stress Disorder, Boston.

In addition, "emerging, exciting evidence" supports the use of the alpha-adrenergic antagonist prazosin for alleviating nightmares and sleep disruptions associated with the disorder, said Dr. Thomas A. Mellman, research associate dean and professor of psychiatry at Howard University, Washington.

Impact of Trauma Exposure

In an era of multiple military deployments and widespread regional conflicts, levels of PTSD and comorbid conditions are increasingly common, noted Dr. Keane, who also is with the department of psychiatry at Boston University.

Courtesy of Tom Allen

"If there is one powerful determinant of who develops PTSD, it is exposure to trauma experiences," he said. "It overrides all of the other risk factors. It outranks everything else, including childhood upbringing."

Many of the scales that are used to assess PTSD and combat exposure were developed after the Vietnam War. The Combat Exposure Scale, published by Dr. Keane and his colleagues in 1989, is a 7-item questionnaire gauging PTSD risk by factors such as the degree of exposure to firefights, the number of casualties in the soldier’s unit, and frequency of exposure to life-threatening situations (Psychol. Assess. 1989;1:53-5).

The scale’s upper limit of the numbers of exposures to firefights is "51 or more." In contrast, U.S. soldiers were exposed to about 400 firefights during a 15-month deployment in the Korengal Valley in Afghanistan, said Dr. Keane, citing Sebastian Junger, an American journalist who was intermittently embedded with a platoon of the 173rd Airborne Brigade in 2007-2008.

"The most upsetting thing ... was the loss of their friends," Mr. Junger wrote. "They felt responsible for their deaths, convinced there was something they could have done to prevent them and a sense of guilt that they should have been killed instead."

Psychosocial Interventions

There are five evidence-based psychosocial interventions for PTSD: exposure therapy, cognitive therapy, anxiety management, cognitive reprocessing therapy, and eye movement desensitization and reprocessing (EMDR).

"It’s very clear that participating in these treatments if you have a diagnosis of PTSD actually leads to remarkable improvement not only in symptoms, but also in life functioning," Dr. Keane said.

Cognitive-behavioral treatments for chronic PTSD approach the problem from two different angles. One approach allows patients to safely confront their traumatic experience through exposure discussions that recall trauma reminders; the other is aimed at modifying the dysfunctional thought processes that underlie PTSD.

One example of the former approach is exposure therapy, in which patients confront the objects, situations, memories, and images they fear in a systematic and repetitive fashion. After an initial relaxation training session, patients relive their experiences through imagined exposures to the traumatic memory, and, when possible, with real-life exposure to the traumatic event (for example, a visit to a car accident site).

"This is a very powerful treatment that effectively reduces symptoms of PTSD and improves psychosocial functioning in virtually every domain that we have tested," Dr. Keane said.

An alternative approach is cognitive therapy, in which patients are helped to change their negative, unrealistic thinking by identifying their dysfunctional, unrealistic thoughts and beliefs ("I’m responsible for it," "It was what I was wearing," "I should never have been there"), and challenge those distortions, helping the patient to replace them with functional, realistic alternatives.

Cognitive processing therapy (CPT) combines elements of the exposure and cognitive therapy approaches. It involves cognitive restructuring focusing on safety, trust, power, esteem, and intimacy. The patient repeatedly writes out the traumatic experience and reads it in 12 weekly sessions.

EMDR has been shown in controlled studies to help patients with PTSD, with an effect comparable to that of exposure therapy in many instances, Dr. Keane said. As in the latter treatment, EMDR accesses trauma images and memories, and helps patients to evaluate the aversive qualities of those images and memories, and to generate alternative cognitive appraisals. The recall is accompanied by sets of lateral eye movements that the patient makes while focusing on her/his response.

"There has been a lot of discussions on the eye movements – are they necessary, are they not necessary – [and] it looks like the best data suggest that they’re not necessary," Dr. Keane said.

Pharmacologic Interventions

When it comes to drug therapies for PTSD, many have been tried and most have been found wanting, Dr. Mellman said.

