Neil Osterweil

BOSTON – For some, the words “palliative care” evoke thoughts of pain- and anxiety-relieving therapies at the end of life, when all other treatments have failed. But in fact, palliative care is, or should, be an integral part of cancer therapies from the outset, say experts in the care of cancer survivors.

“From the beginning, at the time of diagnosis and staging, we need to be thinking about palliative care,” said Dr. Patricia A. Ganz, director of Cancer Prevention and Control Research and the Patients and Survivors Program Area at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

The ultimate aim of palliative care should be research and development of strategies to prevent the long-term and late effects of cancer treatment, she said at the Palliative Care in Oncology Symposium.

Long-term effects are symptoms or problems that begin during cancer treatment and persist when treatment ends, such as fatigue, cognitive complaints, or pain.

Late effects are those that may occur months or years after the end of therapy, such as second cancers, lymphedema, or congestive heart failure.

Dr. Ganz said that it is essential for oncologists to understand the biologic mechanisms of symptoms in order to provide validity and support for patient complaints, develop possible pharmacologic or behavioral solutions, and possibly prevent the development of symptoms in at risk patients. In addition, it is important to understand the potential relationships between symptoms, tumor biology, and disease progression.

Cancer-related fatigue

“Fatigue is an extremely common and distressing side effect of cancer and its treatment. We expect fatigue during treatment, anywhere from 60% to 90% of patients report moderate to severe symptoms of fatigue, and it can sometimes be a treatment-limiting side effect. But what many people are not prepared for, especially patients, is that it may continue after they have completed their primary treatment,” said Julienne E. Bower, Ph.D., of the departments of psychology and psychiatry/biobehavioral sciences at the University of California, Los Angeles.

“Perhaps because they feel like this is something that they are supposed to endure, because they have had this great and hopefully successful treatment for cancer, they often don’t talk about it with their clinicians and physicians, and fatigue is often undertreated. This may be in part because we don’t really understand the mechanisms underlying fatigue,” she said.

ASCO has developed and will soon publish evidence-based clinical practice guidelines for the screening, assessment, and management of cancer-related fatigue. The guidelines apply to patients who have completed therapy with curative intent, rather than patients currently in therapy.

Dr. Bower, who cochaired the guideline development committee, says the most important recommendation is that screening for fatigue should be a regular part of cancer follow-up. Patients with no or only mild fatigue, rated 0-3 on an analog scale, should continue to be monitored at subsequent follow-up visits. Patients with moderate to severe fatigue (4-10) should have a comprehensive fatigue assessment that includes a focused history of fatigue and evaluation of disease status, assessment for potential contributing factors such as medications or comorbidities such as depression, and, if warranted, laboratory evaluation.

The guidelines emphasize that all patients need counseling and education about fatigue, its persistence and prevalence, and general strategies for preventing or managing it, such as physical activity.

Patients with moderate to severe fatigue should be evaluated and treated for contributing factors. These patients may require more intensive treatments. Evidence from the literature supports recommendations for exercise, psychosocial therapies such as psychoeducation and cognitive behavioral therapy, and mind-body treatments such as yoga, acupuncture, and mindfulness, Dr. Bower said at the symposium cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

Inflammation fingered

“The problem here is that we don’t really know what causes fati­­gue, so we’re taking all these different approaches, nonspecific approaches, and I think we have been fortunate to have been having some positive effects. But obviously if we know what the mechanisms are and we know what the risk factors are, we’re going to be able to deliver much more targeted and effective interventions” she commented.

One area of particular interest is inflammation, which can be triggered when immune cells release proinflammatory cytokines (such as interleukins 1 and 6, and tumor necrosis factor–alpha) in response to cancer treatments, infection, and injury.

“These cytokines move their way up to the brain and they cause a variety of behavioral changes, including fatigue,” she said.

This hypothesis is supported by evidence that many patients who have posttreatment fatigue have elevated levels of inflammatory markers,” and we see this across the survivorship trajectory.”

Individual differences in inflammatory response and fatigue may be caused by differences in genetic variations in the expression of proinflammatory genes, setting the stage for inflammation and fatigue after cancer treatment, and suggesting the use of anti-inflammatory medication as potential treatments for fatigue, Dr. Bower explained.

BOSTON – For some, the words “palliative care” evoke thoughts of pain- and anxiety-relieving therapies at the end of life, when all other treatments have failed. But in fact, palliative care is, or should, be an integral part of cancer therapies from the outset, say experts in the care of cancer survivors.

“From the beginning, at the time of diagnosis and staging, we need to be thinking about palliative care,” said Dr. Patricia A. Ganz, director of Cancer Prevention and Control Research and the Patients and Survivors Program Area at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

The ultimate aim of palliative care should be research and development of strategies to prevent the long-term and late effects of cancer treatment, she said at the Palliative Care in Oncology Symposium.

Long-term effects are symptoms or problems that begin during cancer treatment and persist when treatment ends, such as fatigue, cognitive complaints, or pain.

Late effects are those that may occur months or years after the end of therapy, such as second cancers, lymphedema, or congestive heart failure.

Dr. Ganz said that it is essential for oncologists to understand the biologic mechanisms of symptoms in order to provide validity and support for patient complaints, develop possible pharmacologic or behavioral solutions, and possibly prevent the development of symptoms in at risk patients. In addition, it is important to understand the potential relationships between symptoms, tumor biology, and disease progression.

Cancer-related fatigue

“Fatigue is an extremely common and distressing side effect of cancer and its treatment. We expect fatigue during treatment, anywhere from 60% to 90% of patients report moderate to severe symptoms of fatigue, and it can sometimes be a treatment-limiting side effect. But what many people are not prepared for, especially patients, is that it may continue after they have completed their primary treatment,” said Julienne E. Bower, Ph.D., of the departments of psychology and psychiatry/biobehavioral sciences at the University of California, Los Angeles.

“Perhaps because they feel like this is something that they are supposed to endure, because they have had this great and hopefully successful treatment for cancer, they often don’t talk about it with their clinicians and physicians, and fatigue is often undertreated. This may be in part because we don’t really understand the mechanisms underlying fatigue,” she said.

