Diana Mahoney

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

CANCUN, MEXICO - Scleroderma patients on angiotensin-converting enzyme inhibitors at the onset of scleroderma renal crisis do not appear to have worse outcomes than do those not taking the antihypertensive agents prior to the acute renal function deterioration, according to preliminary data from the largest prospective cohort study of incident scleroderma renal crisis to date.

The finding further fuels the ongoing debate over the role of angiotensin-converting enzyme (ACE) inhibitors as prophylaxis for scleroderma renal crisis (SRC), lead investigator Dr. Marie Hudson reported at the annual meeting of the Canadian Rheumatology.

Although the use of ACE inhibitors since the 1980s has dramatically improved the outcome of SRC patients – prior to their widespread use for this indication, SRC mortality was more than 80% – there is still room for substantial improvement, explained Dr. Hudson, noting that the 1- and 5-year survival rates hover around 75% and 65%, respectively, and approximately 19% die within 3 months of diagnosis. It is possible that earlier intervention with ACE inhibitors might improve SRC outcomes. Most likely to benefit are individuals considered at risk for the complication, including those with diffuse and rapidly progressing skin involvement, history of glucocorticoid use, and positive analysis of anti-RNA polymerase III antibodies. But not everyone agrees, she said. "[Opponents] have suggested that prophylactic ACE inhibition could delay the diagnosis [of SRC] because of normalized blood pressure and as a result lead to worse outcomes."

Because a trial of ACE inhibitors in non-SRC patients could carry some risk for participants, Dr. Hudson, a rheumatologist at the Jewish General Hospital and a faculty member at McGill University, Montreal, and her colleagues in the International Scleroderma Renal Crisis study instead sought to evaluate the outcomes of scleroderma patients who presented with incident SRC while taking ACE inhibitors immediately prior to the onset of the condition. To date, they have identified 94 cases of incident SRC nationwide using an ongoing, Internet-based survey in which the investigators e-mail nearly 600 participating physicians worldwide every other week to ask about new cases of SRC, she said. For each new case identified, the investigators collect data on patient demographics, disease characteristics, and exposure to ACE inhibitors. The investigators send recruiting physicians a follow-up case report form 1 year after a patient is identified, she explained, noting that the primary outcome measure is death or dialysis dependence at 1 year after SRC onset.

Of the 94 cases identified so far, 90% had hypertensive SRC and 10% had normotensive SRC; 47% had a history of glucocorticoid use immediately prior to SRC onset, at a mean dose of 17 mg prednisone/day; 15% had anti-RNA polymerase III antibodies; and 23% were on ACE inhibitors prior to the onset of disease, said Dr. Hudson. "Proportionally, more of the normotensive SRC patients were on ACE inhibitors than hypotensive SRC patients."

An analysis of the 1-year follow up data that have been collected to date showed that more than 50% of the patients have died or remain on dialysis at 1 year, Dr. Hudson reported. "So far, there is no evidence that those exposed to ACE inhibitors prior to SRC had worse outcomes," she said, stressing that the findings are preliminary as the collection of 1-year follow-up data is ongoing.

As new data are collected and the findings are validated through additional studies, "we hope to offer new insight into the role of ACE inhibitors in patients with scleroderma," said Dr. Hudson. The use of the Internet-survey technology, in particular, has streamlined the research process because it has facilitated international collaboration and allowed the collection of a substantial amount of information on a rare condition in a short period of time, she said.

Dr. Hudson disclosed a financial relationship with Pfizer, which manufactures several ACE inhibitors.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Hospital/Texas A&M Health Science Center in Temple. "The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects."

Neonatal seizures affect approximately 1-4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, "yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment," Dr. Khan said at the annual meeting of the American Epilepsy Society.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types only in children aged 16 years and older, but "it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients," he said.

To evaluate the efficacy and tolerability of intravenous levetiracetam therapy for acute seizure management during the neonatal period, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns included in the analysis typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

"Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose," Dr. Khan reported, noting that they responded both electrographically and clinically.

After the loading dose, no further seizures were recorded while on intravenous levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported, adding that no major or immediate adverse effects were reported during follow-up, which ranged from 2 to 6 months.

