fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).

ILLUSTRATIVE CASE

A 73-year-old patient you’ve known for your entire career comes in for follow-up after a recent hospitalization, during which he was diagnosed with metastatic non–small-cell lung cancer. “I know things don’t look good,” he says. “I don’t want to die a miserable, painful death. But I’m not going to just roll over and die without fighting this.” What can you do to improve his quality of life while he undergoes cancer treatment?

Palliative care focuses on the prevention and treatment of pain and other debilitating effects of serious illness, with a goal of improving quality of life for patients and their families. Unlike hospice care, which requires a prognosis of less than 6 months of life to qualify for Medicare reimbursement,² eligibility for palliative care is not dependent on prognosis. Indeed, palliative care can occur at the same time as curative or life-prolonging treatment. Palliative care programs include psychosocial and spiritual care for patient and family; management of symptoms such as pain, fatigue, shortness of breath, depression, constipation, and nausea; support for complex decisions, such as discussions of goals, do not resuscitate (DNR) orders, and requests for treatment; and coordination of care across various health care settings.³

Palliative care lowers health care spending
One study found that palliative care consultation was associated with an average savings of $1700 per admission for patients who were discharged, and $4900, on average, for every patient who died in the hospital.⁴ Another study demonstrated an association between states with a higher percentage of hospitals with palliative care services and fewer Medicare hospital deaths; fewer admissions to, and days in, intensive care units in the last 6 months of life; and lower total Medicare spending per enrollee.⁵

A 2008 systematic review of the effectiveness of palliative care revealed that there were methodological limitations in all the existing studies of palliative care, and called for higher quality studies.⁶ The RCT detailed here is a first step toward filling the gap in palliative care research.

STUDY SUMMARY: Intervention group lived longer and felt better

Temel et al enrolled 151 ambulatory patients with biopsy-proven non–small-cell lung cancer. The average age of the enrollees was 64 years, and slightly more than half (51.6%) were female. All had been diagnosed with metastatic cancer within 8 weeks of enrollment in the study.

The patients were randomized to receive either an early referral to the palliative care team along with standard oncology care or standard oncology care alone. Race, marital status, smoking history, presence of brain metastases, and initial cancer therapy—radiation, chemotherapy, or a combination—were similar for both groups.

The study ran for 12 weeks. Those in the intervention group had an initial meeting with a member of the palliative care team, which consisted of board-certified palliative care physicians and advanced practice nurses. Follow-up meetings with the team were scheduled at least monthly, and more frequently if requested by the patient or recommended by either the palliative care team or the oncology team—with an average of 4 meetings over the course of the study. Palliative care team members worked with patients to assess physical and emotional symptoms, coordinate care, and determine and document goals of treatment.

The primary outcome was the change in quality of life (QOL) from baseline to 12 weeks after the initial meeting with the palliative care team. QOL was measured with the Functional Assessment of Cancer Therapy-Lung (FACT-L) tool; scores range from 0 to 136, with higher scores indicating a higher QOL. The researchers used 3 subscales of the FACT-L—physical well-being, functional well-being, and a lung-cancer subscale (LCS) based on questions about 7 symptoms—to create a Trial Outcome Index (TOI), the main outcome measure. The TOI, which is the sum of the subscales, has a range of 0 to 84, with higher scores indicating higher QOL.

Secondary outcome measures were mood, use of health care services, and survival. The researchers assessed mood with 2 tools: the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). The PHQ-9 is a 9-question survey that uses criteria from the Diagnostic and Statistical Manual of Psychiatric Disorders, 4th edition (DSM-IV) to diagnose depression. HADS is a 14-question survey with subscales for depression (HADS-D) and anxiety (HADS-A).

Intervention group had better scores. At study’s end, the control group had average scores of 91.5, 19.3, and 53.0 on the FACT-L, LCS, and TOI, respectively, vs 98.0, 21.0, and 59.0 for the intervention group. The palliative care group had an average increase on the TOI of 2.3 points, while the average for the control group decreased by 2.3 points (P=.04). A comparison of the mean change in scores between the 2 groups indicated statistically significant improvements in the FACT-L and TOI results for the intervention group. The improvement in LCS was not statistically significant.

The palliative care group also had a lower prevalence of depression compared with the controls (4% vs 17% on the PHQ-9 [P=.04]; 16% vs 38% on the HADS-D [P=.01]). For every 8 patients who received early palliative care, 1 less patient was diagnosed with depression. The prevalence of anxiety was not significantly different between groups.

Among patients who died during the study period, those in the palliative care group were less likely to have received aggressive end-of-life interventions compared with the controls (33% vs 54%, respectively, P=.05). Aggressive care was defined as chemotherapy within 14 days of death or little or no hospice care. Those in the early palliative care group also lived significantly longer; median survival was 11.6 months, vs 8.9 months for the control group (P=.02).

WHAT’S NEW: This study highlights the need for early referral

This is the first high-quality RCT to demonstrate improved patient outcomes when palliative care is begun close to the time of cancer diagnosis. Previous studies of late palliative care referrals did not demonstrate improved QOL or more appropriate use of health care services. This study established that patients with lung cancer are less depressed and live longer when they receive palliative care services soon after diagnosis. It also showed a link between palliative care and a reduction in aggressive, possibly inappropriate, end-of-life treatment of metastatic cancer.

Several recent practice guidelines, including that of the Institute for Clinical Systems Improvement (ICSI), recommend that palliative care referrals be made early in the course of a progressive, debilitating illness, regardless of the patient’s life expectancy.⁷ Other organizations, including the Institute of Medicine and the World Health Organization, recommend palliative care as an essential component of comprehensive cancer care.⁸ This study supports both of these recommendations.

CAVEATS: Would extra attention from any clinician work equally well?

No attempt was made to control for the extra attention (an average of 4 visits) that the palliative care team provided to those in the intervention group. Thus, it is possible that the study results could be replicated by having patients meet with their primary care physician or another health professional instead of a palliative care team.