ASCO has developed and will soon publish evidence-based clinical practice guidelines for the screening, assessment, and management of cancer-related fatigue. The guidelines apply to patients who have completed therapy with curative intent, rather than patients currently in therapy.

Dr. Bower, who cochaired the guideline development committee, says the most important recommendation is that screening for fatigue should be a regular part of cancer follow-up. Patients with no or only mild fatigue, rated 0-3 on an analog scale, should continue to be monitored at subsequent follow-up visits. Patients with moderate to severe fatigue (4-10) should have a comprehensive fatigue assessment that includes a focused history of fatigue and evaluation of disease status, assessment for potential contributing factors such as medications or comorbidities such as depression, and, if warranted, laboratory evaluation.

The guidelines emphasize that all patients need counseling and education about fatigue, its persistence and prevalence, and general strategies for preventing or managing it, such as physical activity.

Patients with moderate to severe fatigue should be evaluated and treated for contributing factors. These patients may require more intensive treatments. Evidence from the literature supports recommendations for exercise, psychosocial therapies such as psychoeducation and cognitive behavioral therapy, and mind-body treatments such as yoga, acupuncture, and mindfulness, Dr. Bower said at the symposium cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

Inflammation fingered

“The problem here is that we don’t really know what causes fati­­gue, so we’re taking all these different approaches, nonspecific approaches, and I think we have been fortunate to have been having some positive effects. But obviously if we know what the mechanisms are and we know what the risk factors are, we’re going to be able to deliver much more targeted and effective interventions” she commented.

One area of particular interest is inflammation, which can be triggered when immune cells release proinflammatory cytokines (such as interleukins 1 and 6, and tumor necrosis factor–alpha) in response to cancer treatments, infection, and injury.

“These cytokines move their way up to the brain and they cause a variety of behavioral changes, including fatigue,” she said.

This hypothesis is supported by evidence that many patients who have posttreatment fatigue have elevated levels of inflammatory markers,” and we see this across the survivorship trajectory.”

Individual differences in inflammatory response and fatigue may be caused by differences in genetic variations in the expression of proinflammatory genes, setting the stage for inflammation and fatigue after cancer treatment, and suggesting the use of anti-inflammatory medication as potential treatments for fatigue, Dr. Bower explained.

BOSTON – For some, the words “palliative care” evoke thoughts of pain- and anxiety-relieving therapies at the end of life, when all other treatments have failed. But in fact, palliative care is, or should, be an integral part of cancer therapies from the outset, say experts in the care of cancer survivors.

“From the beginning, at the time of diagnosis and staging, we need to be thinking about palliative care,” said Dr. Patricia A. Ganz, director of Cancer Prevention and Control Research and the Patients and Survivors Program Area at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

The ultimate aim of palliative care should be research and development of strategies to prevent the long-term and late effects of cancer treatment, she said at the Palliative Care in Oncology Symposium.

Long-term effects are symptoms or problems that begin during cancer treatment and persist when treatment ends, such as fatigue, cognitive complaints, or pain.

Late effects are those that may occur months or years after the end of therapy, such as second cancers, lymphedema, or congestive heart failure.

Dr. Ganz said that it is essential for oncologists to understand the biologic mechanisms of symptoms in order to provide validity and support for patient complaints, develop possible pharmacologic or behavioral solutions, and possibly prevent the development of symptoms in at risk patients. In addition, it is important to understand the potential relationships between symptoms, tumor biology, and disease progression.

Cancer-related fatigue

“Fatigue is an extremely common and distressing side effect of cancer and its treatment. We expect fatigue during treatment, anywhere from 60% to 90% of patients report moderate to severe symptoms of fatigue, and it can sometimes be a treatment-limiting side effect. But what many people are not prepared for, especially patients, is that it may continue after they have completed their primary treatment,” said Julienne E. Bower, Ph.D., of the departments of psychology and psychiatry/biobehavioral sciences at the University of California, Los Angeles.

“Perhaps because they feel like this is something that they are supposed to endure, because they have had this great and hopefully successful treatment for cancer, they often don’t talk about it with their clinicians and physicians, and fatigue is often undertreated. This may be in part because we don’t really understand the mechanisms underlying fatigue,” she said.

ASCO has developed and will soon publish evidence-based clinical practice guidelines for the screening, assessment, and management of cancer-related fatigue. The guidelines apply to patients who have completed therapy with curative intent, rather than patients currently in therapy.

Dr. Bower, who cochaired the guideline development committee, says the most important recommendation is that screening for fatigue should be a regular part of cancer follow-up. Patients with no or only mild fatigue, rated 0-3 on an analog scale, should continue to be monitored at subsequent follow-up visits. Patients with moderate to severe fatigue (4-10) should have a comprehensive fatigue assessment that includes a focused history of fatigue and evaluation of disease status, assessment for potential contributing factors such as medications or comorbidities such as depression, and, if warranted, laboratory evaluation.

The guidelines emphasize that all patients need counseling and education about fatigue, its persistence and prevalence, and general strategies for preventing or managing it, such as physical activity.

Patients with moderate to severe fatigue should be evaluated and treated for contributing factors. These patients may require more intensive treatments. Evidence from the literature supports recommendations for exercise, psychosocial therapies such as psychoeducation and cognitive behavioral therapy, and mind-body treatments such as yoga, acupuncture, and mindfulness, Dr. Bower said at the symposium cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

Inflammation fingered

“The problem here is that we don’t really know what causes fati­­gue, so we’re taking all these different approaches, nonspecific approaches, and I think we have been fortunate to have been having some positive effects. But obviously if we know what the mechanisms are and we know what the risk factors are, we’re going to be able to deliver much more targeted and effective interventions” she commented.

One area of particular interest is inflammation, which can be triggered when immune cells release proinflammatory cytokines (such as interleukins 1 and 6, and tumor necrosis factor–alpha) in response to cancer treatments, infection, and injury.

“These cytokines move their way up to the brain and they cause a variety of behavioral changes, including fatigue,” she said.

This hypothesis is supported by evidence that many patients who have posttreatment fatigue have elevated levels of inflammatory markers,” and we see this across the survivorship trajectory.”