Dr. Khan reported that he and his colleagues had no financial disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Healthcare in Temple. “The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects.”

Neonatal seizures affect 1–4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, “yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment,” Dr. Khan said at the meeting.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types in children aged 16 years and older, but “it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients,” he said.

To evaluate the efficacy and tolerability of IV levetiracetam therapy for acute seizure management in neonates, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

“Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose,” Dr. Khan reported.

After the loading dose, no further seizures were recorded while on IV levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported. No major or immediate adverse effects were reported during follow-up of 2–6 months.

Dr. Khan and his colleagues had no disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Healthcare in Temple. “The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects.”

Neonatal seizures affect 1–4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, “yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment,” Dr. Khan said at the meeting.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types in children aged 16 years and older, but “it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients,” he said.

To evaluate the efficacy and tolerability of IV levetiracetam therapy for acute seizure management in neonates, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

“Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose,” Dr. Khan reported.

After the loading dose, no further seizures were recorded while on IV levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported. No major or immediate adverse effects were reported during follow-up of 2–6 months.

Dr. Khan and his colleagues had no disclosures.

SAN ANTONIO – Intravenous levetiracetam safely and effectively halted acute neonatal seizures within 72 hours in a retrospective study of 22 newborns treated with the drug at a Texas hospital.

The findings, if validated through larger studies, could represent a major shift in the management of neonatal seizures, said Dr. Owais Ahmed Khan of Scott & White Healthcare in Temple. “The antiepileptic medications that are currently approved for neonatal seizures – including phenobarbital, phenytoin, and lorazepam – are effective in less than 50% of newborns and can have serious long-term effects.”

Neonatal seizures affect 1–4 of 1,000 live births in North America and are a major predictor of adverse neurologic outcomes, “yet very few antiepileptic medications carry [a Food and Drug Administration–approved] indication for their treatment,” Dr. Khan said at the meeting.

Intravenous levetiracetam (Keppra) is approved as adjunctive treatment for various seizure types in children aged 16 years and older, but “it is being increasingly used off label in pediatric patients because of literature documenting efficacy and safety in adults, along with favorable anecdotal reports in younger patients,” he said.

To evaluate the efficacy and tolerability of IV levetiracetam therapy for acute seizure management in neonates, Dr. Khan and colleagues reviewed the charts of all term and near-term neonates who received the drug at their institution between January 2007 and December 2009. The 12 female and 10 male newborns typically received a bolus dose of 50 mg/kg of levetiracetam followed by a maintenance dose of 25 mg/kg every 12 hours, infused over 15 minutes to 1 hour.

“Nineteen of the newborns [86%] experienced immediate seizure control within 1 hour of the loading dose,” Dr. Khan reported.

After the loading dose, no further seizures were recorded while on IV levetiracetam in seven (32%) of the newborns. Seizures stopped altogether within 24 hours of the loading dose in 14 patients (64%) and within 48 hours in 19 patients (86%). All 22 were seizure free within 72 hours, he said.

All of the newborns were switched to oral levetiracetam while in the hospital, and 81% were discharged home on levetiracetam monotherapy, Dr. Khan reported. No major or immediate adverse effects were reported during follow-up of 2–6 months.

Dr. Khan and his colleagues had no disclosures.

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, “a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging,” the AAP Subcommittee on Febrile Seizures wrote.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6–60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769–72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and her associates (Pediatrics 2011;127:389–94).

Dr. Duffner noted in an interview that the biggest change is in the recommendation regarding lumbar punctures. In the prior guideline, lumbar punctures were strongly considered for children aged 6–12 months and considered for those aged 12–18 months. With the advent of routine immunizations for Haemophilus influenzae and Streptococcus pneumoniae, the risk of simple febrile seizures being caused by bacterial meningitis is much reduced, she said. The caveat is the child who has not been immunized and the child who is on antibiotics which may mask the infection. In those cases, the physician will need to be more cautious in his/her evaluation of the child.

According to the document:

▸ Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or S. pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but “current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity),” the guideline says.