Pharmacotherapy for PTSD is based on neurobiological models of PTSD involving memory and neural structure. These models link PTSD to reactivity or selective attention to trauma stimuli, fragmentary trauma narratives, verbal memory deficits, reduced hippocampal volume, and increased amgydala activation with reduced anterior cingulate activation, he said.

Proposed hormonal and neurotransmitter-related mechanisms include reduced cortisol secretion and increased sensitivity to feedback inhibition, an effect of noradrenergic activity on fear-enhanced learning, and the role of the excitatory amino acid glutamate in neuroexcitation, learning and neurotoxicity, and GABA (gamma-aminobutyric acid) in inhibition.

Some evidence supports the use of selective serotonin reuptake inhibitors (SSRIs), which have been shown in nine randomized controlled trials in primarily female civilian populations to have positive effects on the three PTSD symptom clusters (reexperiencing, avoidance, and hyperarousal). Response rates in these studies have ranged from 53% to 64% (compared with 32% to 38% for placebo), with the effects occurring both with and without comorbid depression. In one study, maintenance efficacy of up to 1 year was seen with patients on sertraline.

However, six other published randomized controlled trials failed to find a benefit for SSRIs for PTSD symptoms, compared with placebo. These studies primarily involved men, many of whom were veterans, Dr. Mellman noted.

Other agents with mixed or limited evidence to support their use in PTSD include atypical antipsychotics, benzodiazepines, MAO inhibitors, tricyclics, and anticonvulsant mood stabilizers, Dr. Mellman said.

Seven small randomized controlled trials have looked at atypicals, primarily risperidone and olanzapine, and primarily in treatment-refractory patients.

"Overall, the evidence does support adjunctive risperidone for refractory cases, and there does seem to be a benefit to sleep for the atypical class," he said.

Regarding benzodiazepines, there appears to be a lack of evidence to support either their efficacy or inefficacy, he added.

"We don’t recommend benzodiazepines as treatment for people with PTSD, but does that mean people with PTSD shouldn’t be exposed to them? I’m not sure. They do calm a person down temporarily, but [we should be] wary of continuous, chronic application," he said.

Prazosin Proves Powerful

Prazosin, originally developed as an antihypertensive agent, has been shown to have efficacy at reducing insomnia and nightmare in veterans with PTSD.

A study of 34 veterans with chronic PTSD and trauma nightmares showed that prazosin "shifted dream characteristics from those typical of trauma-related nightmares to those typical of normal dreams" (Biol. Psychiatry 2007;61:928-34).

"Prazosin also appeals to me from a theoretical standpoint because it preserves REM sleep, in contrast to many pharmacological agents that have the effect of reducing REM sleep, and there’s a particularly interesting animal model that shows that [prazosin] preserves REM sleep against the disruption of an adrenergic agonist, and this may be a model that’s relevant to PTSD," Dr. Mellman said.

Dr. Keane and Dr. Mellman presented their findings at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital, both in Boston. Neither Dr. Keane nor Dr. Mellman had relevant financial disclosures.

BOSTON – Exposure to trauma is ephemeral, but its effects in the form of posttraumatic stress disorder can linger for decades. However, a handful of psychosocial therapies and at least one class of drugs can be effective at reducing the invisible scars of PTSD, investigators reported at a conference on the complexities and challenges of PTSD and traumatic brain injury.

Interventions such as exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing can help PTSD sufferers direct their thoughts away from traumatic events, often with durable results, said Terence M. Keane, Ph.D., director of the behavioral science division of the National Center for Posttraumatic Stress Disorder, Boston.

In addition, "emerging, exciting evidence" supports the use of the alpha-adrenergic antagonist prazosin for alleviating nightmares and sleep disruptions associated with the disorder, said Dr. Thomas A. Mellman, research associate dean and professor of psychiatry at Howard University, Washington.

Impact of Trauma Exposure

In an era of multiple military deployments and widespread regional conflicts, levels of PTSD and comorbid conditions are increasingly common, noted Dr. Keane, who also is with the department of psychiatry at Boston University.

Courtesy of Tom Allen

"If there is one powerful determinant of who develops PTSD, it is exposure to trauma experiences," he said. "It overrides all of the other risk factors. It outranks everything else, including childhood upbringing."