The reduction in depression and increase in survival are clinically significant outcomes. But the improvement in QOL (an average of 7 points better on the 136-point FACT-L scale, or 6 points on the 84-point TOI scale) may not be.

It is important to note, too, that the survival benefits the researchers found may not be generalizable to other kinds of cancers. In addition, most patients (97%) in this study were white, so the findings may be less generalizable to patients of other races. Nonetheless, we think it’s likely that the improvements in QOL and mood revealed in this study would be realized by most patients with terminal cancer who received early palliative care.

CHALLENGES TO IMPLEMENTATION: Palliative care must be explained—and available

Physicians must be able to explain to their patients the difference between palliative care and hospice—most notably, that patients can continue to receive anticancer treatment while receiving palliative care. The recommendation to seek palliative care should not be considered “giving up” on the patient.

In order to refer patients to palliative care early in the course of cancer care, physicians must have access to a palliative care team, which may not be available in all cases. In 2006, only 53% of hospitals with more than 50 beds reported having a palliative care program.⁵ If there is no such program available, physicians can refer to the ICSI guideline on palliative care for more information on how to implement elements of palliative care for their patients with advanced cancer.⁷

ILLUSTRATIVE CASE

A 73-year-old patient you’ve known for your entire career comes in for follow-up after a recent hospitalization, during which he was diagnosed with metastatic non–small-cell lung cancer. “I know things don’t look good,” he says. “I don’t want to die a miserable, painful death. But I’m not going to just roll over and die without fighting this.” What can you do to improve his quality of life while he undergoes cancer treatment?

Palliative care focuses on the prevention and treatment of pain and other debilitating effects of serious illness, with a goal of improving quality of life for patients and their families. Unlike hospice care, which requires a prognosis of less than 6 months of life to qualify for Medicare reimbursement,² eligibility for palliative care is not dependent on prognosis. Indeed, palliative care can occur at the same time as curative or life-prolonging treatment. Palliative care programs include psychosocial and spiritual care for patient and family; management of symptoms such as pain, fatigue, shortness of breath, depression, constipation, and nausea; support for complex decisions, such as discussions of goals, do not resuscitate (DNR) orders, and requests for treatment; and coordination of care across various health care settings.³

Palliative care lowers health care spending
One study found that palliative care consultation was associated with an average savings of $1700 per admission for patients who were discharged, and $4900, on average, for every patient who died in the hospital.⁴ Another study demonstrated an association between states with a higher percentage of hospitals with palliative care services and fewer Medicare hospital deaths; fewer admissions to, and days in, intensive care units in the last 6 months of life; and lower total Medicare spending per enrollee.⁵

A 2008 systematic review of the effectiveness of palliative care revealed that there were methodological limitations in all the existing studies of palliative care, and called for higher quality studies.⁶ The RCT detailed here is a first step toward filling the gap in palliative care research.

STUDY SUMMARY: Intervention group lived longer and felt better

Temel et al enrolled 151 ambulatory patients with biopsy-proven non–small-cell lung cancer. The average age of the enrollees was 64 years, and slightly more than half (51.6%) were female. All had been diagnosed with metastatic cancer within 8 weeks of enrollment in the study.

The patients were randomized to receive either an early referral to the palliative care team along with standard oncology care or standard oncology care alone. Race, marital status, smoking history, presence of brain metastases, and initial cancer therapy—radiation, chemotherapy, or a combination—were similar for both groups.

The study ran for 12 weeks. Those in the intervention group had an initial meeting with a member of the palliative care team, which consisted of board-certified palliative care physicians and advanced practice nurses. Follow-up meetings with the team were scheduled at least monthly, and more frequently if requested by the patient or recommended by either the palliative care team or the oncology team—with an average of 4 meetings over the course of the study. Palliative care team members worked with patients to assess physical and emotional symptoms, coordinate care, and determine and document goals of treatment.

The primary outcome was the change in quality of life (QOL) from baseline to 12 weeks after the initial meeting with the palliative care team. QOL was measured with the Functional Assessment of Cancer Therapy-Lung (FACT-L) tool; scores range from 0 to 136, with higher scores indicating a higher QOL. The researchers used 3 subscales of the FACT-L—physical well-being, functional well-being, and a lung-cancer subscale (LCS) based on questions about 7 symptoms—to create a Trial Outcome Index (TOI), the main outcome measure. The TOI, which is the sum of the subscales, has a range of 0 to 84, with higher scores indicating higher QOL.

Secondary outcome measures were mood, use of health care services, and survival. The researchers assessed mood with 2 tools: the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). The PHQ-9 is a 9-question survey that uses criteria from the Diagnostic and Statistical Manual of Psychiatric Disorders, 4th edition (DSM-IV) to diagnose depression. HADS is a 14-question survey with subscales for depression (HADS-D) and anxiety (HADS-A).

Intervention group had better scores. At study’s end, the control group had average scores of 91.5, 19.3, and 53.0 on the FACT-L, LCS, and TOI, respectively, vs 98.0, 21.0, and 59.0 for the intervention group. The palliative care group had an average increase on the TOI of 2.3 points, while the average for the control group decreased by 2.3 points (P=.04). A comparison of the mean change in scores between the 2 groups indicated statistically significant improvements in the FACT-L and TOI results for the intervention group. The improvement in LCS was not statistically significant.

The palliative care group also had a lower prevalence of depression compared with the controls (4% vs 17% on the PHQ-9 [P=.04]; 16% vs 38% on the HADS-D [P=.01]). For every 8 patients who received early palliative care, 1 less patient was diagnosed with depression. The prevalence of anxiety was not significantly different between groups.

Among patients who died during the study period, those in the palliative care group were less likely to have received aggressive end-of-life interventions compared with the controls (33% vs 54%, respectively, P=.05). Aggressive care was defined as chemotherapy within 14 days of death or little or no hospice care. Those in the early palliative care group also lived significantly longer; median survival was 11.6 months, vs 8.9 months for the control group (P=.02).