▸ Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. “There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years,” the authors wrote.

▸ Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. “When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself,” Dr. Duffner and her associates concluded.

▸ Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. “The literature does not support the use of skull films in evaluation of the child with a febrile seizure,” they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that “CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost,” the authors said.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

View on the News

Lumbar Puncture Advice Helpful

The guidelines on when to do a lumbar puncture “in the context of lack of immunization and pretreatment with antibiotics will be most useful with regard to decision making in this carefully defined patient population,” Dr. Jeffrey Buchhalter said in an interview. The authors “were very specific regarding age of inclusion and consideration of only simple febrile seizures in their recommendation.”

“My general impression is that many individuals who evaluate children with simple febrile seizures recognize the very low utility of neuroimaging but obtain head CT anyway due to concern regarding litigation if anything is missed. The strong recommendation not to obtain skull films is appropriate, but in my experience has not been used with any frequency during the last decade,” he said.

“The guidelines make sense as so much credence is given to observational studies – what we commonly see in clinical practice. Furthermore, the recommendations take into account a benefit/harm consideration that each clinician confronts. Thus, implementation should occur with a caveat regarding perceived medical-legal liability regarding neuroimaging and other testing.

“However, a potential reason not to implement these guidelines is precisely because of the lack of high-quality evidence proving or disproving each recommendation. This is an interesting conundrum that we face in creating guidelines that are truly evidence based yet clinically relevant,” Dr. Buchhalter concluded.

DR. BUCHHALTER is chief of neurology at Phoenix Children's Hospital. Dr. Buchhalter has received personal compensation for activities with the National Institute of Neurological Disorders and Stroke, and he has received research support from Ovation Pharmaceuticals, Inc. and Pfizer Inc.

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, “a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging,” the AAP Subcommittee on Febrile Seizures wrote.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6–60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769–72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and her associates (Pediatrics 2011;127:389–94).

Dr. Duffner noted in an interview that the biggest change is in the recommendation regarding lumbar punctures. In the prior guideline, lumbar punctures were strongly considered for children aged 6–12 months and considered for those aged 12–18 months. With the advent of routine immunizations for Haemophilus influenzae and Streptococcus pneumoniae, the risk of simple febrile seizures being caused by bacterial meningitis is much reduced, she said. The caveat is the child who has not been immunized and the child who is on antibiotics which may mask the infection. In those cases, the physician will need to be more cautious in his/her evaluation of the child.

According to the document:

▸ Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or S. pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but “current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity),” the guideline says.

▸ Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. “There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years,” the authors wrote.

▸ Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. “When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself,” Dr. Duffner and her associates concluded.

▸ Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. “The literature does not support the use of skull films in evaluation of the child with a febrile seizure,” they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that “CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost,” the authors said.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

View on the News

Lumbar Puncture Advice Helpful

The guidelines on when to do a lumbar puncture “in the context of lack of immunization and pretreatment with antibiotics will be most useful with regard to decision making in this carefully defined patient population,” Dr. Jeffrey Buchhalter said in an interview. The authors “were very specific regarding age of inclusion and consideration of only simple febrile seizures in their recommendation.”

“My general impression is that many individuals who evaluate children with simple febrile seizures recognize the very low utility of neuroimaging but obtain head CT anyway due to concern regarding litigation if anything is missed. The strong recommendation not to obtain skull films is appropriate, but in my experience has not been used with any frequency during the last decade,” he said.

“The guidelines make sense as so much credence is given to observational studies – what we commonly see in clinical practice. Furthermore, the recommendations take into account a benefit/harm consideration that each clinician confronts. Thus, implementation should occur with a caveat regarding perceived medical-legal liability regarding neuroimaging and other testing.

“However, a potential reason not to implement these guidelines is precisely because of the lack of high-quality evidence proving or disproving each recommendation. This is an interesting conundrum that we face in creating guidelines that are truly evidence based yet clinically relevant,” Dr. Buchhalter concluded.

DR. BUCHHALTER is chief of neurology at Phoenix Children's Hospital. Dr. Buchhalter has received personal compensation for activities with the National Institute of Neurological Disorders and Stroke, and he has received research support from Ovation Pharmaceuticals, Inc. and Pfizer Inc.