Many of the scales that are used to assess PTSD and combat exposure were developed after the Vietnam War. The Combat Exposure Scale, published by Dr. Keane and his colleagues in 1989, is a 7-item questionnaire gauging PTSD risk by factors such as the degree of exposure to firefights, the number of casualties in the soldier’s unit, and frequency of exposure to life-threatening situations (Psychol. Assess. 1989;1:53-5).

The scale’s upper limit of the numbers of exposures to firefights is "51 or more." In contrast, U.S. soldiers were exposed to about 400 firefights during a 15-month deployment in the Korengal Valley in Afghanistan, said Dr. Keane, citing Sebastian Junger, an American journalist who was intermittently embedded with a platoon of the 173rd Airborne Brigade in 2007-2008.

"The most upsetting thing ... was the loss of their friends," Mr. Junger wrote. "They felt responsible for their deaths, convinced there was something they could have done to prevent them and a sense of guilt that they should have been killed instead."

Psychosocial Interventions

There are five evidence-based psychosocial interventions for PTSD: exposure therapy, cognitive therapy, anxiety management, cognitive reprocessing therapy, and eye movement desensitization and reprocessing (EMDR).

"It’s very clear that participating in these treatments if you have a diagnosis of PTSD actually leads to remarkable improvement not only in symptoms, but also in life functioning," Dr. Keane said.

Cognitive-behavioral treatments for chronic PTSD approach the problem from two different angles. One approach allows patients to safely confront their traumatic experience through exposure discussions that recall trauma reminders; the other is aimed at modifying the dysfunctional thought processes that underlie PTSD.

One example of the former approach is exposure therapy, in which patients confront the objects, situations, memories, and images they fear in a systematic and repetitive fashion. After an initial relaxation training session, patients relive their experiences through imagined exposures to the traumatic memory, and, when possible, with real-life exposure to the traumatic event (for example, a visit to a car accident site).

"This is a very powerful treatment that effectively reduces symptoms of PTSD and improves psychosocial functioning in virtually every domain that we have tested," Dr. Keane said.

An alternative approach is cognitive therapy, in which patients are helped to change their negative, unrealistic thinking by identifying their dysfunctional, unrealistic thoughts and beliefs ("I’m responsible for it," "It was what I was wearing," "I should never have been there"), and challenge those distortions, helping the patient to replace them with functional, realistic alternatives.

Cognitive processing therapy (CPT) combines elements of the exposure and cognitive therapy approaches. It involves cognitive restructuring focusing on safety, trust, power, esteem, and intimacy. The patient repeatedly writes out the traumatic experience and reads it in 12 weekly sessions.

EMDR has been shown in controlled studies to help patients with PTSD, with an effect comparable to that of exposure therapy in many instances, Dr. Keane said. As in the latter treatment, EMDR accesses trauma images and memories, and helps patients to evaluate the aversive qualities of those images and memories, and to generate alternative cognitive appraisals. The recall is accompanied by sets of lateral eye movements that the patient makes while focusing on her/his response.

"There has been a lot of discussions on the eye movements – are they necessary, are they not necessary – [and] it looks like the best data suggest that they’re not necessary," Dr. Keane said.

Pharmacologic Interventions

When it comes to drug therapies for PTSD, many have been tried and most have been found wanting, Dr. Mellman said.

Pharmacotherapy for PTSD is based on neurobiological models of PTSD involving memory and neural structure. These models link PTSD to reactivity or selective attention to trauma stimuli, fragmentary trauma narratives, verbal memory deficits, reduced hippocampal volume, and increased amgydala activation with reduced anterior cingulate activation, he said.

Proposed hormonal and neurotransmitter-related mechanisms include reduced cortisol secretion and increased sensitivity to feedback inhibition, an effect of noradrenergic activity on fear-enhanced learning, and the role of the excitatory amino acid glutamate in neuroexcitation, learning and neurotoxicity, and GABA (gamma-aminobutyric acid) in inhibition.

Some evidence supports the use of selective serotonin reuptake inhibitors (SSRIs), which have been shown in nine randomized controlled trials in primarily female civilian populations to have positive effects on the three PTSD symptom clusters (reexperiencing, avoidance, and hyperarousal). Response rates in these studies have ranged from 53% to 64% (compared with 32% to 38% for placebo), with the effects occurring both with and without comorbid depression. In one study, maintenance efficacy of up to 1 year was seen with patients on sertraline.

