Jane Salodof MacNeil

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said that he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use],” he said.

Dr. Buzdar, professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. “Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said.

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 centers in 21 countries. A combination arm using tamoxifen and anastrozole was dropped after analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%). The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Backs Aromatase Inhibitors but Questions Remain

Dr. Buzdar is also the first author of a consensus statement published by an international panel of 24 breast cancer experts who met in December 2005 to review the major randomized trials of adjuvant treatment with tamoxifen and aromatase inhibitors.

The International Aromatase Inhibitor Expert Panel concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85).

They also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known. “It is possible that shorter or longer periods of adjuvant therapy may be suitable for different patients, depending upon their specific disease characteristics,” the panel wrote.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

Some studies have associated tamoxifen with increased risk of stroke, endometrial cancer, and possibly deep venous thrombosis. The panel found that these risks are not predictable in individual patients, however. It also suggested that stroke risk may be reduced with one or more aromatase inhibitors, but more evidence is needed.

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said that he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use],” he said.

Dr. Buzdar, professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. “Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said.

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 centers in 21 countries. A combination arm using tamoxifen and anastrozole was dropped after analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%). The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Backs Aromatase Inhibitors but Questions Remain

Dr. Buzdar is also the first author of a consensus statement published by an international panel of 24 breast cancer experts who met in December 2005 to review the major randomized trials of adjuvant treatment with tamoxifen and aromatase inhibitors.

The International Aromatase Inhibitor Expert Panel concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85).

They also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known. “It is possible that shorter or longer periods of adjuvant therapy may be suitable for different patients, depending upon their specific disease characteristics,” the panel wrote.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

Some studies have associated tamoxifen with increased risk of stroke, endometrial cancer, and possibly deep venous thrombosis. The panel found that these risks are not predictable in individual patients, however. It also suggested that stroke risk may be reduced with one or more aromatase inhibitors, but more evidence is needed.

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said that he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use],” he said.

Dr. Buzdar, professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. “Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said.

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 centers in 21 countries. A combination arm using tamoxifen and anastrozole was dropped after analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%). The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Backs Aromatase Inhibitors but Questions Remain

Dr. Buzdar is also the first author of a consensus statement published by an international panel of 24 breast cancer experts who met in December 2005 to review the major randomized trials of adjuvant treatment with tamoxifen and aromatase inhibitors.

The International Aromatase Inhibitor Expert Panel concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85).

They also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known. “It is possible that shorter or longer periods of adjuvant therapy may be suitable for different patients, depending upon their specific disease characteristics,” the panel wrote.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

Some studies have associated tamoxifen with increased risk of stroke, endometrial cancer, and possibly deep venous thrombosis. The panel found that these risks are not predictable in individual patients, however. It also suggested that stroke risk may be reduced with one or more aromatase inhibitors, but more evidence is needed.

ATLANTA — Whole-brain radiation therapy can preserve neurocognitive function in patients with brain metastases, according to a 135-patient study presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Jing Li reported that patients lived longer and had better neurocognitive function if their tumors shrank more than 45% during the 2 months after whole-brain radiation therapy (WBRT).

These “good responders” scored better on all eight neurocognitive tests used in the study, compared with “poor responders” with less than 45% tumor shrinkage at the 2-month mark. The effects were statistically significant over the course of the study on tests of executive function and fine motor coordination.

The effects were most dramatic in a small group of 7–9 long-term survivors who demonstrated cognitive improvement when tested 15 months after receiving WBRT.

Magnetic resonance imaging at 4 months showed that brain tumors had shrunk 80% on average from baseline by then in patients who would survive 15 months.

“Neurocognitive function is stable or improving over time in long-term survivors,” said Dr. Li of the University of Wisconsin at Madison. “It appears that the adverse impact of tumor growth on neurocognitive function is greater than that of whole brain radiation therapy. Therefore, improving response is a worthy aim in this patient population.”

Although WBRT is used to reduce neurologic symptoms caused by brain metastases, she said the treatment's effects on neurocognitive skills have up to now gone “largely unstudied.” The lack of data was attributable, she suggested, to inadequate assessment tools and the poor prognosis (4–6 months median survival) in the 10%–30% of cancer patients who develop brain metastases.

For this study, Dr. Li and her colleagues selected 135 of 208 patients in the control arm of a prospective, randomized, multicenter trial that compared WBRT alone with WBRT with motexafin gadolinium enhancement. Only those who survived until the first follow-up magnetic resonance image was taken 2 months later were eligible for the neurocognitive study. All neurocognitive participants had received 30 Gy of radiation in 10 fractions without motexafin gadolinium.

The investigators determined that median tumor shrinkage was 45% at two months for the entire population. They classified patients as good or poor responders based on their relationship to the median.

To determine changes in neurocognitive function, the researchers administered eight tests that had been validated in another pilot study and could be completed within 30 minutes.

The eight tests covered three neurocognitive domains: memory, executive function (decision-making capacity), and fine motor coordination.

Poor responders had a shorter time to neurocognitive deterioration on all eight tests, compared with the good responders, according to Dr. Li. She said this difference was statistically significant on two pegboard tests used to measure fine motor coordination (287 vs. 380 days and 291 vs. 401 days) and the Trail B test of executive function (331 vs. 462 days).

In a discussion of Dr. Li's presentation, Dr. Jeff A. Sloan suggested the differences might have been statistically significant on all eight tests had the investigators chosen a less stringent definition of neurocognitive deterioration. The criterion used was a decline of two standard deviations from baseline on two consecutive measurements or on the last follow-up visit before death.