Individual differences in inflammatory response and fatigue may be caused by differences in genetic variations in the expression of proinflammatory genes, setting the stage for inflammation and fatigue after cancer treatment, and suggesting the use of anti-inflammatory medication as potential treatments for fatigue, Dr. Bower explained.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – An automated system for monitoring the symptoms of patients in home hospice and supporting their caregivers with coaching can both improve patient comfort and relieve at least some of the stress on the caregiver, said investigators in a pilot program.

In a prospective, randomized controlled trial, caregivers assigned to symptom care by phone, in which they received automated coaching tailored to the specific situation, had better overall vitality, and the patients they cared for had less fatigue and anxiety than caregiver-patient pairs assigned to usual care, reported Dr. Kathi Mooney, professor of nursing at the University of Utah College of Nursing, Salt Lake City.

“The family inclusion in hospice care, the philosophy around that, offers the opportunity to extend PROs [patient-reported outcomes] to FCROs, family caregiver reported outcomes. We call that an opportunity to use electronic monitoring to monitor a family,” she said at the Palliative Care in Oncology Symposium.

Dr. Mooney and her colleagues have previously reported on the use of automated symptom monitoring for support of patients undergoing ambulatory chemotherapy. In the current study, she described its application in home-based end-of-life care to support both the patient and the caregiver.

The investigators recruited 319 cancer patient/caregiver dyads from 12 hospices in Illinois, Massachusetts, Oregon, and Utah. The mean age of the patients was 72 years, and the mean age of caregivers was 59 years.

The caregivers were randomly assigned either to the symptom care by phone (SCP) system or to usual care. The SCP system is an automated system in which caregivers phone in to report the patient’s symptoms and their own levels of stress, anxiety, etc., and receive automated responses based on the severity of symptoms and number of days reported without relief. The system offers both patient care and self-care strategies, and identifies and reinforces issues that should be addressed by contacting the hospice team. At the end of the call, the data are sent to the nurse, including alerts to matters that require prompt attention.

Caregivers in each group made daily automated monitoring calls to report 1 or more of 11 patient symptoms and 5 caregiver symptoms on a 0-10 scale, and to report the patient’s and their own distress about the symptoms.

“We have developed algorithms to provide just-in-time, tailored suggestions related to the pattern that they have reported,” Dr. Mooney said.

Data reported by caregivers in the control (usual care) group were recorded but not acted upon, whereas data reported by those in the SCP intervention group triggered the automated coaching and hospice nurse alerts for moderate to severe symptoms.

“People in the usual care group understood that they were just contributing symptom information, and they were told on every call and at consent that if they had any concerns to call their hospice nurse,” Dr. Mooney said.

For clinicians, the automated system triggers an alert at preset thresholds of severity (4-10), as well as trend alerts. Hospice nurses have online and mobile access to the alert website, where they can view a report of symptoms over the previous 24 hours, and review graphs of symptoms over time to see trends. The nurses were instructed to log that they had seen the alert and what their planned action was, which was left to their professional judgment.

The average length of the calls was 7 minutes, 4 seconds for the usual care group, and 7 minutes, 59 seconds for the intervention group. Control group caregivers completed 59% of expected calls, and those in the intervention group completed 64%.

Reported symptoms present in more than 50% of patients included fatigue (88.8%), pain (60.2%), eating/drinking problems (76.6%), difficulty thinking (69.6%), anxiety (67.6%), negative mood (67.3%), bowel problems (61%), and trouble sleeping (58.3%).

Among caregivers, 73.3% reported fatigue, 66.7% anxiety, 61% trouble sleeping, and 57.1% negative mood.

In a mixed-effects model looking at caregiver vitality – a composite of caregiver symptoms – the authors found that the severity of symptoms in the usual care group increased steadily over the course of hospice care, out to at least 91 days. In contrast, the severity of symptoms among caregivers in the SCP group rose only slightly. The between-group difference was significant (P < .001).

Similarly, among patients the overall symptom severity scores were lower for those in the intervention group than for controls (P =.03). Additionally, the onset of benefit, defined as time to the first symptom-free day, was significantly earlier among patients in the SCP group (P < .02)

Patterns of patient and fatigue during the last 8 weeks of life also favored the symptom-care intervention, Dr. Mooney noted.`

Invited discussant Dr. Michael H. Levy, vice chair of medical oncology and director of the pain and palliative care program at Fox Chase Cancer Center in Philadelphia, commented that the SCP system “is interesting, but it’s very expensive, the impact is limited, and it’s challenging to export.”

He noted that for a palliative care support system to be implemented successfully, it would need to be reproducible and applicable to a wide range of health care systems.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

The study was supported by the National Cancer Institute. Dr. Mooney and Dr. Levy reported having no relevant disclosures.

BOSTON – An automated system for monitoring the symptoms of patients in home hospice and supporting their caregivers with coaching can both improve patient comfort and relieve at least some of the stress on the caregiver, said investigators in a pilot program.

In a prospective, randomized controlled trial, caregivers assigned to symptom care by phone, in which they received automated coaching tailored to the specific situation, had better overall vitality, and the patients they cared for had less fatigue and anxiety than caregiver-patient pairs assigned to usual care, reported Dr. Kathi Mooney, professor of nursing at the University of Utah College of Nursing, Salt Lake City.

“The family inclusion in hospice care, the philosophy around that, offers the opportunity to extend PROs [patient-reported outcomes] to FCROs, family caregiver reported outcomes. We call that an opportunity to use electronic monitoring to monitor a family,” she said at the Palliative Care in Oncology Symposium.

Dr. Mooney and her colleagues have previously reported on the use of automated symptom monitoring for support of patients undergoing ambulatory chemotherapy. In the current study, she described its application in home-based end-of-life care to support both the patient and the caregiver.

The investigators recruited 319 cancer patient/caregiver dyads from 12 hospices in Illinois, Massachusetts, Oregon, and Utah. The mean age of the patients was 72 years, and the mean age of caregivers was 59 years.