Identifying the cause of fever should be the top priority when evaluating infants or young children after a simple febrile seizure, and the differential diagnosis should always include meningitis, according to a new clinical practice guideline published by the American Academy of Pediatrics.

In most situations, however, “a simple febrile seizure does not usually require further evaluation, specifically electroencephalography, blood studies, or neuroimaging,” the AAP Subcommittee on Febrile Seizures wrote.

The new guideline replaces the 1996 AAP practice parameter for the neurodiagnostic evaluation of healthy infants and children 6–60 months of age who have had a simple febrile seizure and who present for evaluation within 12 hours of the event (Pediatrics 1996;97:769–72).

The new document is based on a comprehensive review of the evidence-based literature published from 1996 to February 2009, with an emphasis on research that differentiated simple febrile seizures from other seizure types. The final recommendations, presented as action statements relating to the use of lumbar puncture, electroencephalography, laboratory testing, and neuroimaging, were developed based on the quality of supporting evidence and the balance of benefit and harm if the given policy is carried out, said lead author Dr. Patricia K. Duffner, professor of neurology and pediatrics at the State University of New York at Buffalo, and her associates (Pediatrics 2011;127:389–94).

Dr. Duffner noted in an interview that the biggest change is in the recommendation regarding lumbar punctures. In the prior guideline, lumbar punctures were strongly considered for children aged 6–12 months and considered for those aged 12–18 months. With the advent of routine immunizations for Haemophilus influenzae and Streptococcus pneumoniae, the risk of simple febrile seizures being caused by bacterial meningitis is much reduced, she said. The caveat is the child who has not been immunized and the child who is on antibiotics which may mask the infection. In those cases, the physician will need to be more cautious in his/her evaluation of the child.

According to the document:

▸ Lumbar puncture. It is strongly recommended for children who present with febrile seizure and have meningeal signs and symptoms, including neck stiffness, Kernig signs, or Brudzinski signs, or those whose history or exam suggests possible meningitis or intracranial infection. The procedure is optional for infants between 6 and 12 months who have not received scheduled Haemophilus influenzae type b (Hib) or S. pneumoniae immunizations or when immunization status is unknown, and for children with febrile seizure who have been pretreated with antibiotics, which could potentially mask the signs and symptoms of meningitis.

Since the previous practice parameter was published, there has been widespread immunization in the United States for two of the most common causes of bacterial meningitis in this age range: Hib and S. pneumoniae. Compliance with all recommended immunizations does not completely eliminate the possibility of bacterial meningitis from the differential diagnosis, but “current data no longer support routine lumbar puncture in well-appearing, fully immunized children who present with a simple febrile seizure. Moreover, although approximately 25% of young children with meningitis have seizures as the presenting sign of the disease, some are either obtunded or comatose when evaluated by a physician for the seizure, and the remainder most often have obvious clinical signs of meningitis (focal seizures, recurrent seizures, petechial rash, or nuchal rigidity),” the guideline says.

▸ Electroencephalography (EEG). It should not be used routinely in the evaluation of simple febrile seizures in otherwise neurologically healthy children. “There is no evidence that EEG readings performed either at the time of presentation after a simple febrile seizure or within the following month are predictive of either recurrence of febrile seizures or the development of afebrile seizures/epilepsy within the next 2 years,” the authors wrote.

▸ Measurement of serum electrolytes, calcium, phosphorus, magnesium, blood glucose, or complete blood cell count. Such measurements should not be performed routinely for the sole purpose of identifying the cause of a simple febrile seizure. “When fever is present, the decision regarding the need for laboratory testing should be directed toward identifying the source of the fever rather than as part of the routine evaluation of the seizure itself,” Dr. Duffner and her associates concluded.

▸ Neuroimaging. It is not recommended for the routine evaluation of children who present with simple febrile seizures. “The literature does not support the use of skull films in evaluation of the child with a febrile seizure,” they explained, nor have data been published that support or negate the need for CT or MRI in this population.

Data do show that “CT scanning is associated with radiation exposure that may escalate future cancer risk. MRI is associated with risks from required sedation and high cost,” the authors said.