However, six other published randomized controlled trials failed to find a benefit for SSRIs for PTSD symptoms, compared with placebo. These studies primarily involved men, many of whom were veterans, Dr. Mellman noted.

Other agents with mixed or limited evidence to support their use in PTSD include atypical antipsychotics, benzodiazepines, MAO inhibitors, tricyclics, and anticonvulsant mood stabilizers, Dr. Mellman said.

Seven small randomized controlled trials have looked at atypicals, primarily risperidone and olanzapine, and primarily in treatment-refractory patients.

"Overall, the evidence does support adjunctive risperidone for refractory cases, and there does seem to be a benefit to sleep for the atypical class," he said.

Regarding benzodiazepines, there appears to be a lack of evidence to support either their efficacy or inefficacy, he added.

"We don’t recommend benzodiazepines as treatment for people with PTSD, but does that mean people with PTSD shouldn’t be exposed to them? I’m not sure. They do calm a person down temporarily, but [we should be] wary of continuous, chronic application," he said.

Prazosin Proves Powerful

Prazosin, originally developed as an antihypertensive agent, has been shown to have efficacy at reducing insomnia and nightmare in veterans with PTSD.

A study of 34 veterans with chronic PTSD and trauma nightmares showed that prazosin "shifted dream characteristics from those typical of trauma-related nightmares to those typical of normal dreams" (Biol. Psychiatry 2007;61:928-34).

"Prazosin also appeals to me from a theoretical standpoint because it preserves REM sleep, in contrast to many pharmacological agents that have the effect of reducing REM sleep, and there’s a particularly interesting animal model that shows that [prazosin] preserves REM sleep against the disruption of an adrenergic agonist, and this may be a model that’s relevant to PTSD," Dr. Mellman said.

Dr. Keane and Dr. Mellman presented their findings at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital, both in Boston. Neither Dr. Keane nor Dr. Mellman had relevant financial disclosures.

BOSTON – Exposure to trauma is ephemeral, but its effects in the form of posttraumatic stress disorder can linger for decades. However, a handful of psychosocial therapies and at least one class of drugs can be effective at reducing the invisible scars of PTSD, investigators reported at a conference on the complexities and challenges of PTSD and traumatic brain injury.

Interventions such as exposure therapy, cognitive processing therapy, and eye movement desensitization and reprocessing can help PTSD sufferers direct their thoughts away from traumatic events, often with durable results, said Terence M. Keane, Ph.D., director of the behavioral science division of the National Center for Posttraumatic Stress Disorder, Boston.

In addition, "emerging, exciting evidence" supports the use of the alpha-adrenergic antagonist prazosin for alleviating nightmares and sleep disruptions associated with the disorder, said Dr. Thomas A. Mellman, research associate dean and professor of psychiatry at Howard University, Washington.

Impact of Trauma Exposure

In an era of multiple military deployments and widespread regional conflicts, levels of PTSD and comorbid conditions are increasingly common, noted Dr. Keane, who also is with the department of psychiatry at Boston University.

Courtesy of Tom Allen

"If there is one powerful determinant of who develops PTSD, it is exposure to trauma experiences," he said. "It overrides all of the other risk factors. It outranks everything else, including childhood upbringing."

Many of the scales that are used to assess PTSD and combat exposure were developed after the Vietnam War. The Combat Exposure Scale, published by Dr. Keane and his colleagues in 1989, is a 7-item questionnaire gauging PTSD risk by factors such as the degree of exposure to firefights, the number of casualties in the soldier’s unit, and frequency of exposure to life-threatening situations (Psychol. Assess. 1989;1:53-5).

The scale’s upper limit of the numbers of exposures to firefights is "51 or more." In contrast, U.S. soldiers were exposed to about 400 firefights during a 15-month deployment in the Korengal Valley in Afghanistan, said Dr. Keane, citing Sebastian Junger, an American journalist who was intermittently embedded with a platoon of the 173rd Airborne Brigade in 2007-2008.

