Editor's Note: Second in a two-part series

Lest anyone forget, it is essential to support workers having children for one reason—the continuation of the human species, says Rachel Lovins, MD, SFHM, who directs the hospitalist program at Waterbury Hospital in Waterbury, Conn. For HM program directors, that means following pregnancy labor laws. But it also should involve reasonably accommodating hospitalists who are balancing their new baby’s needs with the demands of their profession, says Dr. Lovins and other HM leaders.

"As there are more women in medicine, everybody needs to be more aware of this issue. We don’t want to make good talent feel uncomfortable with the process of taking maternity leave and reducing time," says Michelle Marks, DO, FAAP, SFHM, director of the Center for Pediatric Hospital Medicine at the Cleveland Clinic.

All HM program directors need to be aware of such federal laws as the Pregnancy Discrimination Act and the Family and Medical Leave Act (www.eeoc.gov/laws/types/pregnancy.cfm), as well as the corresponding laws of the state in which they work. Directors can contact their human resources (HR) department for assistance.

"Calling them upfront will save a lot of headaches later on," says Jasen Gundersen, MD, MBA, CPE, SFHM, chief medical officer of the hospital medicine division in Fort Lauderdale, Fla., for Knoxville, Tenn.-based TeamHealth.

Here are some other recommendations on how HM directors can best manage pregnancy issues affecting their team:

The "R" in Relationship

There are many reasons why the director of a hospitalist group should develop a good relationship with the providers in their group, but one of them is that a hospitalist is more likely to tell her director sooner rather than later that she is pregnant, Dr. Marks says.

"Knowing your staff well and knowing them personally helps a lot, too, because you can gauge where they are going personally, as far as marriage, children, that type of thing," she adds.

The earlier a group leader knows a staff member is pregnant, the more time they have to plan for maternity leave. And the better the plan, the easier the leave is on the entire group, says Dr. Gundersen.

Generally, finding out that a physician is pregnant within three to five months of conception provides enough time to make adequate arrangements for coverage, Drs. Marks and Lovins note.

Dr. Weiner

The Conversation

Before scheduling a meeting to discuss maternity leave and plans for returning to work with the hospitalist, the group leader should call HR to see if such a conversation is permissible, says Dr. Marks. A better approach might be to wait until the hospitalist broaches the subject.

"So many times the hospitalist will ask for counseling as far as what are her options of coming back," Dr. Marks says. "That opens the door for an open discussion."

Once the conversation starts, the group leader should gauge the length of maternity leave, her plans for coming back full time or part time, and the anticipated scheduling limitations or childcare considerations, Dr. Gundersen says.

"That’s not to say the pregnant woman can really predict all the time what’s going to happen," says Kerry Weiner, MD, MPH, chief clinical officer for North Hollywood, Calif.-based IPC: The Hospitalist Company, Inc. "Obviously, it’s a medical condition that can change and everyone understands that. It’s getting a feel of what you can actually know at the time."

If it’s the HM director’s intent to call the physician while she is on leave to see how she and the baby are doing and how the maternity leave is going, that should be discussed during the conversation, Dr. Gundersen says.

"If you establish upfront that you are going to make that phone call, I think that’s fine to do," he explains. "If you’re calling constantly and pressuring the person, I don’t think that that’s kosher at all."

The best thing in the world is to have colleagues that you trust and can rely on. That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of.

—Rachel Lovins, MD, SFHM, director, hospitalist program, Waterbury (Conn.) Hospital

The Coverage Plan

Most maternity leaves are from eight to 12 weeks, although the length varies by HM program and individual. It is essential to have your group’s coverage plan outlined well in advance of the maternity leave.

In a private-practice model in which hospitalists work weekdays and have a call-coverage schedule for nights and weekends, a group leader can spread the extra work among the other hospitalists in the group because there are more hospitalists working during the day when patient census is higher, Dr. Weiner says.

Shifting the workload in other schedule models isn’t always as easy. "In the seven-day-on, seven-day-off model, because of that maximum patient-to-doctor ratio, I don’t think there’s any way to do it without hiring help," Dr. Lovins says. "It’s important to recruit per diems all the time. When you’re in a bind is the worst time to do it."

To limit the disruption to patient care and operations quality, the goal when using outside hospitalists is to contract with physicians who have worked with the group before and who know the community, hospital, systems, and patients, Dr. Weiner says.

For HM groups that use a flexible schedule, maternity coverage plans aren’t really needed, says Reuben Tovar, MD, chairman of Hospital Internists of Austin, a physician-owned and -managed hospitalist practice in Texas.

"We’re not salary, so that changes the dynamic completely. People who work more make more, and people who work less make less," he explains. "We are much more liberal about time off, because if a person is taking off to do what is important to them, like taking care of a child, then the rest of us feel better about doing extra work."

Things Change

Plans discussed at the outset with a pregnant hospitalist can change after the child is born, HM group directors caution.

"Particularly for the first child, people say, ‘I’ll come back full blast. Don’t worry about it.’ And they figure out how hard all that is in the first couple of weeks, and then I get a different answer," Dr. Tovar says. "I think the whole mom/wife/doctor thing is tough. I recognize how hard that is. Even though I am not in that role, I can see it."

Dr. Gundersen suggests group directors have a backup plan, in case the maternity leave lasts longer than expected or the transition back to work is delayed. "It really prevents you from putting pressure on the physician," he says.