All of the authors filed conflict of interest statements with the AAP, and any conflicts have been resolved through a process approved by the Board of Directors. The AAP reported having neither solicited nor accepted any commercial involvement in the development of the revised guideline.

View on the News

Lumbar Puncture Advice Helpful

The guidelines on when to do a lumbar puncture “in the context of lack of immunization and pretreatment with antibiotics will be most useful with regard to decision making in this carefully defined patient population,” Dr. Jeffrey Buchhalter said in an interview. The authors “were very specific regarding age of inclusion and consideration of only simple febrile seizures in their recommendation.”

“My general impression is that many individuals who evaluate children with simple febrile seizures recognize the very low utility of neuroimaging but obtain head CT anyway due to concern regarding litigation if anything is missed. The strong recommendation not to obtain skull films is appropriate, but in my experience has not been used with any frequency during the last decade,” he said.

“The guidelines make sense as so much credence is given to observational studies – what we commonly see in clinical practice. Furthermore, the recommendations take into account a benefit/harm consideration that each clinician confronts. Thus, implementation should occur with a caveat regarding perceived medical-legal liability regarding neuroimaging and other testing.

“However, a potential reason not to implement these guidelines is precisely because of the lack of high-quality evidence proving or disproving each recommendation. This is an interesting conundrum that we face in creating guidelines that are truly evidence based yet clinically relevant,” Dr. Buchhalter concluded.

DR. BUCHHALTER is chief of neurology at Phoenix Children's Hospital. Dr. Buchhalter has received personal compensation for activities with the National Institute of Neurological Disorders and Stroke, and he has received research support from Ovation Pharmaceuticals, Inc. and Pfizer Inc.

Most cases of Lyme arthritis are brief and can be managed successfully with oral antibiotics, according to a recent review article. A delayed or missed diagnosis, however, increases the likelihood that the inflammatory response triggered by infection with the tick-borne B orrelia burgdorferi spirochete, will lead to permanent joint damage, according to Dr. Brian G. Smith of Yale University in New Haven, Conn., snd colleagues. For this reason, they stressed, Lyme arthritis “should be considered in the evaluation of patients with monoarticular or pauciarticular joint complaints in a geographic area in which Lyme disease is endemic.”

Timely diagnosis of Lyme arthritis is often hampered by the fact that the clinical presentation – including recurrent episodes of joint swelling, typically in large joints such as the knee, but also possibly in the ankle, wrist, hip, or elbow; large effusions that may be out of proportion to patients' complaints; and, occasionally, fever – can be similar to that of inflammatory arthritides or acute bacterial septic arthritis, especially in children, the authors wrote (J. Am. Acad. Orthop. Surg. 2011;19:91-100).

In patients with acute symptoms, rheumatologists or orthopedic surgeons “may be asked to evaluate a child who presents to the emergency department with an acutely swollen, tender joint as well as other Lyme disease–related symptoms that may be indicative of bacterial septic arthritis, such as malaise or irritability with or without fever and limited weight bearing.” Joint-fluid analyses in patients with both diseases frequently reveal “strikingly elevated joint leukocyte counts,” occasionally leading to unnecessary surgical joint debridement in patients erroneously diagnosed with septic arthritis, they stated.

Because of the similar and overlapping presentations and the fact that an accurate, reliable rapid test for Lyme disease is not widely available, “clinical and laboratory variables should be used as tools in the diagnostic armamentarium,” the authors wrote. Although these variables have not been definitively established, the findings of a retrospective comparison of the clinical indications and laboratory results of children who presented to the emergency department with serologically confirmed Lyme arthritis and those who presented with septic arthritis identified a negative history of fever, knee involvement, and normal C-reactive protein (CRP) levels as important predictors of Lyme arthritis (Pediatrics. 2009; 123:959-65).

More recently, the authors of the current study conducted a review of children who presented to their institution with joint effusion, and determined that – relative to patients with septic arthritis – those with Lyme arthritis “had a lower average peripheral white blood count, lower percentage of neutrophils in the differential, were less likely to present with a temperature [greater than] 101.5[° F], and were less likely to refuse to bear weight on the affected extremity,” they wrote. “No statistically significant difference existed between the two groups with regard to erythrocyte sedimentation rate and CRP level” (J. Bone Joint Surg. Am. 2011;93:252-60).