"The most upsetting thing ... was the loss of their friends," Mr. Junger wrote. "They felt responsible for their deaths, convinced there was something they could have done to prevent them and a sense of guilt that they should have been killed instead."

Psychosocial Interventions

There are five evidence-based psychosocial interventions for PTSD: exposure therapy, cognitive therapy, anxiety management, cognitive reprocessing therapy, and eye movement desensitization and reprocessing (EMDR).

"It’s very clear that participating in these treatments if you have a diagnosis of PTSD actually leads to remarkable improvement not only in symptoms, but also in life functioning," Dr. Keane said.

Cognitive-behavioral treatments for chronic PTSD approach the problem from two different angles. One approach allows patients to safely confront their traumatic experience through exposure discussions that recall trauma reminders; the other is aimed at modifying the dysfunctional thought processes that underlie PTSD.

One example of the former approach is exposure therapy, in which patients confront the objects, situations, memories, and images they fear in a systematic and repetitive fashion. After an initial relaxation training session, patients relive their experiences through imagined exposures to the traumatic memory, and, when possible, with real-life exposure to the traumatic event (for example, a visit to a car accident site).

"This is a very powerful treatment that effectively reduces symptoms of PTSD and improves psychosocial functioning in virtually every domain that we have tested," Dr. Keane said.

An alternative approach is cognitive therapy, in which patients are helped to change their negative, unrealistic thinking by identifying their dysfunctional, unrealistic thoughts and beliefs ("I’m responsible for it," "It was what I was wearing," "I should never have been there"), and challenge those distortions, helping the patient to replace them with functional, realistic alternatives.

Cognitive processing therapy (CPT) combines elements of the exposure and cognitive therapy approaches. It involves cognitive restructuring focusing on safety, trust, power, esteem, and intimacy. The patient repeatedly writes out the traumatic experience and reads it in 12 weekly sessions.

EMDR has been shown in controlled studies to help patients with PTSD, with an effect comparable to that of exposure therapy in many instances, Dr. Keane said. As in the latter treatment, EMDR accesses trauma images and memories, and helps patients to evaluate the aversive qualities of those images and memories, and to generate alternative cognitive appraisals. The recall is accompanied by sets of lateral eye movements that the patient makes while focusing on her/his response.

"There has been a lot of discussions on the eye movements – are they necessary, are they not necessary – [and] it looks like the best data suggest that they’re not necessary," Dr. Keane said.

Pharmacologic Interventions

When it comes to drug therapies for PTSD, many have been tried and most have been found wanting, Dr. Mellman said.

Pharmacotherapy for PTSD is based on neurobiological models of PTSD involving memory and neural structure. These models link PTSD to reactivity or selective attention to trauma stimuli, fragmentary trauma narratives, verbal memory deficits, reduced hippocampal volume, and increased amgydala activation with reduced anterior cingulate activation, he said.

Proposed hormonal and neurotransmitter-related mechanisms include reduced cortisol secretion and increased sensitivity to feedback inhibition, an effect of noradrenergic activity on fear-enhanced learning, and the role of the excitatory amino acid glutamate in neuroexcitation, learning and neurotoxicity, and GABA (gamma-aminobutyric acid) in inhibition.

Some evidence supports the use of selective serotonin reuptake inhibitors (SSRIs), which have been shown in nine randomized controlled trials in primarily female civilian populations to have positive effects on the three PTSD symptom clusters (reexperiencing, avoidance, and hyperarousal). Response rates in these studies have ranged from 53% to 64% (compared with 32% to 38% for placebo), with the effects occurring both with and without comorbid depression. In one study, maintenance efficacy of up to 1 year was seen with patients on sertraline.

However, six other published randomized controlled trials failed to find a benefit for SSRIs for PTSD symptoms, compared with placebo. These studies primarily involved men, many of whom were veterans, Dr. Mellman noted.

Other agents with mixed or limited evidence to support their use in PTSD include atypical antipsychotics, benzodiazepines, MAO inhibitors, tricyclics, and anticonvulsant mood stabilizers, Dr. Mellman said.