The caregivers were randomly assigned either to the symptom care by phone (SCP) system or to usual care. The SCP system is an automated system in which caregivers phone in to report the patient’s symptoms and their own levels of stress, anxiety, etc., and receive automated responses based on the severity of symptoms and number of days reported without relief. The system offers both patient care and self-care strategies, and identifies and reinforces issues that should be addressed by contacting the hospice team. At the end of the call, the data are sent to the nurse, including alerts to matters that require prompt attention.

Caregivers in each group made daily automated monitoring calls to report 1 or more of 11 patient symptoms and 5 caregiver symptoms on a 0-10 scale, and to report the patient’s and their own distress about the symptoms.

“We have developed algorithms to provide just-in-time, tailored suggestions related to the pattern that they have reported,” Dr. Mooney said.

Data reported by caregivers in the control (usual care) group were recorded but not acted upon, whereas data reported by those in the SCP intervention group triggered the automated coaching and hospice nurse alerts for moderate to severe symptoms.

“People in the usual care group understood that they were just contributing symptom information, and they were told on every call and at consent that if they had any concerns to call their hospice nurse,” Dr. Mooney said.

For clinicians, the automated system triggers an alert at preset thresholds of severity (4-10), as well as trend alerts. Hospice nurses have online and mobile access to the alert website, where they can view a report of symptoms over the previous 24 hours, and review graphs of symptoms over time to see trends. The nurses were instructed to log that they had seen the alert and what their planned action was, which was left to their professional judgment.

The average length of the calls was 7 minutes, 4 seconds for the usual care group, and 7 minutes, 59 seconds for the intervention group. Control group caregivers completed 59% of expected calls, and those in the intervention group completed 64%.

Reported symptoms present in more than 50% of patients included fatigue (88.8%), pain (60.2%), eating/drinking problems (76.6%), difficulty thinking (69.6%), anxiety (67.6%), negative mood (67.3%), bowel problems (61%), and trouble sleeping (58.3%).

Among caregivers, 73.3% reported fatigue, 66.7% anxiety, 61% trouble sleeping, and 57.1% negative mood.

In a mixed-effects model looking at caregiver vitality – a composite of caregiver symptoms – the authors found that the severity of symptoms in the usual care group increased steadily over the course of hospice care, out to at least 91 days. In contrast, the severity of symptoms among caregivers in the SCP group rose only slightly. The between-group difference was significant (P < .001).

Similarly, among patients the overall symptom severity scores were lower for those in the intervention group than for controls (P =.03). Additionally, the onset of benefit, defined as time to the first symptom-free day, was significantly earlier among patients in the SCP group (P < .02)

Patterns of patient and fatigue during the last 8 weeks of life also favored the symptom-care intervention, Dr. Mooney noted.`

Invited discussant Dr. Michael H. Levy, vice chair of medical oncology and director of the pain and palliative care program at Fox Chase Cancer Center in Philadelphia, commented that the SCP system “is interesting, but it’s very expensive, the impact is limited, and it’s challenging to export.”

He noted that for a palliative care support system to be implemented successfully, it would need to be reproducible and applicable to a wide range of health care systems.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

The study was supported by the National Cancer Institute. Dr. Mooney and Dr. Levy reported having no relevant disclosures.

BOSTON – An automated system for monitoring the symptoms of patients in home hospice and supporting their caregivers with coaching can both improve patient comfort and relieve at least some of the stress on the caregiver, said investigators in a pilot program.

In a prospective, randomized controlled trial, caregivers assigned to symptom care by phone, in which they received automated coaching tailored to the specific situation, had better overall vitality, and the patients they cared for had less fatigue and anxiety than caregiver-patient pairs assigned to usual care, reported Dr. Kathi Mooney, professor of nursing at the University of Utah College of Nursing, Salt Lake City.

“The family inclusion in hospice care, the philosophy around that, offers the opportunity to extend PROs [patient-reported outcomes] to FCROs, family caregiver reported outcomes. We call that an opportunity to use electronic monitoring to monitor a family,” she said at the Palliative Care in Oncology Symposium.

Dr. Mooney and her colleagues have previously reported on the use of automated symptom monitoring for support of patients undergoing ambulatory chemotherapy. In the current study, she described its application in home-based end-of-life care to support both the patient and the caregiver.

The investigators recruited 319 cancer patient/caregiver dyads from 12 hospices in Illinois, Massachusetts, Oregon, and Utah. The mean age of the patients was 72 years, and the mean age of caregivers was 59 years.

The caregivers were randomly assigned either to the symptom care by phone (SCP) system or to usual care. The SCP system is an automated system in which caregivers phone in to report the patient’s symptoms and their own levels of stress, anxiety, etc., and receive automated responses based on the severity of symptoms and number of days reported without relief. The system offers both patient care and self-care strategies, and identifies and reinforces issues that should be addressed by contacting the hospice team. At the end of the call, the data are sent to the nurse, including alerts to matters that require prompt attention.

Caregivers in each group made daily automated monitoring calls to report 1 or more of 11 patient symptoms and 5 caregiver symptoms on a 0-10 scale, and to report the patient’s and their own distress about the symptoms.

“We have developed algorithms to provide just-in-time, tailored suggestions related to the pattern that they have reported,” Dr. Mooney said.

Data reported by caregivers in the control (usual care) group were recorded but not acted upon, whereas data reported by those in the SCP intervention group triggered the automated coaching and hospice nurse alerts for moderate to severe symptoms.

“People in the usual care group understood that they were just contributing symptom information, and they were told on every call and at consent that if they had any concerns to call their hospice nurse,” Dr. Mooney said.

For clinicians, the automated system triggers an alert at preset thresholds of severity (4-10), as well as trend alerts. Hospice nurses have online and mobile access to the alert website, where they can view a report of symptoms over the previous 24 hours, and review graphs of symptoms over time to see trends. The nurses were instructed to log that they had seen the alert and what their planned action was, which was left to their professional judgment.

The average length of the calls was 7 minutes, 4 seconds for the usual care group, and 7 minutes, 59 seconds for the intervention group. Control group caregivers completed 59% of expected calls, and those in the intervention group completed 64%.