WHAT’S NEW: This study highlights the need for early referral

This is the first high-quality RCT to demonstrate improved patient outcomes when palliative care is begun close to the time of cancer diagnosis. Previous studies of late palliative care referrals did not demonstrate improved QOL or more appropriate use of health care services. This study established that patients with lung cancer are less depressed and live longer when they receive palliative care services soon after diagnosis. It also showed a link between palliative care and a reduction in aggressive, possibly inappropriate, end-of-life treatment of metastatic cancer.

Several recent practice guidelines, including that of the Institute for Clinical Systems Improvement (ICSI), recommend that palliative care referrals be made early in the course of a progressive, debilitating illness, regardless of the patient’s life expectancy.⁷ Other organizations, including the Institute of Medicine and the World Health Organization, recommend palliative care as an essential component of comprehensive cancer care.⁸ This study supports both of these recommendations.

CAVEATS: Would extra attention from any clinician work equally well?

No attempt was made to control for the extra attention (an average of 4 visits) that the palliative care team provided to those in the intervention group. Thus, it is possible that the study results could be replicated by having patients meet with their primary care physician or another health professional instead of a palliative care team.

The reduction in depression and increase in survival are clinically significant outcomes. But the improvement in QOL (an average of 7 points better on the 136-point FACT-L scale, or 6 points on the 84-point TOI scale) may not be.

It is important to note, too, that the survival benefits the researchers found may not be generalizable to other kinds of cancers. In addition, most patients (97%) in this study were white, so the findings may be less generalizable to patients of other races. Nonetheless, we think it’s likely that the improvements in QOL and mood revealed in this study would be realized by most patients with terminal cancer who received early palliative care.

CHALLENGES TO IMPLEMENTATION: Palliative care must be explained—and available

Physicians must be able to explain to their patients the difference between palliative care and hospice—most notably, that patients can continue to receive anticancer treatment while receiving palliative care. The recommendation to seek palliative care should not be considered “giving up” on the patient.

In order to refer patients to palliative care early in the course of cancer care, physicians must have access to a palliative care team, which may not be available in all cases. In 2006, only 53% of hospitals with more than 50 beds reported having a palliative care program.⁵ If there is no such program available, physicians can refer to the ICSI guideline on palliative care for more information on how to implement elements of palliative care for their patients with advanced cancer.⁷

ILLUSTRATIVE CASE

A 73-year-old patient you’ve known for your entire career comes in for follow-up after a recent hospitalization, during which he was diagnosed with metastatic non–small-cell lung cancer. “I know things don’t look good,” he says. “I don’t want to die a miserable, painful death. But I’m not going to just roll over and die without fighting this.” What can you do to improve his quality of life while he undergoes cancer treatment?

Palliative care focuses on the prevention and treatment of pain and other debilitating effects of serious illness, with a goal of improving quality of life for patients and their families. Unlike hospice care, which requires a prognosis of less than 6 months of life to qualify for Medicare reimbursement,² eligibility for palliative care is not dependent on prognosis. Indeed, palliative care can occur at the same time as curative or life-prolonging treatment. Palliative care programs include psychosocial and spiritual care for patient and family; management of symptoms such as pain, fatigue, shortness of breath, depression, constipation, and nausea; support for complex decisions, such as discussions of goals, do not resuscitate (DNR) orders, and requests for treatment; and coordination of care across various health care settings.³

Palliative care lowers health care spending
One study found that palliative care consultation was associated with an average savings of $1700 per admission for patients who were discharged, and $4900, on average, for every patient who died in the hospital.⁴ Another study demonstrated an association between states with a higher percentage of hospitals with palliative care services and fewer Medicare hospital deaths; fewer admissions to, and days in, intensive care units in the last 6 months of life; and lower total Medicare spending per enrollee.⁵

A 2008 systematic review of the effectiveness of palliative care revealed that there were methodological limitations in all the existing studies of palliative care, and called for higher quality studies.⁶ The RCT detailed here is a first step toward filling the gap in palliative care research.

STUDY SUMMARY: Intervention group lived longer and felt better

Temel et al enrolled 151 ambulatory patients with biopsy-proven non–small-cell lung cancer. The average age of the enrollees was 64 years, and slightly more than half (51.6%) were female. All had been diagnosed with metastatic cancer within 8 weeks of enrollment in the study.

The patients were randomized to receive either an early referral to the palliative care team along with standard oncology care or standard oncology care alone. Race, marital status, smoking history, presence of brain metastases, and initial cancer therapy—radiation, chemotherapy, or a combination—were similar for both groups.

The study ran for 12 weeks. Those in the intervention group had an initial meeting with a member of the palliative care team, which consisted of board-certified palliative care physicians and advanced practice nurses. Follow-up meetings with the team were scheduled at least monthly, and more frequently if requested by the patient or recommended by either the palliative care team or the oncology team—with an average of 4 meetings over the course of the study. Palliative care team members worked with patients to assess physical and emotional symptoms, coordinate care, and determine and document goals of treatment.

The primary outcome was the change in quality of life (QOL) from baseline to 12 weeks after the initial meeting with the palliative care team. QOL was measured with the Functional Assessment of Cancer Therapy-Lung (FACT-L) tool; scores range from 0 to 136, with higher scores indicating a higher QOL. The researchers used 3 subscales of the FACT-L—physical well-being, functional well-being, and a lung-cancer subscale (LCS) based on questions about 7 symptoms—to create a Trial Outcome Index (TOI), the main outcome measure. The TOI, which is the sum of the subscales, has a range of 0 to 84, with higher scores indicating higher QOL.