Following an accurate diagnosis, “Lyme arthritis has an excellent prognosis with appropriate management,” the authors stressed. In adults without neurologic involvement, this includes a 28-day course of 100-mg doxycycline twice daily, 500-mg amoxicillin three times daily, or 500-mg cefuroxime axetil twice daily. The recommended treatment for children is a 28-day course of 50-mg/kg amoxicillin divided into three doses daily, 30-mg/kg cefuroxime axetil divided into two doses daily, or – for patients aged 8 years or older – 4-mg/kg doxycycline divided into two doses daily, they wrote.

Patients with mild persistent or recurrent synovitis after the initial therapeutic course should repeat the 28-day antibiotic course, whereas those with moderate to severe persistent arthritis should begin a 2-week or 4-week course of parenteral antibiotics, the authors wrote, noting that those with persistent symptoms after two treatment courses should undergo polymerase chain reaction (PCR) testing. Patients with positive PCR results should repeat the oral antibiotic regimen for 28 days, whereas those with negative PCR results may be treated with NSAIDs and intra-articular corticosteroids, they stated. Hydroxychloroquine, which may have antispirochetal and anti-inflammatory effects, may be used in the negative PCR patients, and “there may be a role for certain disease-modifying antirheumatic agents in the management of chronic Lyme arthritis, but experience with their use in this setting is limited,” they said.

For patients with antibiotic-refractory Lyme arthritis, “arthroscopic synovectomy is a reasonable treatment option,” the authors wrote, alluding to small case series demonstrating marked resolution of joint inflammation and maintained improvement follow the surgical procedure in treatment-refractory patients.

Increased awareness of the symptoms and risk factors associated with Lyme disease is needed to improve detection and treatment of Lyme arthritis, and further research is warranted to better distinguish between Lyme arthritis and other types of arthritis in symptomatic patients because the management approaches are inherently different, the authors concluded.

Dr. Smith disclosed a financial relationship with Stryker. Study coauthor Dr. Eugene D. Shapiro, also of Yale University, disclosed affiliations with the American Board of Pediatrics' Board on Infectious Diseases, and the American Lyme Disease Foundation.

The skin rash rash characteric of Lyme disease is shown here on the thigh of a 59-year-old woman.

Source ©Caliendo/CMSP.com

Most cases of Lyme arthritis are brief and can be managed successfully with oral antibiotics, according to a recent review article. A delayed or missed diagnosis, however, increases the likelihood that the inflammatory response triggered by infection with the tick-borne B orrelia burgdorferi spirochete, will lead to permanent joint damage, according to Dr. Brian G. Smith of Yale University in New Haven, Conn., snd colleagues. For this reason, they stressed, Lyme arthritis “should be considered in the evaluation of patients with monoarticular or pauciarticular joint complaints in a geographic area in which Lyme disease is endemic.”

Timely diagnosis of Lyme arthritis is often hampered by the fact that the clinical presentation – including recurrent episodes of joint swelling, typically in large joints such as the knee, but also possibly in the ankle, wrist, hip, or elbow; large effusions that may be out of proportion to patients' complaints; and, occasionally, fever – can be similar to that of inflammatory arthritides or acute bacterial septic arthritis, especially in children, the authors wrote (J. Am. Acad. Orthop. Surg. 2011;19:91-100).

In patients with acute symptoms, rheumatologists or orthopedic surgeons “may be asked to evaluate a child who presents to the emergency department with an acutely swollen, tender joint as well as other Lyme disease–related symptoms that may be indicative of bacterial septic arthritis, such as malaise or irritability with or without fever and limited weight bearing.” Joint-fluid analyses in patients with both diseases frequently reveal “strikingly elevated joint leukocyte counts,” occasionally leading to unnecessary surgical joint debridement in patients erroneously diagnosed with septic arthritis, they stated.