Reported symptoms present in more than 50% of patients included fatigue (88.8%), pain (60.2%), eating/drinking problems (76.6%), difficulty thinking (69.6%), anxiety (67.6%), negative mood (67.3%), bowel problems (61%), and trouble sleeping (58.3%).

Among caregivers, 73.3% reported fatigue, 66.7% anxiety, 61% trouble sleeping, and 57.1% negative mood.

In a mixed-effects model looking at caregiver vitality – a composite of caregiver symptoms – the authors found that the severity of symptoms in the usual care group increased steadily over the course of hospice care, out to at least 91 days. In contrast, the severity of symptoms among caregivers in the SCP group rose only slightly. The between-group difference was significant (P < .001).

Similarly, among patients the overall symptom severity scores were lower for those in the intervention group than for controls (P =.03). Additionally, the onset of benefit, defined as time to the first symptom-free day, was significantly earlier among patients in the SCP group (P < .02)

Patterns of patient and fatigue during the last 8 weeks of life also favored the symptom-care intervention, Dr. Mooney noted.`

Invited discussant Dr. Michael H. Levy, vice chair of medical oncology and director of the pain and palliative care program at Fox Chase Cancer Center in Philadelphia, commented that the SCP system “is interesting, but it’s very expensive, the impact is limited, and it’s challenging to export.”

He noted that for a palliative care support system to be implemented successfully, it would need to be reproducible and applicable to a wide range of health care systems.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

The study was supported by the National Cancer Institute. Dr. Mooney and Dr. Levy reported having no relevant disclosures.

BOSTON – What clinicians see and what patients feel may be two different things, but optimal care for patients with cancer depends on smooth two-way communication between patients who are sometimes afraid to be a bother, and caregivers who sometimes fail to pick up on patient distress, said an investigator who studied patient-reported outcomes.

“We really have a propensity to underestimate symptoms – not only the incidence, but also the severity of the symptom, and also what type of distress that symptom is causing for that individual patient,” said Jeannine M. Brant, Ph.D., an oncology nurse specialist and nurse scientist at the Billings (Mont.) Clinic. “We need to incorporate PROs [patient-reported outcomes] into our clinical practice,” she said at the inaugural American Society of Clinical Oncology (ASCO) Palliative Care Symposium.

She and her colleagues were recently surprised, she said, when an otherwise healthy-looking rectal cancer survivor, an avid runner, reported having a high level of distress due to unpredictable bouts of diarrhea and fatigue. The patient said she had not reported the symptoms earlier because they seemed to be “a small trade-off for having my life back.”

With the help of the support team, which provided nutritional consultation and antidiarrheal agents, the patient was soon back on her feet and running again, and reported a high quality of life.

The case “points out the need to ask patients about their symptoms, because if we don’t ask about them, we’re not going to know what they’re experiencing,” Dr. Brant said.

ASCO’s Quality Oncology Practice Initiative (QOPI) calls for starting the PRO process before the first administration of a new chemotherapy regimen. In addition, it calls for an assessment of the patient’s psychosocial concerns and needs, with appropriate action taken when indicated, at each clinical visit or treatment day during a chemotherapy regimen.

Barriers to PROs

Patients may be selective about what they report to their caregivers, with reasons that may include the desire to be a “good” patient, willingness to exchange some discomfort or unpleasant symptoms for better disease control, a fear that their symptoms might halt or interrupt their treatment, limited time spent with their clinicians, the perception that nothing can be done to control symptoms, or sheer embarrassment.

On the clinical side, physicians and nurses may have gaps in their knowledge and attitudes about symptoms, or may fail to ask because they are short on time and are concerned that having a discussion of symptoms will “open a can of worms” that they will then have to deal with. Additionally, clinicians may be hampered by the lack of a consistent process for integrating PROs into the electronic health records, Dr. Brant said.

There are currently several electronic platforms that can help to automate and simplify the PRO report process. In general, the systems allow patients to report physical, social, functional, and quality of life symptoms, and help clinicians assess satisfaction with treatment, how well the patient is coping, and treatment adherence. Some systems offer tips to patients about what to report and how to best frame it during their clinic visit.

Capturing toxicities

The National Cancer Institute is currently developing a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), to be used in tandem with the CTCAE, Dr. Brant noted.

Drawing on a symptoms library of 78 adverse events from the CTCAE, the PRO-CTCAE contains questions for evaluating symptom occurrence, frequency, severity, and interference. Patients can respond online, with computer tablets, or via an interactive voice response telephone system. Based on the responses, the system can assign a severity grade and record events for review by clinicians.

“This is looking at the patient experience and not trying simply to decide what the patient is experiencing as a result of a drug,” Dr. Brant said.

Automated care plan

Dr. Brant also described her experience with a semiautomated care planning system (On Q), which uses patient-reported data and clinical data to generate a customized draft patient care plan incorporating oncology quality standards, guidelines, and current research.

The system can generate supportive care plans that offer specific recommendations about distress screening, survivorship care, surveillance, and follow-up.

In a pilot study of the system with 23 breast cancer patients at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, and 18 patients with gynecologic cancers at the Billings Clinic, more than 90% of patients reported being satisfied with the system and said they would recommend it to others. Patients received a copy of the care plan on a flash drive or on paper if they preferred.

One patient commented that “the care plan reminds you to bring up issues, guides the discussion, and gives doctors a better overall picture of what’s going on with you.”

The study funding source was not reported. Dr. Brant disclosed receiving honoraria and serving on the speakers bureau of Genentech.

BOSTON – What clinicians see and what patients feel may be two different things, but optimal care for patients with cancer depends on smooth two-way communication between patients who are sometimes afraid to be a bother, and caregivers who sometimes fail to pick up on patient distress, said an investigator who studied patient-reported outcomes.

“We really have a propensity to underestimate symptoms – not only the incidence, but also the severity of the symptom, and also what type of distress that symptom is causing for that individual patient,” said Jeannine M. Brant, Ph.D., an oncology nurse specialist and nurse scientist at the Billings (Mont.) Clinic. “We need to incorporate PROs [patient-reported outcomes] into our clinical practice,” she said at the inaugural American Society of Clinical Oncology (ASCO) Palliative Care Symposium.