Seven small randomized controlled trials have looked at atypicals, primarily risperidone and olanzapine, and primarily in treatment-refractory patients.

"Overall, the evidence does support adjunctive risperidone for refractory cases, and there does seem to be a benefit to sleep for the atypical class," he said.

Regarding benzodiazepines, there appears to be a lack of evidence to support either their efficacy or inefficacy, he added.

"We don’t recommend benzodiazepines as treatment for people with PTSD, but does that mean people with PTSD shouldn’t be exposed to them? I’m not sure. They do calm a person down temporarily, but [we should be] wary of continuous, chronic application," he said.

Prazosin Proves Powerful

Prazosin, originally developed as an antihypertensive agent, has been shown to have efficacy at reducing insomnia and nightmare in veterans with PTSD.

A study of 34 veterans with chronic PTSD and trauma nightmares showed that prazosin "shifted dream characteristics from those typical of trauma-related nightmares to those typical of normal dreams" (Biol. Psychiatry 2007;61:928-34).

"Prazosin also appeals to me from a theoretical standpoint because it preserves REM sleep, in contrast to many pharmacological agents that have the effect of reducing REM sleep, and there’s a particularly interesting animal model that shows that [prazosin] preserves REM sleep against the disruption of an adrenergic agonist, and this may be a model that’s relevant to PTSD," Dr. Mellman said.

Dr. Keane and Dr. Mellman presented their findings at a symposium supported by the Home Base Program, a joint project of the Red Sox Foundation and Massachusetts General Hospital, both in Boston. Neither Dr. Keane nor Dr. Mellman had relevant financial disclosures.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – That lenalidomide can improve overall and progression-free survival rates in multiple myeloma patients is evident, but whether the drug also increases their risk of second primary cancers is debatable.

Of three studies looking at the question, only one found an association between secondary primary malignancies and lenalidomide (Revlimid) in first-line therapy, investigators reported at the American Society of Clinical Oncology annual meeting.

And even then the risk was low – far less than the risk of death from multiple myeloma without a lenalidomide-containing regimen, said Dr. Antonio P. Palumbo of the University of Torino (Italy) and the Italian Multiple Myeloma Study Group.

Two other studies – one with 6-year follow-up data on continuous lenalidomide in first-line therapy and the other on lenalidomide in relapsed/refractory disease – failed to spot a signal for second cancer risk.

"I think it’s fair to say that currently we lack clear answers due to small numbers and study limitations," said Dr. C. Ola Landgren of the National Cancer Institute, the invited discussant for all three papers.

"I think we need to put both benefits and risks into the algorithms when we think about these things. ... I also think despite the fact that we don’t have clear data, we always have to discuss these things with our patients, and we as doctors have to stay updated as more information emerges," he said.

Three randomized clinical trials stirred the debate by reporting in separate presentations at the 2010 annual meeting of the American Society of Hematology that they saw more hematologic malignancies in lenalidomide treatment arms than in control groups (McCarthy, P.L. et al, abstract 37; Attal, M. et al, abstract 310; Palumbo, A. et al, abstract 622).

Despite these reports, 25 years after a multiple myeloma diagnosis, the cumulative incidence of all second cancers is about 8%, whereas the cumulative probability of death from competing causes is more than 90%, suggesting that any risk of a second malignancy is far outweighed by the risk of multiple myeloma and its sequelae, Dr. Landgren pointed out.

First-Line Therapy: Italian Experience

In the first of the three studies presented at ASCO 2011, Dr. Palumbo’s group looked at second-cancer rates among patients randomly assigned to first-line therapy with either melphalan and prednisone alone, or to melphalan, prednisone, and lenalidomide with or without lenalidomide maintenance in the international MM-015 trial.

They found that at a median follow-up of 30 months, 12 of 150 (8%) patients on melphalan-prednisone plus lenalidomide with maintenance (MPR-R) developed an invasive second primary malignancy, compared with 9 of 152 patients (5.9%) on the same combination without lenalidomide maintenance (MPR), and 4 of 153 (2.6%) patients on melphalan and prednisone only.