Because of the similar and overlapping presentations and the fact that an accurate, reliable rapid test for Lyme disease is not widely available, “clinical and laboratory variables should be used as tools in the diagnostic armamentarium,” the authors wrote. Although these variables have not been definitively established, the findings of a retrospective comparison of the clinical indications and laboratory results of children who presented to the emergency department with serologically confirmed Lyme arthritis and those who presented with septic arthritis identified a negative history of fever, knee involvement, and normal C-reactive protein (CRP) levels as important predictors of Lyme arthritis (Pediatrics. 2009; 123:959-65).

More recently, the authors of the current study conducted a review of children who presented to their institution with joint effusion, and determined that – relative to patients with septic arthritis – those with Lyme arthritis “had a lower average peripheral white blood count, lower percentage of neutrophils in the differential, were less likely to present with a temperature [greater than] 101.5[° F], and were less likely to refuse to bear weight on the affected extremity,” they wrote. “No statistically significant difference existed between the two groups with regard to erythrocyte sedimentation rate and CRP level” (J. Bone Joint Surg. Am. 2011;93:252-60).

Following an accurate diagnosis, “Lyme arthritis has an excellent prognosis with appropriate management,” the authors stressed. In adults without neurologic involvement, this includes a 28-day course of 100-mg doxycycline twice daily, 500-mg amoxicillin three times daily, or 500-mg cefuroxime axetil twice daily. The recommended treatment for children is a 28-day course of 50-mg/kg amoxicillin divided into three doses daily, 30-mg/kg cefuroxime axetil divided into two doses daily, or – for patients aged 8 years or older – 4-mg/kg doxycycline divided into two doses daily, they wrote.

Patients with mild persistent or recurrent synovitis after the initial therapeutic course should repeat the 28-day antibiotic course, whereas those with moderate to severe persistent arthritis should begin a 2-week or 4-week course of parenteral antibiotics, the authors wrote, noting that those with persistent symptoms after two treatment courses should undergo polymerase chain reaction (PCR) testing. Patients with positive PCR results should repeat the oral antibiotic regimen for 28 days, whereas those with negative PCR results may be treated with NSAIDs and intra-articular corticosteroids, they stated. Hydroxychloroquine, which may have antispirochetal and anti-inflammatory effects, may be used in the negative PCR patients, and “there may be a role for certain disease-modifying antirheumatic agents in the management of chronic Lyme arthritis, but experience with their use in this setting is limited,” they said.

For patients with antibiotic-refractory Lyme arthritis, “arthroscopic synovectomy is a reasonable treatment option,” the authors wrote, alluding to small case series demonstrating marked resolution of joint inflammation and maintained improvement follow the surgical procedure in treatment-refractory patients.

Increased awareness of the symptoms and risk factors associated with Lyme disease is needed to improve detection and treatment of Lyme arthritis, and further research is warranted to better distinguish between Lyme arthritis and other types of arthritis in symptomatic patients because the management approaches are inherently different, the authors concluded.

Dr. Smith disclosed a financial relationship with Stryker. Study coauthor Dr. Eugene D. Shapiro, also of Yale University, disclosed affiliations with the American Board of Pediatrics' Board on Infectious Diseases, and the American Lyme Disease Foundation.

The skin rash rash characteric of Lyme disease is shown here on the thigh of a 59-year-old woman.

Source ©Caliendo/CMSP.com

Most cases of Lyme arthritis are brief and can be managed successfully with oral antibiotics, according to a recent review article. A delayed or missed diagnosis, however, increases the likelihood that the inflammatory response triggered by infection with the tick-borne B orrelia burgdorferi spirochete, will lead to permanent joint damage, according to Dr. Brian G. Smith of Yale University in New Haven, Conn., snd colleagues. For this reason, they stressed, Lyme arthritis “should be considered in the evaluation of patients with monoarticular or pauciarticular joint complaints in a geographic area in which Lyme disease is endemic.”

Timely diagnosis of Lyme arthritis is often hampered by the fact that the clinical presentation – including recurrent episodes of joint swelling, typically in large joints such as the knee, but also possibly in the ankle, wrist, hip, or elbow; large effusions that may be out of proportion to patients' complaints; and, occasionally, fever – can be similar to that of inflammatory arthritides or acute bacterial septic arthritis, especially in children, the authors wrote (J. Am. Acad. Orthop. Surg. 2011;19:91-100).