She and her colleagues were recently surprised, she said, when an otherwise healthy-looking rectal cancer survivor, an avid runner, reported having a high level of distress due to unpredictable bouts of diarrhea and fatigue. The patient said she had not reported the symptoms earlier because they seemed to be “a small trade-off for having my life back.”

With the help of the support team, which provided nutritional consultation and antidiarrheal agents, the patient was soon back on her feet and running again, and reported a high quality of life.

The case “points out the need to ask patients about their symptoms, because if we don’t ask about them, we’re not going to know what they’re experiencing,” Dr. Brant said.

ASCO’s Quality Oncology Practice Initiative (QOPI) calls for starting the PRO process before the first administration of a new chemotherapy regimen. In addition, it calls for an assessment of the patient’s psychosocial concerns and needs, with appropriate action taken when indicated, at each clinical visit or treatment day during a chemotherapy regimen.

Barriers to PROs

Patients may be selective about what they report to their caregivers, with reasons that may include the desire to be a “good” patient, willingness to exchange some discomfort or unpleasant symptoms for better disease control, a fear that their symptoms might halt or interrupt their treatment, limited time spent with their clinicians, the perception that nothing can be done to control symptoms, or sheer embarrassment.

On the clinical side, physicians and nurses may have gaps in their knowledge and attitudes about symptoms, or may fail to ask because they are short on time and are concerned that having a discussion of symptoms will “open a can of worms” that they will then have to deal with. Additionally, clinicians may be hampered by the lack of a consistent process for integrating PROs into the electronic health records, Dr. Brant said.

There are currently several electronic platforms that can help to automate and simplify the PRO report process. In general, the systems allow patients to report physical, social, functional, and quality of life symptoms, and help clinicians assess satisfaction with treatment, how well the patient is coping, and treatment adherence. Some systems offer tips to patients about what to report and how to best frame it during their clinic visit.

Capturing toxicities

The National Cancer Institute is currently developing a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), to be used in tandem with the CTCAE, Dr. Brant noted.

Drawing on a symptoms library of 78 adverse events from the CTCAE, the PRO-CTCAE contains questions for evaluating symptom occurrence, frequency, severity, and interference. Patients can respond online, with computer tablets, or via an interactive voice response telephone system. Based on the responses, the system can assign a severity grade and record events for review by clinicians.

“This is looking at the patient experience and not trying simply to decide what the patient is experiencing as a result of a drug,” Dr. Brant said.

Automated care plan

Dr. Brant also described her experience with a semiautomated care planning system (On Q), which uses patient-reported data and clinical data to generate a customized draft patient care plan incorporating oncology quality standards, guidelines, and current research.

The system can generate supportive care plans that offer specific recommendations about distress screening, survivorship care, surveillance, and follow-up.

In a pilot study of the system with 23 breast cancer patients at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, and 18 patients with gynecologic cancers at the Billings Clinic, more than 90% of patients reported being satisfied with the system and said they would recommend it to others. Patients received a copy of the care plan on a flash drive or on paper if they preferred.

One patient commented that “the care plan reminds you to bring up issues, guides the discussion, and gives doctors a better overall picture of what’s going on with you.”

The study funding source was not reported. Dr. Brant disclosed receiving honoraria and serving on the speakers bureau of Genentech.

BOSTON – What clinicians see and what patients feel may be two different things, but optimal care for patients with cancer depends on smooth two-way communication between patients who are sometimes afraid to be a bother, and caregivers who sometimes fail to pick up on patient distress, said an investigator who studied patient-reported outcomes.

“We really have a propensity to underestimate symptoms – not only the incidence, but also the severity of the symptom, and also what type of distress that symptom is causing for that individual patient,” said Jeannine M. Brant, Ph.D., an oncology nurse specialist and nurse scientist at the Billings (Mont.) Clinic. “We need to incorporate PROs [patient-reported outcomes] into our clinical practice,” she said at the inaugural American Society of Clinical Oncology (ASCO) Palliative Care Symposium.

She and her colleagues were recently surprised, she said, when an otherwise healthy-looking rectal cancer survivor, an avid runner, reported having a high level of distress due to unpredictable bouts of diarrhea and fatigue. The patient said she had not reported the symptoms earlier because they seemed to be “a small trade-off for having my life back.”

With the help of the support team, which provided nutritional consultation and antidiarrheal agents, the patient was soon back on her feet and running again, and reported a high quality of life.

The case “points out the need to ask patients about their symptoms, because if we don’t ask about them, we’re not going to know what they’re experiencing,” Dr. Brant said.

ASCO’s Quality Oncology Practice Initiative (QOPI) calls for starting the PRO process before the first administration of a new chemotherapy regimen. In addition, it calls for an assessment of the patient’s psychosocial concerns and needs, with appropriate action taken when indicated, at each clinical visit or treatment day during a chemotherapy regimen.

Barriers to PROs

Patients may be selective about what they report to their caregivers, with reasons that may include the desire to be a “good” patient, willingness to exchange some discomfort or unpleasant symptoms for better disease control, a fear that their symptoms might halt or interrupt their treatment, limited time spent with their clinicians, the perception that nothing can be done to control symptoms, or sheer embarrassment.

On the clinical side, physicians and nurses may have gaps in their knowledge and attitudes about symptoms, or may fail to ask because they are short on time and are concerned that having a discussion of symptoms will “open a can of worms” that they will then have to deal with. Additionally, clinicians may be hampered by the lack of a consistent process for integrating PROs into the electronic health records, Dr. Brant said.

There are currently several electronic platforms that can help to automate and simplify the PRO report process. In general, the systems allow patients to report physical, social, functional, and quality of life symptoms, and help clinicians assess satisfaction with treatment, how well the patient is coping, and treatment adherence. Some systems offer tips to patients about what to report and how to best frame it during their clinic visit.

Capturing toxicities

The National Cancer Institute is currently developing a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), to be used in tandem with the CTCAE, Dr. Brant noted.