If a hospitalist who had planned to come back full time decides that she wants to work less, a director should check with HR to see what the process would entail.

"Generally, we have to negotiate a time frame for when they can drop down" to part-time hours, Dr. Marks says. "It usually takes three to four months for me to be able to adjust staffing to make it work."

Back to Work

Physicians can return from maternity leave in a reduced role, but they very rarely drop out of medicine entirely, Dr. Marks says.

"[They] have put in a lot of time to get where they are," she says. "Plus, women in medicine are usually high achievers and very interested in their careers."

Yet hospitalist leaders should recognize that returning to work after having a baby is stressful. It will take some time for the returning hospitalist to develop a rhythm between her duties as a mother and a doctor.

Directors can review the hospitalist’s nonclinical roles, help with priorities, and perhaps reassign some of the responsibilities to colleagues, Dr. Marks says. With more women breastfeeding, it is important to provide a convenient space with a door that locks for women to breast-pump at work, she and the other directors say.

"The best thing in the world is to have colleagues that you trust and can rely on," Dr. Lovins says. "That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of."

Lisa Ryan is a freelance writer based in New Jersey.

Editor's Note: Second in a two-part series

Lest anyone forget, it is essential to support workers having children for one reason—the continuation of the human species, says Rachel Lovins, MD, SFHM, who directs the hospitalist program at Waterbury Hospital in Waterbury, Conn. For HM program directors, that means following pregnancy labor laws. But it also should involve reasonably accommodating hospitalists who are balancing their new baby’s needs with the demands of their profession, says Dr. Lovins and other HM leaders.

"As there are more women in medicine, everybody needs to be more aware of this issue. We don’t want to make good talent feel uncomfortable with the process of taking maternity leave and reducing time," says Michelle Marks, DO, FAAP, SFHM, director of the Center for Pediatric Hospital Medicine at the Cleveland Clinic.

All HM program directors need to be aware of such federal laws as the Pregnancy Discrimination Act and the Family and Medical Leave Act (www.eeoc.gov/laws/types/pregnancy.cfm), as well as the corresponding laws of the state in which they work. Directors can contact their human resources (HR) department for assistance.

"Calling them upfront will save a lot of headaches later on," says Jasen Gundersen, MD, MBA, CPE, SFHM, chief medical officer of the hospital medicine division in Fort Lauderdale, Fla., for Knoxville, Tenn.-based TeamHealth.

Here are some other recommendations on how HM directors can best manage pregnancy issues affecting their team:

The "R" in Relationship

There are many reasons why the director of a hospitalist group should develop a good relationship with the providers in their group, but one of them is that a hospitalist is more likely to tell her director sooner rather than later that she is pregnant, Dr. Marks says.

"Knowing your staff well and knowing them personally helps a lot, too, because you can gauge where they are going personally, as far as marriage, children, that type of thing," she adds.

The earlier a group leader knows a staff member is pregnant, the more time they have to plan for maternity leave. And the better the plan, the easier the leave is on the entire group, says Dr. Gundersen.

Generally, finding out that a physician is pregnant within three to five months of conception provides enough time to make adequate arrangements for coverage, Drs. Marks and Lovins note.

Dr. Weiner

The Conversation

Before scheduling a meeting to discuss maternity leave and plans for returning to work with the hospitalist, the group leader should call HR to see if such a conversation is permissible, says Dr. Marks. A better approach might be to wait until the hospitalist broaches the subject.

"So many times the hospitalist will ask for counseling as far as what are her options of coming back," Dr. Marks says. "That opens the door for an open discussion."

Once the conversation starts, the group leader should gauge the length of maternity leave, her plans for coming back full time or part time, and the anticipated scheduling limitations or childcare considerations, Dr. Gundersen says.

"That’s not to say the pregnant woman can really predict all the time what’s going to happen," says Kerry Weiner, MD, MPH, chief clinical officer for North Hollywood, Calif.-based IPC: The Hospitalist Company, Inc. "Obviously, it’s a medical condition that can change and everyone understands that. It’s getting a feel of what you can actually know at the time."

If it’s the HM director’s intent to call the physician while she is on leave to see how she and the baby are doing and how the maternity leave is going, that should be discussed during the conversation, Dr. Gundersen says.

"If you establish upfront that you are going to make that phone call, I think that’s fine to do," he explains. "If you’re calling constantly and pressuring the person, I don’t think that that’s kosher at all."

The best thing in the world is to have colleagues that you trust and can rely on. That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of.

—Rachel Lovins, MD, SFHM, director, hospitalist program, Waterbury (Conn.) Hospital

The Coverage Plan

Most maternity leaves are from eight to 12 weeks, although the length varies by HM program and individual. It is essential to have your group’s coverage plan outlined well in advance of the maternity leave.

In a private-practice model in which hospitalists work weekdays and have a call-coverage schedule for nights and weekends, a group leader can spread the extra work among the other hospitalists in the group because there are more hospitalists working during the day when patient census is higher, Dr. Weiner says.

Shifting the workload in other schedule models isn’t always as easy. "In the seven-day-on, seven-day-off model, because of that maximum patient-to-doctor ratio, I don’t think there’s any way to do it without hiring help," Dr. Lovins says. "It’s important to recruit per diems all the time. When you’re in a bind is the worst time to do it."