Secondary outcome measures were mood, use of health care services, and survival. The researchers assessed mood with 2 tools: the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). The PHQ-9 is a 9-question survey that uses criteria from the Diagnostic and Statistical Manual of Psychiatric Disorders, 4th edition (DSM-IV) to diagnose depression. HADS is a 14-question survey with subscales for depression (HADS-D) and anxiety (HADS-A).

Intervention group had better scores. At study’s end, the control group had average scores of 91.5, 19.3, and 53.0 on the FACT-L, LCS, and TOI, respectively, vs 98.0, 21.0, and 59.0 for the intervention group. The palliative care group had an average increase on the TOI of 2.3 points, while the average for the control group decreased by 2.3 points (P=.04). A comparison of the mean change in scores between the 2 groups indicated statistically significant improvements in the FACT-L and TOI results for the intervention group. The improvement in LCS was not statistically significant.

The palliative care group also had a lower prevalence of depression compared with the controls (4% vs 17% on the PHQ-9 [P=.04]; 16% vs 38% on the HADS-D [P=.01]). For every 8 patients who received early palliative care, 1 less patient was diagnosed with depression. The prevalence of anxiety was not significantly different between groups.

Among patients who died during the study period, those in the palliative care group were less likely to have received aggressive end-of-life interventions compared with the controls (33% vs 54%, respectively, P=.05). Aggressive care was defined as chemotherapy within 14 days of death or little or no hospice care. Those in the early palliative care group also lived significantly longer; median survival was 11.6 months, vs 8.9 months for the control group (P=.02).

WHAT’S NEW: This study highlights the need for early referral

This is the first high-quality RCT to demonstrate improved patient outcomes when palliative care is begun close to the time of cancer diagnosis. Previous studies of late palliative care referrals did not demonstrate improved QOL or more appropriate use of health care services. This study established that patients with lung cancer are less depressed and live longer when they receive palliative care services soon after diagnosis. It also showed a link between palliative care and a reduction in aggressive, possibly inappropriate, end-of-life treatment of metastatic cancer.

Several recent practice guidelines, including that of the Institute for Clinical Systems Improvement (ICSI), recommend that palliative care referrals be made early in the course of a progressive, debilitating illness, regardless of the patient’s life expectancy.⁷ Other organizations, including the Institute of Medicine and the World Health Organization, recommend palliative care as an essential component of comprehensive cancer care.⁸ This study supports both of these recommendations.

CAVEATS: Would extra attention from any clinician work equally well?

No attempt was made to control for the extra attention (an average of 4 visits) that the palliative care team provided to those in the intervention group. Thus, it is possible that the study results could be replicated by having patients meet with their primary care physician or another health professional instead of a palliative care team.

The reduction in depression and increase in survival are clinically significant outcomes. But the improvement in QOL (an average of 7 points better on the 136-point FACT-L scale, or 6 points on the 84-point TOI scale) may not be.

It is important to note, too, that the survival benefits the researchers found may not be generalizable to other kinds of cancers. In addition, most patients (97%) in this study were white, so the findings may be less generalizable to patients of other races. Nonetheless, we think it’s likely that the improvements in QOL and mood revealed in this study would be realized by most patients with terminal cancer who received early palliative care.

CHALLENGES TO IMPLEMENTATION: Palliative care must be explained—and available

Physicians must be able to explain to their patients the difference between palliative care and hospice—most notably, that patients can continue to receive anticancer treatment while receiving palliative care. The recommendation to seek palliative care should not be considered “giving up” on the patient.

In order to refer patients to palliative care early in the course of cancer care, physicians must have access to a palliative care team, which may not be available in all cases. In 2006, only 53% of hospitals with more than 50 beds reported having a palliative care program.⁵ If there is no such program available, physicians can refer to the ICSI guideline on palliative care for more information on how to implement elements of palliative care for their patients with advanced cancer.⁷

At its October 2010 meeting, the Advisory Committee on Immunization Practices (ACIP) made 2 additions to its recommendations for quadrivalent meningococcal conjugate vaccine (MCV4), based on evolving knowledge of the vaccine and its duration of protection.

• A booster dose at age 16 has been added to the routine schedule for those vaccinated at ages 11 to 12 years. A booster dose has also been added for those vaccinated at ages 13 to 15 years, although the recommended timing of this booster had not been finalized at press time.
• A 2-dose primary series, 2 months apart, is now recommended for patients at higher risk of meningococcal disease. The high-risk category includes those with persistent complement component deficiency, asplenia, or human immunodeficiency virus (HIV). High-risk patients who were previously vaccinated should receive a booster dose at the earliest opportunity and continue to receive boosters at the appropriate interval (3-5 years).

Meningitis is rare but serious
Meningococcal meningitis is a potentially devastating disease in adolescents and young adults. It has a case fatality rate of about 20%, and the sequelae for survivors can be severe: 3.1% require limb amputations and another 10.9% suffer neurological deficits.¹ Thankfully, meningococcal disease is rare, occurring at rates below 1 in 200,000 in the 11- to 15-year-old age group and less than 1 in 100,000 in the 16- to 21-year-old age group.²

Routine immunization with MCV4 is recommended for adolescents
In 2007, ACIP recommended routine use of MCV4 for adolescents between the ages of 11 and 18 years. The recommendation gave preference to immunization at ages 11 to 12 years, along with the other adolescent vaccines given at that time.³ Updated recommendations in effect in 2010 state that those at highest risk for meningococcal infection (those with functional or anatomic asplenia, C3 complement deficiency, or HIV infection) should be vaccinated with MCV4 starting at age 2 and revaccinated every 3 years if last vaccinated at 2 to 6 years, and every 5 years if last vaccinated at or after age 7.^4,5 TABLE 1 lists the recommendations for MCV4 in place prior to the October 2010 ACIP meeting.