Drawing on a symptoms library of 78 adverse events from the CTCAE, the PRO-CTCAE contains questions for evaluating symptom occurrence, frequency, severity, and interference. Patients can respond online, with computer tablets, or via an interactive voice response telephone system. Based on the responses, the system can assign a severity grade and record events for review by clinicians.

“This is looking at the patient experience and not trying simply to decide what the patient is experiencing as a result of a drug,” Dr. Brant said.

Automated care plan

Dr. Brant also described her experience with a semiautomated care planning system (On Q), which uses patient-reported data and clinical data to generate a customized draft patient care plan incorporating oncology quality standards, guidelines, and current research.

The system can generate supportive care plans that offer specific recommendations about distress screening, survivorship care, surveillance, and follow-up.

In a pilot study of the system with 23 breast cancer patients at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, and 18 patients with gynecologic cancers at the Billings Clinic, more than 90% of patients reported being satisfied with the system and said they would recommend it to others. Patients received a copy of the care plan on a flash drive or on paper if they preferred.

One patient commented that “the care plan reminds you to bring up issues, guides the discussion, and gives doctors a better overall picture of what’s going on with you.”

The study funding source was not reported. Dr. Brant disclosed receiving honoraria and serving on the speakers bureau of Genentech.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

BOSTON – Central lymph node dissection may not be necessary in patients with small parathyroid carcinomas, results of a data review suggest.

Among 405 U.S. patients treated in the last two decades for parathyroid carcinomas, disease-specific mortality and degree of local tumor invasion did not differ depending on nodal involvement, reported Dr. Kun-Tai Hsu, an associate research specialist in the surgery department at the University of Wisconsin, Madison.

Patients with tumors greater than 3 cm in diameter and distal metastasis had worse disease-specific mortality, and larger tumors were significantly more likely to be associated with positive lymph nodes, Dr. Hsu reported at the annual meeting of the American Association of Endocrine Surgeons.

The findings raise the question of whether central lymph node dissection is necessary for all patients with parathyroid carcinomas, but "our conclusions may not translate directly into definitive recommendations," said Dr. Hsu, who advised further study of whether patients with tumors larger than 3 cm may benefit from lymph node dissection.

Parathyroid carcinomas are rare cancers, accounting for 0.005% of all malignancies and less than 1% of primary hyperparathyroidism. The current standard of therapy is en bloc removal of the parathyroid tumor and ipsilateral lobectomy, isthmusectomy, and central lymph node dissection.

Over at least 5 years of follow-up, neither tumor size nor lymph node status was significantly predictive of outcomes in an earlier retrospective study of 286 patients treated in the 1980s and 1990s.

In addition, a 2006 study using data from the Surveillance, Epidemiology and End Results (SEER) database showed a significant increase in the incidence of this malignancy from 1988 through 2003. The authors identified younger age, female sex, more recent diagnosis, and absence of distant metastases as favorable prognostic factors (Cancer 2007;109:1736-41).

What the previous studies could not answer, however, was whether lymph node metastases were associated with worse disease-specific mortality and whether central lymph node dissection might improve survival in patients with parathyroid carcinomas, Dr. Hsu noted.

He and his colleagues queried SEER for disease-specific survival outcomes and lymph-node status of all patients treated in the United States for parathyroid carcinomas from 1988 through 2010.

They identified 212 female and 193 male patients. Among all patients, 112 (27.7%) had tumors 3 cm or greater, and 12 (3%) had positive lymph nodes. Median follow-up was 68 months.

In a multivariate analysis of disease-specific mortality predictors adjusted for sex and age only, tumors 3 cm or greater and the presence of metastasis were predictive of worse survival, with respective hazard ratios of 5.35 (P = .01) and 45.1 (P less than .01).

Similarly, an analysis adjusted for sex, age, and year of diagnosis showed that tumor size but not age or sex significantly predicted lymph node metastasis (HR, 19.48; P = .02)

A comparison of outcomes between patients with and without lymph node examinations found no differences in disease-specific mortality by sex, age, year of diagnosis, tumor size, local invasion, or metastasis. Significant predictors of disease-specific mortality in this analysis included surgery type (parathyroidectomy, en bloc excision, or debulking), the use of radiation, and white race.

Dr. Hsu noted that the study was limited by its retrospective design, lack of information on other significant clinical variables, lack of detailed follow-up data, and the possibility of misclassification or miscoding of cases.

He acknowledged that uncertainty about the diagnosis is a drawback to SEER-based studies, but that given the rarity of the disease, SEER data are the most reliable source of information.

The study was supported by the Wisconsin Surgical Outcomes Research Program. Dr. Hsu reported having no relevant disclosures. Study coauthor Dr. Rebecca Sippel is a member of this publication’s editorial advisory board.

BOSTON – Central lymph node dissection may not be necessary in patients with small parathyroid carcinomas, results of a data review suggest.

Among 405 U.S. patients treated in the last two decades for parathyroid carcinomas, disease-specific mortality and degree of local tumor invasion did not differ depending on nodal involvement, reported Dr. Kun-Tai Hsu, an associate research specialist in the surgery department at the University of Wisconsin, Madison.

Patients with tumors greater than 3 cm in diameter and distal metastasis had worse disease-specific mortality, and larger tumors were significantly more likely to be associated with positive lymph nodes, Dr. Hsu reported at the annual meeting of the American Association of Endocrine Surgeons.

The findings raise the question of whether central lymph node dissection is necessary for all patients with parathyroid carcinomas, but "our conclusions may not translate directly into definitive recommendations," said Dr. Hsu, who advised further study of whether patients with tumors larger than 3 cm may benefit from lymph node dissection.

Parathyroid carcinomas are rare cancers, accounting for 0.005% of all malignancies and less than 1% of primary hyperparathyroidism. The current standard of therapy is en bloc removal of the parathyroid tumor and ipsilateral lobectomy, isthmusectomy, and central lymph node dissection.

Over at least 5 years of follow-up, neither tumor size nor lymph node status was significantly predictive of outcomes in an earlier retrospective study of 286 patients treated in the 1980s and 1990s.

In addition, a 2006 study using data from the Surveillance, Epidemiology and End Results (SEER) database showed a significant increase in the incidence of this malignancy from 1988 through 2003. The authors identified younger age, female sex, more recent diagnosis, and absence of distant metastases as favorable prognostic factors (Cancer 2007;109:1736-41).