To limit the disruption to patient care and operations quality, the goal when using outside hospitalists is to contract with physicians who have worked with the group before and who know the community, hospital, systems, and patients, Dr. Weiner says.

For HM groups that use a flexible schedule, maternity coverage plans aren’t really needed, says Reuben Tovar, MD, chairman of Hospital Internists of Austin, a physician-owned and -managed hospitalist practice in Texas.

"We’re not salary, so that changes the dynamic completely. People who work more make more, and people who work less make less," he explains. "We are much more liberal about time off, because if a person is taking off to do what is important to them, like taking care of a child, then the rest of us feel better about doing extra work."

Things Change

Plans discussed at the outset with a pregnant hospitalist can change after the child is born, HM group directors caution.

"Particularly for the first child, people say, ‘I’ll come back full blast. Don’t worry about it.’ And they figure out how hard all that is in the first couple of weeks, and then I get a different answer," Dr. Tovar says. "I think the whole mom/wife/doctor thing is tough. I recognize how hard that is. Even though I am not in that role, I can see it."

Dr. Gundersen suggests group directors have a backup plan, in case the maternity leave lasts longer than expected or the transition back to work is delayed. "It really prevents you from putting pressure on the physician," he says.

If a hospitalist who had planned to come back full time decides that she wants to work less, a director should check with HR to see what the process would entail.

"Generally, we have to negotiate a time frame for when they can drop down" to part-time hours, Dr. Marks says. "It usually takes three to four months for me to be able to adjust staffing to make it work."

Back to Work

Physicians can return from maternity leave in a reduced role, but they very rarely drop out of medicine entirely, Dr. Marks says.

"[They] have put in a lot of time to get where they are," she says. "Plus, women in medicine are usually high achievers and very interested in their careers."

Yet hospitalist leaders should recognize that returning to work after having a baby is stressful. It will take some time for the returning hospitalist to develop a rhythm between her duties as a mother and a doctor.

Directors can review the hospitalist’s nonclinical roles, help with priorities, and perhaps reassign some of the responsibilities to colleagues, Dr. Marks says. With more women breastfeeding, it is important to provide a convenient space with a door that locks for women to breast-pump at work, she and the other directors say.

"The best thing in the world is to have colleagues that you trust and can rely on," Dr. Lovins says. "That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of."

Lisa Ryan is a freelance writer based in New Jersey.

Editor's Note: Second in a two-part series

Lest anyone forget, it is essential to support workers having children for one reason—the continuation of the human species, says Rachel Lovins, MD, SFHM, who directs the hospitalist program at Waterbury Hospital in Waterbury, Conn. For HM program directors, that means following pregnancy labor laws. But it also should involve reasonably accommodating hospitalists who are balancing their new baby’s needs with the demands of their profession, says Dr. Lovins and other HM leaders.

"As there are more women in medicine, everybody needs to be more aware of this issue. We don’t want to make good talent feel uncomfortable with the process of taking maternity leave and reducing time," says Michelle Marks, DO, FAAP, SFHM, director of the Center for Pediatric Hospital Medicine at the Cleveland Clinic.

All HM program directors need to be aware of such federal laws as the Pregnancy Discrimination Act and the Family and Medical Leave Act (www.eeoc.gov/laws/types/pregnancy.cfm), as well as the corresponding laws of the state in which they work. Directors can contact their human resources (HR) department for assistance.

"Calling them upfront will save a lot of headaches later on," says Jasen Gundersen, MD, MBA, CPE, SFHM, chief medical officer of the hospital medicine division in Fort Lauderdale, Fla., for Knoxville, Tenn.-based TeamHealth.

Here are some other recommendations on how HM directors can best manage pregnancy issues affecting their team:

The "R" in Relationship

There are many reasons why the director of a hospitalist group should develop a good relationship with the providers in their group, but one of them is that a hospitalist is more likely to tell her director sooner rather than later that she is pregnant, Dr. Marks says.

"Knowing your staff well and knowing them personally helps a lot, too, because you can gauge where they are going personally, as far as marriage, children, that type of thing," she adds.

The earlier a group leader knows a staff member is pregnant, the more time they have to plan for maternity leave. And the better the plan, the easier the leave is on the entire group, says Dr. Gundersen.

Generally, finding out that a physician is pregnant within three to five months of conception provides enough time to make adequate arrangements for coverage, Drs. Marks and Lovins note.

Dr. Weiner

The Conversation

Before scheduling a meeting to discuss maternity leave and plans for returning to work with the hospitalist, the group leader should call HR to see if such a conversation is permissible, says Dr. Marks. A better approach might be to wait until the hospitalist broaches the subject.

"So many times the hospitalist will ask for counseling as far as what are her options of coming back," Dr. Marks says. "That opens the door for an open discussion."

Once the conversation starts, the group leader should gauge the length of maternity leave, her plans for coming back full time or part time, and the anticipated scheduling limitations or childcare considerations, Dr. Gundersen says.

"That’s not to say the pregnant woman can really predict all the time what’s going to happen," says Kerry Weiner, MD, MPH, chief clinical officer for North Hollywood, Calif.-based IPC: The Hospitalist Company, Inc. "Obviously, it’s a medical condition that can change and everyone understands that. It’s getting a feel of what you can actually know at the time."

If it’s the HM director’s intent to call the physician while she is on leave to see how she and the baby are doing and how the maternity leave is going, that should be discussed during the conversation, Dr. Gundersen says.