Two MCV4 products are licensed for use in the United States: Menactra (Sanofi Pasteur) and Menveo (Novartis). Both contain antigens against 4 serotypes, A, C, Y, and W-135. Neither protects against type B, which causes a majority of the disease in infants.⁶ In recent years, serotype A disease has become extremely rare in the United States.⁶ MCV4 coverage for adolescents ages 13 to 17 years is increasing, going from 41.8% in 2008 to 53.6% in 2009.⁷

TABLE 1
Recommendations for MCV4 prior to October 2010^3-5

The new recommendations: One is more controversial than the other

The recommendation for a 2-dose primary series in high-risk groups was not controversial. The same conditions that place individuals at highest risk for meningococcal infection also result in a less robust response to a single dose of the vaccine, and a 2-dose series is needed to achieve protective antibody levels in a high proportion of those vaccine recipients.⁸ This recommendation will affect relatively few patients.

The recommendation for booster doses in the general adolescent population generated a lot more debate. Studies performed since the licensure of MCV4 have shown that levels of protective antibodies decline over time. Five years after vaccination, 50% of vaccine recipients have levels below that considered fully protective.² One small case-control study of 107 cases suggested that the number of years from receipt of the vaccine was a risk factor for meningococcal disease.²

However, rates of meningococcal meningitis in adolescents have been declining over the past few years (TABLE 2), and there are no surveillance data to support the conclusion that teens vaccinated at ages 11 to 12 years are at increased risk as they age. In addition, the number of cases is very low (TABLE 3) and the cost benefit analysis of a booster dose of MCV4 is very unfavorable.^1,2

TABLE 2
Rates* of serogroup C, Y, and W-135 meningococcal disease^†

TABLE 3
Average annual number of cases of C, Y, and W-135 meningococcal disease

ACIP weighed the options for a booster dose
Three options were presented at the October 2010 ACIP meeting:

• Option 1: No change to the current recommendation for vaccination of 11- to 12-year-olds. Wait and see what happens to disease incidence over several more years.
• Option 2: Move the age of vaccination to 15 years with no booster. This would allow protection to persist through the years of highest risk (16-21 years).
• Option 3: Keep the recommendation for vaccination at ages 11 to 12 years, and add a booster dose at age 16.

The first option was the least cost effective: $281,000/quality-adjusted life year (QALY). The second option was the most cost effective at $121,000/QALY. The last option came out in the middle: $157,000/QALY, but it would save the most lives—9 more per year compared with Option 2.¹ There is, however, a caveat with regard to the cost-effectiveness estimates. The numbers were obtained using incidence data from the year 2000; incidence has declined since then, and cost-effectiveness estimates would be much less favorable using today’s rates.

These issues were discussed at length, and the decision to add a booster dose at age 16 was made on a close vote. This decision illustrates how difficult vaccine policy-making has become in recent years, when choices must be made about recommending safe, effective, and expensive vaccines to prevent illnesses that are both rare and serious.

The new MCV4 recommendations will be added to the child immunization schedule for 2011.

The take-home message for family physicians is to strive to increase the proportion of 11- to 12-year-olds who are fully vaccinated and in 2011 to begin to advise those who are between the ages of 16 and 20 years of the recommendation for a booster dose of MCV4.

At its October 2010 meeting, the Advisory Committee on Immunization Practices (ACIP) made 2 additions to its recommendations for quadrivalent meningococcal conjugate vaccine (MCV4), based on evolving knowledge of the vaccine and its duration of protection.

• A booster dose at age 16 has been added to the routine schedule for those vaccinated at ages 11 to 12 years. A booster dose has also been added for those vaccinated at ages 13 to 15 years, although the recommended timing of this booster had not been finalized at press time.
• A 2-dose primary series, 2 months apart, is now recommended for patients at higher risk of meningococcal disease. The high-risk category includes those with persistent complement component deficiency, asplenia, or human immunodeficiency virus (HIV). High-risk patients who were previously vaccinated should receive a booster dose at the earliest opportunity and continue to receive boosters at the appropriate interval (3-5 years).

Meningitis is rare but serious
Meningococcal meningitis is a potentially devastating disease in adolescents and young adults. It has a case fatality rate of about 20%, and the sequelae for survivors can be severe: 3.1% require limb amputations and another 10.9% suffer neurological deficits.¹ Thankfully, meningococcal disease is rare, occurring at rates below 1 in 200,000 in the 11- to 15-year-old age group and less than 1 in 100,000 in the 16- to 21-year-old age group.²

Routine immunization with MCV4 is recommended for adolescents
In 2007, ACIP recommended routine use of MCV4 for adolescents between the ages of 11 and 18 years. The recommendation gave preference to immunization at ages 11 to 12 years, along with the other adolescent vaccines given at that time.³ Updated recommendations in effect in 2010 state that those at highest risk for meningococcal infection (those with functional or anatomic asplenia, C3 complement deficiency, or HIV infection) should be vaccinated with MCV4 starting at age 2 and revaccinated every 3 years if last vaccinated at 2 to 6 years, and every 5 years if last vaccinated at or after age 7.^4,5 TABLE 1 lists the recommendations for MCV4 in place prior to the October 2010 ACIP meeting.

Two MCV4 products are licensed for use in the United States: Menactra (Sanofi Pasteur) and Menveo (Novartis). Both contain antigens against 4 serotypes, A, C, Y, and W-135. Neither protects against type B, which causes a majority of the disease in infants.⁶ In recent years, serotype A disease has become extremely rare in the United States.⁶ MCV4 coverage for adolescents ages 13 to 17 years is increasing, going from 41.8% in 2008 to 53.6% in 2009.⁷

TABLE 1
Recommendations for MCV4 prior to October 2010^3-5

The new recommendations: One is more controversial than the other

The recommendation for a 2-dose primary series in high-risk groups was not controversial. The same conditions that place individuals at highest risk for meningococcal infection also result in a less robust response to a single dose of the vaccine, and a 2-dose series is needed to achieve protective antibody levels in a high proportion of those vaccine recipients.⁸ This recommendation will affect relatively few patients.