Hematologic malignancies accounted for 7 of the 12 new cancers among patients treated with MPR-R, 5 of 9 on MPR, and 1 of 4 on MP. Solid tumors accounted for the remaining invasive cancers in each group. In addition, one patient on MPR-R, four on MPR, and five on MP developed nonmelanoma skin cancers.

In an additional analysis of 9 pooled experimental studies, the investigators found that among 1,788 patients followed for more than 1 year, the risk of dying of myeloma was greater than 40% out to 7 years compared with about a 2% risk of developing a second hematologic malignancy, and a 3% risk of developing a solid tumor.

Among patients receiving lenalidomide and an alkylating agent, the risk of developing any malignancy was around 7%, and the risk of dying of myeloma was about 27%. The risk of a second malignancy was lower – about 2% out to 6 years– among those patients who did not receive lenalidomide, but their risk of dying of myeloma was about 45%, Dr. Palumbo said.

He also pointed out that in the general population, the risk of a second primary malignancy among 65- to 74-year-olds is around 2% per 100 patient-years, and that the risk doubles among people 85 and older.

First-Line Therapy: BiRD Regimen

In the second study, Dr. Adriana Rossi and her colleagues at Cornell University, New York, and New York–Presbyterian Hospital examined the incidence of second primary cancers in 68 transplant-eligible patients receiving lenalidomide in first-line therapy as part of the BiRD regimen (clarithromycin [Biaxin], lenalidomide, and dexamethasone).

There were five solid tumors (two colon, one metastatic melanoma, one pancreas, and one prostate), but no hematologic malignancies. The melanoma was diagnosed 8 months after the primary myeloma diagnosis; the other cases occurred 25-53 months after the initial myeloma diagnosis (median, 31.2 months). The authors found no association between second primary cancers and a specific multiple myeloma chromosomal abnormality, prior malignancy, transplant status, study status, or sex.

The incidence rate of second primary malignancy was similar to that of all primary cancers reported among people 65 and older in the U.S. Surveillance, Epidemiology, and End Results (SEER) data set spanning 2003-2007, they noted.

"Routine screening and prevention measures should continue as medically indicated for all patients, including examination for skin cancers, and as survival in patients with multiple myeloma continues to improve, so will our understanding of their risk of development of second primary malignancies," she said.

Relapsed/Refractory Disease

The third trial looked at the risk of new primary cancers in patients receiving lenalidomide and dexamethasone for relapsed/refractory disease.

Dr. Meletios Dimopoulos of the University of Athens and colleagues in the international MM-009/010 trials performed a pooled analysis comparing the incidence of second primary cancers in 704 patients who received dexamethasone with either lenalidomide or placebo, and compared them with standard incidence rates.

They found that there were no differences in incidence rates of invasive second primary malignancies between patients in the lenalidomide plus dexamethasone arm or dexamethasone-only arms, and that the incidence rates of second primary cancers in general were low and similar to the background rate among people of similar age in the general population.

Additionally, patients who received lenalidomide and dexamethasone had significantly better overall survival (median, 38 months) despite the fact that about half of all patients in the placebo/dexamathesaone arm (median, 31.6 months) were crossed over to lenalidomide-based therapy (P = .045).

"The overall benefit-risk ratio of the use of lenalidomide in the relapsed/refractory setting remains strongly positive," said the presenter of the abstract, Dr. Ruben Niesvizky of Cornell University.

Lenalidomide is not approved as first-line therapy in the United States. Dr. Palumbo’s study was supported by the Fondazione Neoplasie Sangue Onlus. Dr. Rossi’s and Dr. Dimopoulos’s studies were funded by Celgene. Dr. Palumbo has received honoraria and served as a consultant to Celgene and other companies. Dr. Rossi said she had no relevant financial relationships to disclose. Dr. Dimopoulos disclosed receiving honoraria from Celgene. Dr. Niesvizky said he had received honoraria and research funding from Celgene; he also served in a consulting/advisory role for Celgene and other companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.

CHICAGO – Patients with high-risk, diffuse, aggressive non-Hodgkin’s lymphoma fared better when they received an autologous stem cell transplant during their first remission after chemotherapy than did similar patients who received standard chemotherapy alone, investigators reported at the annual meeting of the American Society of Clinical Oncology.