"If you establish upfront that you are going to make that phone call, I think that’s fine to do," he explains. "If you’re calling constantly and pressuring the person, I don’t think that that’s kosher at all."

The best thing in the world is to have colleagues that you trust and can rely on. That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of.

—Rachel Lovins, MD, SFHM, director, hospitalist program, Waterbury (Conn.) Hospital

The Coverage Plan

Most maternity leaves are from eight to 12 weeks, although the length varies by HM program and individual. It is essential to have your group’s coverage plan outlined well in advance of the maternity leave.

In a private-practice model in which hospitalists work weekdays and have a call-coverage schedule for nights and weekends, a group leader can spread the extra work among the other hospitalists in the group because there are more hospitalists working during the day when patient census is higher, Dr. Weiner says.

Shifting the workload in other schedule models isn’t always as easy. "In the seven-day-on, seven-day-off model, because of that maximum patient-to-doctor ratio, I don’t think there’s any way to do it without hiring help," Dr. Lovins says. "It’s important to recruit per diems all the time. When you’re in a bind is the worst time to do it."

To limit the disruption to patient care and operations quality, the goal when using outside hospitalists is to contract with physicians who have worked with the group before and who know the community, hospital, systems, and patients, Dr. Weiner says.

For HM groups that use a flexible schedule, maternity coverage plans aren’t really needed, says Reuben Tovar, MD, chairman of Hospital Internists of Austin, a physician-owned and -managed hospitalist practice in Texas.

"We’re not salary, so that changes the dynamic completely. People who work more make more, and people who work less make less," he explains. "We are much more liberal about time off, because if a person is taking off to do what is important to them, like taking care of a child, then the rest of us feel better about doing extra work."

Things Change

Plans discussed at the outset with a pregnant hospitalist can change after the child is born, HM group directors caution.

"Particularly for the first child, people say, ‘I’ll come back full blast. Don’t worry about it.’ And they figure out how hard all that is in the first couple of weeks, and then I get a different answer," Dr. Tovar says. "I think the whole mom/wife/doctor thing is tough. I recognize how hard that is. Even though I am not in that role, I can see it."

Dr. Gundersen suggests group directors have a backup plan, in case the maternity leave lasts longer than expected or the transition back to work is delayed. "It really prevents you from putting pressure on the physician," he says.

If a hospitalist who had planned to come back full time decides that she wants to work less, a director should check with HR to see what the process would entail.

"Generally, we have to negotiate a time frame for when they can drop down" to part-time hours, Dr. Marks says. "It usually takes three to four months for me to be able to adjust staffing to make it work."

Back to Work

Physicians can return from maternity leave in a reduced role, but they very rarely drop out of medicine entirely, Dr. Marks says.

"[They] have put in a lot of time to get where they are," she says. "Plus, women in medicine are usually high achievers and very interested in their careers."

Yet hospitalist leaders should recognize that returning to work after having a baby is stressful. It will take some time for the returning hospitalist to develop a rhythm between her duties as a mother and a doctor.

Directors can review the hospitalist’s nonclinical roles, help with priorities, and perhaps reassign some of the responsibilities to colleagues, Dr. Marks says. With more women breastfeeding, it is important to provide a convenient space with a door that locks for women to breast-pump at work, she and the other directors say.

"The best thing in the world is to have colleagues that you trust and can rely on," Dr. Lovins says. "That way, people can help each other out in emergencies, like if someone has to take their kid to the doctor. That’s the kind of program I want to have and would want to be part of."

Lisa Ryan is a freelance writer based in New Jersey.

Background: The management of young febrile infants with UTIs is marked by uncertainty and variation. Although recent studies have demonstrated the safety and efficacy of oral antibiotics as primary treatment in infants younger than six months of age, younger infants tend to receive a longer duration of intravenous antibiotics. This might reflect a lack of clear delineation of the risk of adverse events and bacteremia in this population.

Study design: Retrospective chart review.

Setting: Twenty primarily tertiary-care EDs.

Synopsis: Infants aged 29 to 60 days with febrile UTIs were identified through laboratory and chart review at the participating centers. Bacteremia and adverse events (death, shock, bacterial meningitis, intensive care, surgical intervention, or other substantial clinical complications) were identified, as well as patients with a high-risk past medical history (PMH) or who were clinically ill on examination, based on a priori definitions of chart wording.

Adverse events occurred in 2.8% of the 1,895 patients; bacteremia occurred in 6.5%. Recursive partitioning analysis was used to identify a very-low-risk population for adverse events—those who were not clinically ill and without high-risk PMH (prediction model sensitivity 98% and negative predictive value 99.9%)—but it was not as successful in accurately identifying infants at very low risk for bacteremia.

Limitations of this study include the lack of a clear description of the adverse events identified (and their presumed relationship to the UTIs), the reliance on ED documentation, and conservative definitions of bacterial meningitis. Nonetheless, this is a study of significant magnitude in a population marked by uncertainty. Results of this study further strengthen data that support the feasibility of outpatient antibiotic therapy in well-appearing infants.

Bottom line: Well-appearing infants aged 29-60 days and without significant past medical history are at very low risk for adverse events.

Citation: Schnadower D, Kupperman N, Macias CG, et al. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126:1074-1083.