The recommendation for booster doses in the general adolescent population generated a lot more debate. Studies performed since the licensure of MCV4 have shown that levels of protective antibodies decline over time. Five years after vaccination, 50% of vaccine recipients have levels below that considered fully protective.² One small case-control study of 107 cases suggested that the number of years from receipt of the vaccine was a risk factor for meningococcal disease.²

However, rates of meningococcal meningitis in adolescents have been declining over the past few years (TABLE 2), and there are no surveillance data to support the conclusion that teens vaccinated at ages 11 to 12 years are at increased risk as they age. In addition, the number of cases is very low (TABLE 3) and the cost benefit analysis of a booster dose of MCV4 is very unfavorable.^1,2

TABLE 2
Rates* of serogroup C, Y, and W-135 meningococcal disease^†

TABLE 3
Average annual number of cases of C, Y, and W-135 meningococcal disease

ACIP weighed the options for a booster dose
Three options were presented at the October 2010 ACIP meeting:

• Option 1: No change to the current recommendation for vaccination of 11- to 12-year-olds. Wait and see what happens to disease incidence over several more years.
• Option 2: Move the age of vaccination to 15 years with no booster. This would allow protection to persist through the years of highest risk (16-21 years).
• Option 3: Keep the recommendation for vaccination at ages 11 to 12 years, and add a booster dose at age 16.

The first option was the least cost effective: $281,000/quality-adjusted life year (QALY). The second option was the most cost effective at $121,000/QALY. The last option came out in the middle: $157,000/QALY, but it would save the most lives—9 more per year compared with Option 2.¹ There is, however, a caveat with regard to the cost-effectiveness estimates. The numbers were obtained using incidence data from the year 2000; incidence has declined since then, and cost-effectiveness estimates would be much less favorable using today’s rates.

These issues were discussed at length, and the decision to add a booster dose at age 16 was made on a close vote. This decision illustrates how difficult vaccine policy-making has become in recent years, when choices must be made about recommending safe, effective, and expensive vaccines to prevent illnesses that are both rare and serious.

The new MCV4 recommendations will be added to the child immunization schedule for 2011.

The take-home message for family physicians is to strive to increase the proportion of 11- to 12-year-olds who are fully vaccinated and in 2011 to begin to advise those who are between the ages of 16 and 20 years of the recommendation for a booster dose of MCV4.

At its October 2010 meeting, the Advisory Committee on Immunization Practices (ACIP) made 2 additions to its recommendations for quadrivalent meningococcal conjugate vaccine (MCV4), based on evolving knowledge of the vaccine and its duration of protection.

• A booster dose at age 16 has been added to the routine schedule for those vaccinated at ages 11 to 12 years. A booster dose has also been added for those vaccinated at ages 13 to 15 years, although the recommended timing of this booster had not been finalized at press time.
• A 2-dose primary series, 2 months apart, is now recommended for patients at higher risk of meningococcal disease. The high-risk category includes those with persistent complement component deficiency, asplenia, or human immunodeficiency virus (HIV). High-risk patients who were previously vaccinated should receive a booster dose at the earliest opportunity and continue to receive boosters at the appropriate interval (3-5 years).

Meningitis is rare but serious
Meningococcal meningitis is a potentially devastating disease in adolescents and young adults. It has a case fatality rate of about 20%, and the sequelae for survivors can be severe: 3.1% require limb amputations and another 10.9% suffer neurological deficits.¹ Thankfully, meningococcal disease is rare, occurring at rates below 1 in 200,000 in the 11- to 15-year-old age group and less than 1 in 100,000 in the 16- to 21-year-old age group.²

Routine immunization with MCV4 is recommended for adolescents
In 2007, ACIP recommended routine use of MCV4 for adolescents between the ages of 11 and 18 years. The recommendation gave preference to immunization at ages 11 to 12 years, along with the other adolescent vaccines given at that time.³ Updated recommendations in effect in 2010 state that those at highest risk for meningococcal infection (those with functional or anatomic asplenia, C3 complement deficiency, or HIV infection) should be vaccinated with MCV4 starting at age 2 and revaccinated every 3 years if last vaccinated at 2 to 6 years, and every 5 years if last vaccinated at or after age 7.^4,5 TABLE 1 lists the recommendations for MCV4 in place prior to the October 2010 ACIP meeting.

Two MCV4 products are licensed for use in the United States: Menactra (Sanofi Pasteur) and Menveo (Novartis). Both contain antigens against 4 serotypes, A, C, Y, and W-135. Neither protects against type B, which causes a majority of the disease in infants.⁶ In recent years, serotype A disease has become extremely rare in the United States.⁶ MCV4 coverage for adolescents ages 13 to 17 years is increasing, going from 41.8% in 2008 to 53.6% in 2009.⁷

TABLE 1
Recommendations for MCV4 prior to October 2010^3-5

The new recommendations: One is more controversial than the other

The recommendation for a 2-dose primary series in high-risk groups was not controversial. The same conditions that place individuals at highest risk for meningococcal infection also result in a less robust response to a single dose of the vaccine, and a 2-dose series is needed to achieve protective antibody levels in a high proportion of those vaccine recipients.⁸ This recommendation will affect relatively few patients.

The recommendation for booster doses in the general adolescent population generated a lot more debate. Studies performed since the licensure of MCV4 have shown that levels of protective antibodies decline over time. Five years after vaccination, 50% of vaccine recipients have levels below that considered fully protective.² One small case-control study of 107 cases suggested that the number of years from receipt of the vaccine was a risk factor for meningococcal disease.²

However, rates of meningococcal meningitis in adolescents have been declining over the past few years (TABLE 2), and there are no surveillance data to support the conclusion that teens vaccinated at ages 11 to 12 years are at increased risk as they age. In addition, the number of cases is very low (TABLE 3) and the cost benefit analysis of a booster dose of MCV4 is very unfavorable.^1,2

TABLE 2
Rates* of serogroup C, Y, and W-135 meningococcal disease^†

TABLE 3
Average annual number of cases of C, Y, and W-135 meningococcal disease

ACIP weighed the options for a booster dose
Three options were presented at the October 2010 ACIP meeting:

• Option 1: No change to the current recommendation for vaccination of 11- to 12-year-olds. Wait and see what happens to disease incidence over several more years.
• Option 2: Move the age of vaccination to 15 years with no booster. This would allow protection to persist through the years of highest risk (16-21 years).
• Option 3: Keep the recommendation for vaccination at ages 11 to 12 years, and add a booster dose at age 16.