The estimated 2-year progression-free survival rate reached 69% among patients who were randomized to receive the CHOP regimen with or without rituximab for six cycles, followed by an autologous stem cell transplant (ASCT). In comparison, only 56% of patients who received eight cycles of CHOP with or without rituximab but no transplant were deemed progression free at that point (hazard ratio, 1.72; P = .0005).

The difference in progression-free survival has not yet led to a survival advantage, however, because patients who relapsed in the chemotherapy-only arm went on to transplant and have had generally good outcomes, Dr. Patrick J. Stiff of Loyola University Hospital, Maywood, Ill., reported on behalf of colleagues in the U.S./Canadian Intergroup trial SWOG S9704.

The 2-year estimated overall survival rate was 74% in transplanted patients and 71% in those who received chemotherapy alone (P = .16).

High-dose chemotherapy with ASCT is the standard of care for relapsed, diffuse, intermediate- and high-grade non-Hodgkin’s lymphoma (NHL) that is sensitive to chemotherapy. Several prospective trials have tested various combinations of high-dose therapy and transplant in patients in first complete remission, but with mixed results, Dr. Stiff noted.

In the absence of a better curative approach, the SWOG (Southwest Oncology Group) – in conjunction with the ECOG (Eastern Cooperative Oncology Group), CALGB (Cancer and Leukemia Group B), and the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) – started a prospective, randomized, phase III trial comparing six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by ASCT vs. eight cycles of CHOP for patients with high-intermediate and high IPI (International Prognostic Index) scores for diffuse, aggressive NHL.

The protocol was amended in 2003 to incorporate rituximab for all CD20-positive B-cell lymphomas, following results of other phase III trials that showed a significant survival advantage when the monoclonal antibody was added.

"While incorporation of rituximab into induction regimens has improved the outcome of patients with diffuse aggressive lymphomas, those with high-risk disease still have only about a 50% long-term survival," Dr. Stiff said.

All patients in the study received CHOP or R-CHOP (CHOP plus rituximab) for five cycles, with those having partial remission or better going on to randomization, and those having a response worse than partial remission being assigned to a different therapy off protocol.

For the randomization, patients were assigned to receive either one additional cycle of CHOP or R-CHOP followed by autologous transplant, or three additional cycles of CHOP/R-CHOP.

Of 397 patients registered in the trial, 253 were eligible for the randomization; 128 were assigned to chemotherapy only, and 125 to chemotherapy plus ASCT.

Following randomization, there were two toxicity-related deaths in the CHOP/R-CHOP–only arm, one from cardiovascular causes and the other from infection. One patient in this arm received rituximab only.

In the transplant arm, nine patients did not undergo ASCT; six of these patients died from treatment-related toxicity, including lung toxicities in three patients, and hemorrhage, infection, and graft-versus-host disease in one patient each.

"The postrelapse data indicate that the difference between the progression-free and overall survival was largely attributable to those patients who received a salvage transplant on the standard [chemotherapy-only] arm," Dr. Stiff said.

Nearly half (62) of those in the chemotherapy-only arm relapsed after therapy; of these, 29 underwent salvage autotransplantation, and 11 were in a second complete remission. An additional seven of those who relapsed had a second complete remission following alternative therapies.

A comparison of the effect of disease histology (B-cell vs. T-cell lymphoma) on outcome found no difference between autotransplantation and standard therapy. Looking at B-cell lymphomas only, the authors also found no evidence that rituximab had a differential effect.

Dr. Julie Vose of the University of Nebraska Medical Center in Omaha, the invited discussant, said that further analysis of subsets of patients are needed because, statistically, there were not enough patients who received rituximab for an analysis by IPI risk category.

Other questions that need to be answered are whether a complete response is necessary (or if a partial response would be adequate) for a patient to go on to transplantation, and whether there may be differential benefits to therapy for patients with activated B-cell lymphoma vs. germinal center B-cell, she said.

The trial was sponsored by the SWOG in collaboration with the ECOG, CALGB, the NCIC, and the U.S. National Cancer Institute. Dr. Stiff had no relevant relationships to disclose. Some coauthors have received honoraria or research funding from or serve as consultants to various drug companies.