Background: The management of young febrile infants with UTIs is marked by uncertainty and variation. Although recent studies have demonstrated the safety and efficacy of oral antibiotics as primary treatment in infants younger than six months of age, younger infants tend to receive a longer duration of intravenous antibiotics. This might reflect a lack of clear delineation of the risk of adverse events and bacteremia in this population.

Study design: Retrospective chart review.

Setting: Twenty primarily tertiary-care EDs.

Synopsis: Infants aged 29 to 60 days with febrile UTIs were identified through laboratory and chart review at the participating centers. Bacteremia and adverse events (death, shock, bacterial meningitis, intensive care, surgical intervention, or other substantial clinical complications) were identified, as well as patients with a high-risk past medical history (PMH) or who were clinically ill on examination, based on a priori definitions of chart wording.

Adverse events occurred in 2.8% of the 1,895 patients; bacteremia occurred in 6.5%. Recursive partitioning analysis was used to identify a very-low-risk population for adverse events—those who were not clinically ill and without high-risk PMH (prediction model sensitivity 98% and negative predictive value 99.9%)—but it was not as successful in accurately identifying infants at very low risk for bacteremia.

Limitations of this study include the lack of a clear description of the adverse events identified (and their presumed relationship to the UTIs), the reliance on ED documentation, and conservative definitions of bacterial meningitis. Nonetheless, this is a study of significant magnitude in a population marked by uncertainty. Results of this study further strengthen data that support the feasibility of outpatient antibiotic therapy in well-appearing infants.

Bottom line: Well-appearing infants aged 29-60 days and without significant past medical history are at very low risk for adverse events.

Citation: Schnadower D, Kupperman N, Macias CG, et al. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126:1074-1083.

Background: The management of young febrile infants with UTIs is marked by uncertainty and variation. Although recent studies have demonstrated the safety and efficacy of oral antibiotics as primary treatment in infants younger than six months of age, younger infants tend to receive a longer duration of intravenous antibiotics. This might reflect a lack of clear delineation of the risk of adverse events and bacteremia in this population.

Study design: Retrospective chart review.

Setting: Twenty primarily tertiary-care EDs.

Synopsis: Infants aged 29 to 60 days with febrile UTIs were identified through laboratory and chart review at the participating centers. Bacteremia and adverse events (death, shock, bacterial meningitis, intensive care, surgical intervention, or other substantial clinical complications) were identified, as well as patients with a high-risk past medical history (PMH) or who were clinically ill on examination, based on a priori definitions of chart wording.

Adverse events occurred in 2.8% of the 1,895 patients; bacteremia occurred in 6.5%. Recursive partitioning analysis was used to identify a very-low-risk population for adverse events—those who were not clinically ill and without high-risk PMH (prediction model sensitivity 98% and negative predictive value 99.9%)—but it was not as successful in accurately identifying infants at very low risk for bacteremia.

Limitations of this study include the lack of a clear description of the adverse events identified (and their presumed relationship to the UTIs), the reliance on ED documentation, and conservative definitions of bacterial meningitis. Nonetheless, this is a study of significant magnitude in a population marked by uncertainty. Results of this study further strengthen data that support the feasibility of outpatient antibiotic therapy in well-appearing infants.

Bottom line: Well-appearing infants aged 29-60 days and without significant past medical history are at very low risk for adverse events.

Citation: Schnadower D, Kupperman N, Macias CG, et al. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126:1074-1083.

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CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

CASE Joe G, a 44-year-old man who has been your patient for years, comes to your office 48 hours after having a seizure. He has no history of seizures, had no warning signs or symptoms, and felt fine all day, but simply collapsed when the seizure occurred. He was transported to the emergency department (ED), and found to be postictal, with no further seizure activity. The ED work-up included a hemogram, comprehensive metabolic panel, and computed tomography brain scan, all of which were normal. An hour later, Joe had a normal neurological exam, then underwent electroencephalography (EEG) and magnetic resonance imaging (MRI) and was discharged home without medication.

How would you treat this patient?

About 10% of Americans will experience a seizure at some point in their lives,^1,2 and more than 3 million have epilepsy.³ The incidence ranges from 1% among 20-year-olds to more than 3% by the age of 75.^1,2

To adequately care for such patients—whether they have had multiple seizures or only one—you need to know whether they’re at risk for recurrences, when (or if) to prescribe an AED, and which agents provide optimal seizure control with the fewest adverse effects. You also need to know when a referral to an epilepsy specialist is indicated, when or whether it’s safe for patients to stop taking antiseizure medication, and how to address lifestyle issues that patients with epilepsy often need help with.

This review addresses these and other questions.

Is it epilepsy? How to respond to a single seizure

A seizure—a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neural activity in the brain—can be either focal (partial) or generalized. In addition, seizures can be broadly divided into 2 categories, based on etiology:

Provoked seizures are caused by an acute structural, toxic, or metabolic insult to the brain, and, presumably, would not have occurred if the underlying medical condition did not exist. Treating the cause—eg, alcohol withdrawal, hyponatremia, or hypoglycemia—should prevent a recurrence.