What the previous studies could not answer, however, was whether lymph node metastases were associated with worse disease-specific mortality and whether central lymph node dissection might improve survival in patients with parathyroid carcinomas, Dr. Hsu noted.

He and his colleagues queried SEER for disease-specific survival outcomes and lymph-node status of all patients treated in the United States for parathyroid carcinomas from 1988 through 2010.

They identified 212 female and 193 male patients. Among all patients, 112 (27.7%) had tumors 3 cm or greater, and 12 (3%) had positive lymph nodes. Median follow-up was 68 months.

In a multivariate analysis of disease-specific mortality predictors adjusted for sex and age only, tumors 3 cm or greater and the presence of metastasis were predictive of worse survival, with respective hazard ratios of 5.35 (P = .01) and 45.1 (P less than .01).

Similarly, an analysis adjusted for sex, age, and year of diagnosis showed that tumor size but not age or sex significantly predicted lymph node metastasis (HR, 19.48; P = .02)

A comparison of outcomes between patients with and without lymph node examinations found no differences in disease-specific mortality by sex, age, year of diagnosis, tumor size, local invasion, or metastasis. Significant predictors of disease-specific mortality in this analysis included surgery type (parathyroidectomy, en bloc excision, or debulking), the use of radiation, and white race.

Dr. Hsu noted that the study was limited by its retrospective design, lack of information on other significant clinical variables, lack of detailed follow-up data, and the possibility of misclassification or miscoding of cases.

He acknowledged that uncertainty about the diagnosis is a drawback to SEER-based studies, but that given the rarity of the disease, SEER data are the most reliable source of information.

The study was supported by the Wisconsin Surgical Outcomes Research Program. Dr. Hsu reported having no relevant disclosures. Study coauthor Dr. Rebecca Sippel is a member of this publication’s editorial advisory board.

BOSTON – Central lymph node dissection may not be necessary in patients with small parathyroid carcinomas, results of a data review suggest.

Among 405 U.S. patients treated in the last two decades for parathyroid carcinomas, disease-specific mortality and degree of local tumor invasion did not differ depending on nodal involvement, reported Dr. Kun-Tai Hsu, an associate research specialist in the surgery department at the University of Wisconsin, Madison.

Patients with tumors greater than 3 cm in diameter and distal metastasis had worse disease-specific mortality, and larger tumors were significantly more likely to be associated with positive lymph nodes, Dr. Hsu reported at the annual meeting of the American Association of Endocrine Surgeons.

The findings raise the question of whether central lymph node dissection is necessary for all patients with parathyroid carcinomas, but "our conclusions may not translate directly into definitive recommendations," said Dr. Hsu, who advised further study of whether patients with tumors larger than 3 cm may benefit from lymph node dissection.

Parathyroid carcinomas are rare cancers, accounting for 0.005% of all malignancies and less than 1% of primary hyperparathyroidism. The current standard of therapy is en bloc removal of the parathyroid tumor and ipsilateral lobectomy, isthmusectomy, and central lymph node dissection.

Over at least 5 years of follow-up, neither tumor size nor lymph node status was significantly predictive of outcomes in an earlier retrospective study of 286 patients treated in the 1980s and 1990s.

In addition, a 2006 study using data from the Surveillance, Epidemiology and End Results (SEER) database showed a significant increase in the incidence of this malignancy from 1988 through 2003. The authors identified younger age, female sex, more recent diagnosis, and absence of distant metastases as favorable prognostic factors (Cancer 2007;109:1736-41).

What the previous studies could not answer, however, was whether lymph node metastases were associated with worse disease-specific mortality and whether central lymph node dissection might improve survival in patients with parathyroid carcinomas, Dr. Hsu noted.

He and his colleagues queried SEER for disease-specific survival outcomes and lymph-node status of all patients treated in the United States for parathyroid carcinomas from 1988 through 2010.

They identified 212 female and 193 male patients. Among all patients, 112 (27.7%) had tumors 3 cm or greater, and 12 (3%) had positive lymph nodes. Median follow-up was 68 months.

In a multivariate analysis of disease-specific mortality predictors adjusted for sex and age only, tumors 3 cm or greater and the presence of metastasis were predictive of worse survival, with respective hazard ratios of 5.35 (P = .01) and 45.1 (P less than .01).

Similarly, an analysis adjusted for sex, age, and year of diagnosis showed that tumor size but not age or sex significantly predicted lymph node metastasis (HR, 19.48; P = .02)

A comparison of outcomes between patients with and without lymph node examinations found no differences in disease-specific mortality by sex, age, year of diagnosis, tumor size, local invasion, or metastasis. Significant predictors of disease-specific mortality in this analysis included surgery type (parathyroidectomy, en bloc excision, or debulking), the use of radiation, and white race.

Dr. Hsu noted that the study was limited by its retrospective design, lack of information on other significant clinical variables, lack of detailed follow-up data, and the possibility of misclassification or miscoding of cases.

He acknowledged that uncertainty about the diagnosis is a drawback to SEER-based studies, but that given the rarity of the disease, SEER data are the most reliable source of information.

The study was supported by the Wisconsin Surgical Outcomes Research Program. Dr. Hsu reported having no relevant disclosures. Study coauthor Dr. Rebecca Sippel is a member of this publication’s editorial advisory board.

CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.

Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.

Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.

The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.

"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.

The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.

"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.

In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

Independent Review

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.

Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.

The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.

For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.

In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.

At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.

Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.

The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.

Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.

"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.

The most common side effects were hypertension and pneumonia.

The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.

CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.

Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.

Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.

The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.

"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.

The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.

"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.

In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

Independent Review

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.

Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.

The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.

For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.

In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.

At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.

Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.

The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.

Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.

"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.

The most common side effects were hypertension and pneumonia.

The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.

CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.

Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.

Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.

The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.

"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.

The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.

"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.

In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

Independent Review

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.

Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.

The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.

For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.

In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.

At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.

Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.

The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.

Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.

"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.

The most common side effects were hypertension and pneumonia.

The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.