The first option was the least cost effective: $281,000/quality-adjusted life year (QALY). The second option was the most cost effective at $121,000/QALY. The last option came out in the middle: $157,000/QALY, but it would save the most lives—9 more per year compared with Option 2.¹ There is, however, a caveat with regard to the cost-effectiveness estimates. The numbers were obtained using incidence data from the year 2000; incidence has declined since then, and cost-effectiveness estimates would be much less favorable using today’s rates.

These issues were discussed at length, and the decision to add a booster dose at age 16 was made on a close vote. This decision illustrates how difficult vaccine policy-making has become in recent years, when choices must be made about recommending safe, effective, and expensive vaccines to prevent illnesses that are both rare and serious.

The new MCV4 recommendations will be added to the child immunization schedule for 2011.

The take-home message for family physicians is to strive to increase the proportion of 11- to 12-year-olds who are fully vaccinated and in 2011 to begin to advise those who are between the ages of 16 and 20 years of the recommendation for a booster dose of MCV4.

Evidence summary

A hematocrit >50% is the most frequent testosterone-related adverse event in clinical trials. In a meta-analysis of 19 randomized controlled trials (RCTs)—with a total of 1084 subjects, 651 on testosterone, 433 on placebo—testosterone-treated men were nearly 4 times as likely as placebo-treated men to have a hematocrit >50% (odds ratio [OR]=3.67; 95% confidence interval [CI], 1.82-7.51; number needed to harm [NNH]=14).¹ The clinical significance of the increase is unclear.

Increased BMD at lumbar spine
A meta-analysis of 5 RCTs with a total of 264 subjects (135 on testosterone, 129 on placebo) demonstrated a 3.7% (95% CI, 1.0%-6.4%) absolute increase over baseline in lumbar spine BMD after ?12 to 36 months of treatment.² However, pooled effects on lumbar spine BMD across all studies failed to reach statistical significance because of differences in baseline bone density among subjects (BMD increase=0.03 g/cm²; 95% CI, 0-0.07).

No studies in this meta-analysis showed statistically significant improvement in BMD at the femoral neck. We found no studies that demonstrated reduced fracture risk in patients taking testosterone replacement.

No correlation between testosterone therapy and cancer

Although testosterone can stimulate the growth of locally advanced and metastatic prostate cancer,3 at least 16 longitudinal studies have failed to show any correlation between testosterone replacement and the development of malignancy.4 In the previously mentioned meta-analysis of 19 RCTs, rates of prostate cancer, PSA >4 ng/mL, increase in International Prostate Symptom Score (IPSS) >4, and prostate biopsies were all numerically higher in testosterone-treated men, but the differences between the testosterone and placebo groups weren’t statistically significant.1 Moreover, the average serum PSA level in the testosterone-treated men increased only 0.3 ng/mL from a baseline of 1.3 ng/mL.

Testosterone lowers total cholesterol
A meta-analysis of 30 RCTs (1642 men, 808 on testosterone therapy, 834 on placebo) that assessed testosterone’s effect on lipid levels found that testosterone reduced total cholesterol levels by 16 mg/dL (95% CI, 6-26 mg/dL); effects on all other lipid fractions weren’t significant.⁵

A second meta-analysis of 16 RCTs (578 men, 320 on testosterone therapy, 258 on placebo) similarly showed that testosterone lowered total cholesterol levels by 8 mg/dL (95% CI, 4-14 mg/dL) and that its effects on other lipid fractions weren’t significant.² The previously mentioned meta-analyses of 19 and 30 RCTs found no significant difference in cardiovascular events between testosterone- and placebo-treated groups.^1,5

Optimal testosterone level is unknown
Data are inadequate to determine the optimal serum level of testosterone for efficacy and safety.³ Expert opinion suggests that because therapy is empiric, monitoring clinical response may help guide treatment more than testosterone level.⁶

What about the liver?
Oral testosterone can be associated with hepatotoxicity; it is seldom used in the United States. Liver monitoring is unnecessary for patients receiving testosterone by injection, patch, or transbuccal tablet.^7,8

Recommendations

Consensus guidelines for monitoring men on testosterone therapy overlap considerably with regard to monitoring clinical effectiveness, prostate measures, hematocrit, and BMD (TABLE).^3,6,9,10 Assessing testosterone level is recommended, with the aim of achieving levels in the mid-normal range.¹⁰

Table
Monitoring testosterone therapy: What the consensus guidelines say

Evidence summary

A hematocrit >50% is the most frequent testosterone-related adverse event in clinical trials. In a meta-analysis of 19 randomized controlled trials (RCTs)—with a total of 1084 subjects, 651 on testosterone, 433 on placebo—testosterone-treated men were nearly 4 times as likely as placebo-treated men to have a hematocrit >50% (odds ratio [OR]=3.67; 95% confidence interval [CI], 1.82-7.51; number needed to harm [NNH]=14).¹ The clinical significance of the increase is unclear.

Increased BMD at lumbar spine
A meta-analysis of 5 RCTs with a total of 264 subjects (135 on testosterone, 129 on placebo) demonstrated a 3.7% (95% CI, 1.0%-6.4%) absolute increase over baseline in lumbar spine BMD after ?12 to 36 months of treatment.² However, pooled effects on lumbar spine BMD across all studies failed to reach statistical significance because of differences in baseline bone density among subjects (BMD increase=0.03 g/cm²; 95% CI, 0-0.07).