Unprovoked seizures have no apparent underlying cause. Epilepsy is defined as a chronic condition characterized by ≥2 unprovoked seizures at least 24 hours apart, and epilepsy syndromes are classified as localization-related or generalized (TABLE 1).^1,4,5

Generally, epileptologists do not recommend symptomatic treatment of a first unprovoked seizure⁶—a consensus based on several randomized controlled trials that found immediate treatment with an AED reduced the risk of a subsequent seizure in the short term, but did not affect long-term outcomes or the development of epilepsy.⁷

Treatment should begin after a single seizure, however, if the seizure was prolonged or there is an increased risk of recurrence.⁶ Factors that increase this risk include an abnormal EEG, particularly if the abnormality is epileptiform; the presence of a brain lesion; a localized (focal) seizure; and an abnormal neurologic exam.⁸ A history of status epilepticus—a single, unremitting seizure lasting ≥5 to 10 minutes or frequent seizures without a return to neurologic baseline in between—or complex febrile seizures, and a family history of epilepsy are risk factors for recurrence, as well.⁷

When the patient is a child. Prescribing an AED for a child after a first unprovoked seizure is not indicated to prevent the development of epilepsy, but may be considered, as for adults, in circumstances where the benefit of reducing the risk of a second seizure outweighs the risk of pharmacologic and psychosocial adverse effects.⁹

CASE Joe’s ED records show that his MRI was normal, but his EEG revealed an epileptogenic focus on the right temporal region—a finding that indicates that he has an elevated risk of recurrence and is a candidate for an AED. Before selecting a particular agent, you review his chart.

Joe is taking a thiazide diuretic and a calcium channel blocker for hypertension. He was a heavy drinker until he had an episode of pancreatitis 10 years ago, and has been abstinent ever since. About 5 years ago, he suffered from depression and was treated with sertraline, but the depression resolved and the drug was discontinued 3 years ago. The patient’s mother and brother have type 2 diabetes and his father had a myocardial infarction before the age of 60. Joe was laid off from his sales job 18 months ago and is actively seeking employment. At this point, you consider a broad-spectrum AED that would not interact with his current medications or adversely affect his medical conditions, and would be relatively inexpensive.

TABLE 1
Identifying seizures and types of epilepsy:^1,4,5 International League Against Epilepsy classification

What to consider in a first-line drug

The number of AEDs on the market has increased sharply in the past few years, giving physicians many medications to choose from. Selecting the optimal drug is particularly important for the initial treatment, as many patients remain on the first AED for years. Second-generation AEDs have been found to be as effective as, and better tolerated than, first-generation antiseizure drugs. But all AEDs carry a warning of a potential increase in suicide risk and the need to monitor patients for behavior changes.¹⁰

Before selecting an AED for a particular patient, consider the following questions:

What type of seizure? AEDs are generally classified by spectrum of activity into “narrow-spectrum” and “broad-spectrum.” Narrow-spectrum drugs are more effective for controlling partial seizures, but have the potential to exacerbate generalized seizures; broad-spectrum AEDs can be used for both. (TABLE 2^11-18 lists indications for first- and second-generation AEDs based on type of epilepsy.) If there’s no definitive diagnosis of the type of epilepsy a patient has, use a broad-spectrum drug.

What other drugs is the patient taking? If the AED will be added to the patient’s current medication regimen, look closely at potential pharmacodynamic drug-drug interactions, and consider whether a dosage adjustment is needed. Determine, too, whether the patient has any comorbidities that could affect his or her response to the AED.

Side effects, such as weight gain or loss, urolithiasis, and hepatic enzyme induction, are key considerations. (TABLE W1,^19-24 which details dose, side effects, and costs of first- and second-generation AEDs, can be found at jfponline.com.)

Is the patient elderly? AED clearance is reduced in the elderly, so lower doses are needed. Reduction in serum albumin increases the free or active component of highly protein-bound drugs, increasing the likelihood of adverse effects.

Is the patient female? Some AEDs may have effects on women’s hormonal function, sexuality, bone health, and pregnancy.²⁵ Hepatic enzyme inducers increase the clearance of oral contraceptives, reducing their efficacy. Vitamin D and calcium metabolism can also be affected, which can lead to osteomalacia. Valproate treatment in women is associated with higher levels of insulin, testosterone, and triglycerides.²⁶ Cytochrome P-450-activating AEDs in general are associated with higher testosterone levels and reduced libido.²⁷

Potential pregnancy is another consideration. Women with epilepsy are able to bear healthy children. What’s more, patients whose seizures are controlled with AEDs should be maintained on medication throughout pregnancy, as the risk of fetal harm from seizures generally outweighs the teratogenicity of the drug.²⁸

Although large studies are limited, a study of 1532 infants exposed to AEDs in the first trimester did not find an increase in major birth defects compared with infants without such exposure.²⁹ More recently, a large observational cohort study conducted in more than 40 countries found that the possibility of harm to a developing fetus is not only drug-specific but also dose-related.³⁰ (To learn more, see “Pregnancy and epilepsy—when you’re managing both,” in the December 2010 issue of The Journal of Family Practice.)

Is cost a factor? Finally, consider the cost of the AED you would like to prescribe, and whether the patient has a prescription drug plan or the means to pay for his prescription.

CASE After a discussion of potential side effects, including the potential for suicidal ideation associated with AEDs, you prescribe carbamazepine for Joe as seizure prophylaxis, because it is the least expensive of the broad-spectrum AEDs and is unlikely to exacerbate his previous pancreatitis or interact with his current medications.