In patients with acute symptoms, rheumatologists or orthopedic surgeons “may be asked to evaluate a child who presents to the emergency department with an acutely swollen, tender joint as well as other Lyme disease–related symptoms that may be indicative of bacterial septic arthritis, such as malaise or irritability with or without fever and limited weight bearing.” Joint-fluid analyses in patients with both diseases frequently reveal “strikingly elevated joint leukocyte counts,” occasionally leading to unnecessary surgical joint debridement in patients erroneously diagnosed with septic arthritis, they stated.

Because of the similar and overlapping presentations and the fact that an accurate, reliable rapid test for Lyme disease is not widely available, “clinical and laboratory variables should be used as tools in the diagnostic armamentarium,” the authors wrote. Although these variables have not been definitively established, the findings of a retrospective comparison of the clinical indications and laboratory results of children who presented to the emergency department with serologically confirmed Lyme arthritis and those who presented with septic arthritis identified a negative history of fever, knee involvement, and normal C-reactive protein (CRP) levels as important predictors of Lyme arthritis (Pediatrics. 2009; 123:959-65).

More recently, the authors of the current study conducted a review of children who presented to their institution with joint effusion, and determined that – relative to patients with septic arthritis – those with Lyme arthritis “had a lower average peripheral white blood count, lower percentage of neutrophils in the differential, were less likely to present with a temperature [greater than] 101.5[° F], and were less likely to refuse to bear weight on the affected extremity,” they wrote. “No statistically significant difference existed between the two groups with regard to erythrocyte sedimentation rate and CRP level” (J. Bone Joint Surg. Am. 2011;93:252-60).

Following an accurate diagnosis, “Lyme arthritis has an excellent prognosis with appropriate management,” the authors stressed. In adults without neurologic involvement, this includes a 28-day course of 100-mg doxycycline twice daily, 500-mg amoxicillin three times daily, or 500-mg cefuroxime axetil twice daily. The recommended treatment for children is a 28-day course of 50-mg/kg amoxicillin divided into three doses daily, 30-mg/kg cefuroxime axetil divided into two doses daily, or – for patients aged 8 years or older – 4-mg/kg doxycycline divided into two doses daily, they wrote.

Patients with mild persistent or recurrent synovitis after the initial therapeutic course should repeat the 28-day antibiotic course, whereas those with moderate to severe persistent arthritis should begin a 2-week or 4-week course of parenteral antibiotics, the authors wrote, noting that those with persistent symptoms after two treatment courses should undergo polymerase chain reaction (PCR) testing. Patients with positive PCR results should repeat the oral antibiotic regimen for 28 days, whereas those with negative PCR results may be treated with NSAIDs and intra-articular corticosteroids, they stated. Hydroxychloroquine, which may have antispirochetal and anti-inflammatory effects, may be used in the negative PCR patients, and “there may be a role for certain disease-modifying antirheumatic agents in the management of chronic Lyme arthritis, but experience with their use in this setting is limited,” they said.

For patients with antibiotic-refractory Lyme arthritis, “arthroscopic synovectomy is a reasonable treatment option,” the authors wrote, alluding to small case series demonstrating marked resolution of joint inflammation and maintained improvement follow the surgical procedure in treatment-refractory patients.

Increased awareness of the symptoms and risk factors associated with Lyme disease is needed to improve detection and treatment of Lyme arthritis, and further research is warranted to better distinguish between Lyme arthritis and other types of arthritis in symptomatic patients because the management approaches are inherently different, the authors concluded.

Dr. Smith disclosed a financial relationship with Stryker. Study coauthor Dr. Eugene D. Shapiro, also of Yale University, disclosed affiliations with the American Board of Pediatrics' Board on Infectious Diseases, and the American Lyme Disease Foundation.

The skin rash rash characteric of Lyme disease is shown here on the thigh of a 59-year-old woman.

Source ©Caliendo/CMSP.com