No studies in this meta-analysis showed statistically significant improvement in BMD at the femoral neck. We found no studies that demonstrated reduced fracture risk in patients taking testosterone replacement.

No correlation between testosterone therapy and cancer

Although testosterone can stimulate the growth of locally advanced and metastatic prostate cancer,3 at least 16 longitudinal studies have failed to show any correlation between testosterone replacement and the development of malignancy.4 In the previously mentioned meta-analysis of 19 RCTs, rates of prostate cancer, PSA >4 ng/mL, increase in International Prostate Symptom Score (IPSS) >4, and prostate biopsies were all numerically higher in testosterone-treated men, but the differences between the testosterone and placebo groups weren’t statistically significant.1 Moreover, the average serum PSA level in the testosterone-treated men increased only 0.3 ng/mL from a baseline of 1.3 ng/mL.

Testosterone lowers total cholesterol
A meta-analysis of 30 RCTs (1642 men, 808 on testosterone therapy, 834 on placebo) that assessed testosterone’s effect on lipid levels found that testosterone reduced total cholesterol levels by 16 mg/dL (95% CI, 6-26 mg/dL); effects on all other lipid fractions weren’t significant.⁵

A second meta-analysis of 16 RCTs (578 men, 320 on testosterone therapy, 258 on placebo) similarly showed that testosterone lowered total cholesterol levels by 8 mg/dL (95% CI, 4-14 mg/dL) and that its effects on other lipid fractions weren’t significant.² The previously mentioned meta-analyses of 19 and 30 RCTs found no significant difference in cardiovascular events between testosterone- and placebo-treated groups.^1,5

Optimal testosterone level is unknown
Data are inadequate to determine the optimal serum level of testosterone for efficacy and safety.³ Expert opinion suggests that because therapy is empiric, monitoring clinical response may help guide treatment more than testosterone level.⁶

What about the liver?
Oral testosterone can be associated with hepatotoxicity; it is seldom used in the United States. Liver monitoring is unnecessary for patients receiving testosterone by injection, patch, or transbuccal tablet.^7,8

Recommendations

Consensus guidelines for monitoring men on testosterone therapy overlap considerably with regard to monitoring clinical effectiveness, prostate measures, hematocrit, and BMD (TABLE).^3,6,9,10 Assessing testosterone level is recommended, with the aim of achieving levels in the mid-normal range.¹⁰

Table
Monitoring testosterone therapy: What the consensus guidelines say

Evidence summary

A hematocrit >50% is the most frequent testosterone-related adverse event in clinical trials. In a meta-analysis of 19 randomized controlled trials (RCTs)—with a total of 1084 subjects, 651 on testosterone, 433 on placebo—testosterone-treated men were nearly 4 times as likely as placebo-treated men to have a hematocrit >50% (odds ratio [OR]=3.67; 95% confidence interval [CI], 1.82-7.51; number needed to harm [NNH]=14).¹ The clinical significance of the increase is unclear.

Increased BMD at lumbar spine
A meta-analysis of 5 RCTs with a total of 264 subjects (135 on testosterone, 129 on placebo) demonstrated a 3.7% (95% CI, 1.0%-6.4%) absolute increase over baseline in lumbar spine BMD after ?12 to 36 months of treatment.² However, pooled effects on lumbar spine BMD across all studies failed to reach statistical significance because of differences in baseline bone density among subjects (BMD increase=0.03 g/cm²; 95% CI, 0-0.07).

No studies in this meta-analysis showed statistically significant improvement in BMD at the femoral neck. We found no studies that demonstrated reduced fracture risk in patients taking testosterone replacement.

No correlation between testosterone therapy and cancer

Although testosterone can stimulate the growth of locally advanced and metastatic prostate cancer,3 at least 16 longitudinal studies have failed to show any correlation between testosterone replacement and the development of malignancy.4 In the previously mentioned meta-analysis of 19 RCTs, rates of prostate cancer, PSA >4 ng/mL, increase in International Prostate Symptom Score (IPSS) >4, and prostate biopsies were all numerically higher in testosterone-treated men, but the differences between the testosterone and placebo groups weren’t statistically significant.1 Moreover, the average serum PSA level in the testosterone-treated men increased only 0.3 ng/mL from a baseline of 1.3 ng/mL.

Testosterone lowers total cholesterol
A meta-analysis of 30 RCTs (1642 men, 808 on testosterone therapy, 834 on placebo) that assessed testosterone’s effect on lipid levels found that testosterone reduced total cholesterol levels by 16 mg/dL (95% CI, 6-26 mg/dL); effects on all other lipid fractions weren’t significant.⁵

A second meta-analysis of 16 RCTs (578 men, 320 on testosterone therapy, 258 on placebo) similarly showed that testosterone lowered total cholesterol levels by 8 mg/dL (95% CI, 4-14 mg/dL) and that its effects on other lipid fractions weren’t significant.² The previously mentioned meta-analyses of 19 and 30 RCTs found no significant difference in cardiovascular events between testosterone- and placebo-treated groups.^1,5

Optimal testosterone level is unknown
Data are inadequate to determine the optimal serum level of testosterone for efficacy and safety.³ Expert opinion suggests that because therapy is empiric, monitoring clinical response may help guide treatment more than testosterone level.⁶

What about the liver?
Oral testosterone can be associated with hepatotoxicity; it is seldom used in the United States. Liver monitoring is unnecessary for patients receiving testosterone by injection, patch, or transbuccal tablet.^7,8

Recommendations

Consensus guidelines for monitoring men on testosterone therapy overlap considerably with regard to monitoring clinical effectiveness, prostate measures, hematocrit, and BMD (TABLE).^3,6,9,10 Assessing testosterone level is recommended, with the aim of achieving levels in the mid-normal range.¹⁰

Table
Monitoring testosterone therapy: What the consensus guidelines say