TABLE 2
Choosing an AED: What to consider^11-18

TABLE W1
A closer look at antiepileptic drugs^19-24

When to add a second AED

Monotherapy is the preferred method of epilepsy treatment, and controls seizures for 70% to 90% of patients.^31,32 If seizures continue and potential adverse effects prevent you from increasing the dosage, switching to a different AED, then tapering off the first agent, is recommended.^33,34

If the new AED fails to provide adequate seizure control, consider combination therapy. An additional 10% to 15% of patients with epilepsy achieve control with dual therapy.^33,34

Many second-generation agents are approved for adjunctive therapy. However, the use of 2 AEDs increases the risk of toxicities and drug interactions, and requires complex dosage adjustments, which should be done slowly and cautiously. Combination therapy also increases costs and may cause a decrease in compliance.^33,34

Noncompliance is the single most common reason for treatment failure in patients with epilepsy, occurring at an estimated rate of up to 60%.^35,36 The complexity of the drug regimen is the major cause, regardless of patient age, sex, psychomotor development, seizure type, or seizure frequency.^35,36

Because of the lack of good clinical trials of combination antiepilepsy therapy, no evidence is available to indicate which AEDs are safe and effective when taken together. There is, however, evidence that certain combinations should be avoided due to the risk of increased adverse effects. These include phenobarbital/valproate, phenytoin/carbamazepine, and carbamazepine/lamotrigine.²⁵

Managing the patient who is seizure-free

After a patient has been seizure-free for 2 to 5 years, consider a reduction in, or a discontinuation of, his or her AED. The relapse rate varies from 10% to 70%, with meta-analyses showing a rate of 25% in the first year and 29% in the second year.^19,37 The American Academy of Neurology (AAN) has published an evidence-based guideline for discontinuing AEDs in seizure-free patients, available at www.aan.com/professionals/practice/pdfs/gl0007.pdf.

Withdrawal should be gradual and, for patients on combination therapy, carried out one drug at a time to prevent a recurrence of seizures or status epilepticus. The AAN recommends a 2- to- 3-month withdrawal period for AEDs (and longer for benzodiazepines), although relapse rates have been found to be lower when the medication is withdrawn more slowly, over about 6 months.^19,34 If seizures recur after withdrawal, restart the AEDs at previous dosages.^19,34,38

Should the patient drive?

For patients with epilepsy, loss of independence related to driving restrictions is a major source of stress. A 10-year follow-up study of Danish patients with epilepsy found a 7-fold increase in motor vehicle accidents (MVAs) in patients with seizure disorders.³⁹ Other studies have shown that the seizure-free interval is the best predictor of involvement in an MVA.⁴⁰

The risk of driving accidents decreases as the seizure-free interval increases. Unfortunately, however, a decline in patient compliance is also associated with longer seizure-free intervals—creating the potential for recurrence and driving risk. Because of this discrepancy, a consensus statement from the AAN, American Epilepsy Society, and Epilepsy Foundation of America recommends a minimum 3-month seizure-free interval before patients are allowed to drive.⁴¹

Use clinical judgment in deciding whether to extend the seizure-free period. State laws vary widely regarding the need to report patients with seizure disorders, limitations on professional drivers, and seizure-free intervals required, so it is important to be familiar with the laws in your state. The Epilepsy Foundation has a helpful online resource with a database detailing individual state statutes (http://www.epilepsyfoundation.org/living/wellness/transportation/driverlicensing.cfm).

The danger of uncontrolled seizures

Overall, AEDs effectively control 70% of 80% of cases; the remaining 20% to 30% are considered medically refractory.³⁸ What’s more, after 2 AED failures, a patient’s chances of achieving full seizure control with additional drugs are no better than 10% to 20%.⁴² And, as more drugs are tried, the likelihood of full control declines even further.⁴³

Patients with uncontrolled seizures have a cumulative risk of sudden unexpected death in epilepsy (SUDEP) of 0.5% per year.⁴⁴ Cognitive decline is associated with uncontrolled epilepsy, as well. In children, frequent seizures may significantly alter neuronal networks, affecting cognitive and motor development.

Is your patient a candidate for surgery?

Patients with disabling complex partial seizures that remain uncontrolled after 2 or more AED trials (either as monotherapy or in combination) should be referred to an epilepsy specialty center for evaluation for surgery.⁴⁵ This should be considered as early as possible to afford the patient the best chance of achieving seizure control.

Successful epilepsy surgery—in which the portion of the brain causing the misfiring that causes the seizures is removed—often results in a better quality of life; it is also cost effective.⁴⁶ Not everyone with refractory epilepsy is a candidate for surgery, of course. Among those who are, however, 50% to 70% of patients can expect to have improved seizure control.⁴⁷

Status epilepticus is a medical emergency

A patient who develops status epilepticus is at high risk and requires immediate, and simultaneous, evaluation and treatment. Status epilepticus carries nearly a 20% mortality from the first episode,⁴⁸ and the 10-year mortality rate after an episode of status epilepticus is as high as 40%.⁴⁹

Although most of the deaths associated with status epilepticus are due to the underlying pathology, early treatment can prevent or ameliorate complications from rhabdomyolysis and irreversible anoxic neuronal damage.⁵⁰

A benzodiazepine (typically, a 10-mg IV bolus of diazepam) is the initial treatment for status epilepticus, followed by or concurrent with fosphenytoin (15-18 mg/kg). If status epilepticus remains refractory to first-line drugs (lasting >30 minutes), intubation and transfer to an intensive care setting may be required, and a neurological consult should be obtained.

Pharmacologic treatment of status epilepticus falls into 3 main classes: benzodiazepines, standard AEDs, and general anesthetics such as propofol. Benzodiazepines act very rapidly to control most prolonged seizures, and are the first-line treatment choice. Diazepam has long been the mainstay of treatment, and is usually readily available. However, in both a large systematic review and a head-to-head trial, lorazepam was found to be superior to diazepam in ending seizure activity and maintaining seizure control without the use of other medications^51,52—and is now the drug of choice for initial treatment of status epilepticus.

CASE You continue to see Joe every 3 to 4 months to monitor his basic blood work and mood. A year after his seizure, he remains seizure-free and is tolerating the AED without any adverse effects.

CORRESPONDENCE
William J. Geiger, MD, FAAFP, Medical College of Wisconsin, Columbia St. Mary’s Family Medicine Residency, 1121 East North Avenue, Milwaukee, WI 53212; [email protected]

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.

Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.

Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.

And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.

Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.

The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.

Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.

More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.

AMSTERDAM – Wide adoption of stereotactic ablative radiation as radiotherapy for elderly patients with stage 1 non–small cell lung cancer in the Netherlands produced a dramatic rise in overall survival during the 2000s.

Dutch national data showed that median overall survival in patients aged 75 year or older with stage I NSCLC that was treated with radiation therapy jumped from 17 months in 2001-2003 to 26 months in 2007-2009 (P = .001), an improvement largely attributable to substantially increased use of sterotactic ablative radiation therapy (SABR), Dr. Cornelis J.A. Haasbeek said at the World Conference on Lung Cancer, which was sponsored by the International Association for the Study of Lung Cancer.

Dutch radiation oncologists began using SABR in 2003, and by 2009 more than 75% of early-stage NSCLC patients who received radiation therapy had it in the form of SABR.

"Our study provides high-level evidence to support the efficacy of modern SABR," said Dr. Haasbeek, a radiation oncologist at Vrije Universiteit Medische Centrum, Amsterdam.

SABR cut the number of treatments needed, compared with conventional radiation therapy, by 5- to 10-fold while also boosting efficacy, and it offers a better option for patients who are too old and frail to undergo surgical resection of their cancer. SABR is also a reasonable option for selected operable patients, said Dr. Suresh Senan, professor and vice-chairman of radiation oncology at Vrije Universiteit Amsterdam and senior investigator of the new report.

"The emerging data say that SABR is an option in patients who do not want to accept the risks of surgery, or for patients told by their surgeons that they have a significantly increased surgical risk. SABR is curative treatment for a frail group, producing excellent local control with very low toxicity," Dr. Senan said in an interview. "Elderly patients who could undergo open surgery should also be informed about SABR as an alternative curative, outpatient modality."

The main drawback of SABR compared with surgery is less-extensive long-term experience. "We have no track record of more than 5 years in a substantial number of patients, so there may still be surprises on recurrences," he said.

"What is important is that patients make a [treatment] decision, and are not told that they are too old for treatment. Surgery has the advantages of allowing for accurate tissue diagnosis and intraoperative staging, and in patients with emphysema, removal of the affected lung can improve lung function," commented Dr. David A. Waller, a thoracic surgeon at Glenfield Hospital in Leicester, England. "The risk [from surgery] is the general anesthesia, especially in patients with existing cardiovascular morbidity. It’s the patients with comorbidities who might do best with radiation therapy."

Speaking as a discussant of the Dutch report, Dr. Hak Choy said that the new findings and prior results make SABR a clear choice for elderly, inoperable patients, but existing data did not yet adequately support substituting SABR for surgery in operable patients. The definitive role for SABR in operable patients will grow clearer with results from two randomized studies now underway that compare SABR and surgery in high-risk operable patients, said Dr. Choy, a professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

To assess the impact that SABR had on stage I NSCLC in elderly patients in the Netherlands during the 2000s, Dr. Senan, Dr. Haasbeek, and their associates analyzed data from the Netherlands Cancer Registry. The registry had 4,605 patients aged 75 or older with stage I NSCLC during 2001-2009. This included 1,678 patients who were treated with surgery (37%), 1, 570 treated with radiotherapy (34%), and 1,337 treated by neither method (29%). During the 9 years reviewed, the percentage of patients undergoing radiotherapy increased from 31% of patients in 2001-2003 to 38% in 2007-2009. This paralleled a drop in untreated patients from 32% to 25%. Surgery use stayed flat over the period.

Median overall survival for all patients rose from 16 months in 2001-2003 to 24 months in 2007-2009 (P = .001), a change linked to survival increases in both radiation-treated patients and those who got surgery. Patients with surgical resections had a median overall survival of 36 months in 2001-2003, and median survival not yet occurred in patients with surgery in 2007-2009.

The better median survival in the surgery patients in part depends on the superior physical status of patients eligible for surgery. Other factors that may have boosted postsurgical survival include improved perioperative care, reduced numbers of higher-risk patients treated with surgery as radiation use increased, improved surgical techniques such as video assistance, and a trend toward more surgery being done in specialized centers, Dr. Haasbeek said.

Patients who had neither surgery nor radiation therapy had a similar, poor median survival of about 7 months during both periods.

Dr. Senan said that he has received honoraria as a speaker for Varian Medical Systems, and that his department received research support from Varian. Dr. Haasbeek said he had no disclosures. Dr. Waller had no disclosures.