“Two standard deviations is a huge change, a profound change,” Dr. Sloan of the Mayo Clinic in Rochester, Minn., said, praising the study for its rigor. “… [T]he bar was set so high, it is not surprising that only three of these eight [findings] were significant.”

ATLANTA — Whole-brain radiation therapy can preserve neurocognitive function in patients with brain metastases, according to a 135-patient study presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Jing Li reported that patients lived longer and had better neurocognitive function if their tumors shrank more than 45% during the 2 months after whole-brain radiation therapy (WBRT).

These “good responders” scored better on all eight neurocognitive tests used in the study, compared with “poor responders” with less than 45% tumor shrinkage at the 2-month mark. The effects were statistically significant over the course of the study on tests of executive function and fine motor coordination.

The effects were most dramatic in a small group of 7–9 long-term survivors who demonstrated cognitive improvement when tested 15 months after receiving WBRT.

Magnetic resonance imaging at 4 months showed that brain tumors had shrunk 80% on average from baseline by then in patients who would survive 15 months.

“Neurocognitive function is stable or improving over time in long-term survivors,” said Dr. Li of the University of Wisconsin at Madison. “It appears that the adverse impact of tumor growth on neurocognitive function is greater than that of whole brain radiation therapy. Therefore, improving response is a worthy aim in this patient population.”

Although WBRT is used to reduce neurologic symptoms caused by brain metastases, she said the treatment's effects on neurocognitive skills have up to now gone “largely unstudied.” The lack of data was attributable, she suggested, to inadequate assessment tools and the poor prognosis (4–6 months median survival) in the 10%–30% of cancer patients who develop brain metastases.

For this study, Dr. Li and her colleagues selected 135 of 208 patients in the control arm of a prospective, randomized, multicenter trial that compared WBRT alone with WBRT with motexafin gadolinium enhancement. Only those who survived until the first follow-up magnetic resonance image was taken 2 months later were eligible for the neurocognitive study. All neurocognitive participants had received 30 Gy of radiation in 10 fractions without motexafin gadolinium.

The investigators determined that median tumor shrinkage was 45% at two months for the entire population. They classified patients as good or poor responders based on their relationship to the median.

To determine changes in neurocognitive function, the researchers administered eight tests that had been validated in another pilot study and could be completed within 30 minutes.

The eight tests covered three neurocognitive domains: memory, executive function (decision-making capacity), and fine motor coordination.

Poor responders had a shorter time to neurocognitive deterioration on all eight tests, compared with the good responders, according to Dr. Li. She said this difference was statistically significant on two pegboard tests used to measure fine motor coordination (287 vs. 380 days and 291 vs. 401 days) and the Trail B test of executive function (331 vs. 462 days).

In a discussion of Dr. Li's presentation, Dr. Jeff A. Sloan suggested the differences might have been statistically significant on all eight tests had the investigators chosen a less stringent definition of neurocognitive deterioration. The criterion used was a decline of two standard deviations from baseline on two consecutive measurements or on the last follow-up visit before death.

“Two standard deviations is a huge change, a profound change,” Dr. Sloan of the Mayo Clinic in Rochester, Minn., said, praising the study for its rigor. “… [T]he bar was set so high, it is not surprising that only three of these eight [findings] were significant.”

ATLANTA — Whole-brain radiation therapy can preserve neurocognitive function in patients with brain metastases, according to a 135-patient study presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Jing Li reported that patients lived longer and had better neurocognitive function if their tumors shrank more than 45% during the 2 months after whole-brain radiation therapy (WBRT).

These “good responders” scored better on all eight neurocognitive tests used in the study, compared with “poor responders” with less than 45% tumor shrinkage at the 2-month mark. The effects were statistically significant over the course of the study on tests of executive function and fine motor coordination.

The effects were most dramatic in a small group of 7–9 long-term survivors who demonstrated cognitive improvement when tested 15 months after receiving WBRT.

Magnetic resonance imaging at 4 months showed that brain tumors had shrunk 80% on average from baseline by then in patients who would survive 15 months.

“Neurocognitive function is stable or improving over time in long-term survivors,” said Dr. Li of the University of Wisconsin at Madison. “It appears that the adverse impact of tumor growth on neurocognitive function is greater than that of whole brain radiation therapy. Therefore, improving response is a worthy aim in this patient population.”

Although WBRT is used to reduce neurologic symptoms caused by brain metastases, she said the treatment's effects on neurocognitive skills have up to now gone “largely unstudied.” The lack of data was attributable, she suggested, to inadequate assessment tools and the poor prognosis (4–6 months median survival) in the 10%–30% of cancer patients who develop brain metastases.

For this study, Dr. Li and her colleagues selected 135 of 208 patients in the control arm of a prospective, randomized, multicenter trial that compared WBRT alone with WBRT with motexafin gadolinium enhancement. Only those who survived until the first follow-up magnetic resonance image was taken 2 months later were eligible for the neurocognitive study. All neurocognitive participants had received 30 Gy of radiation in 10 fractions without motexafin gadolinium.

The investigators determined that median tumor shrinkage was 45% at two months for the entire population. They classified patients as good or poor responders based on their relationship to the median.

To determine changes in neurocognitive function, the researchers administered eight tests that had been validated in another pilot study and could be completed within 30 minutes.

The eight tests covered three neurocognitive domains: memory, executive function (decision-making capacity), and fine motor coordination.

Poor responders had a shorter time to neurocognitive deterioration on all eight tests, compared with the good responders, according to Dr. Li. She said this difference was statistically significant on two pegboard tests used to measure fine motor coordination (287 vs. 380 days and 291 vs. 401 days) and the Trail B test of executive function (331 vs. 462 days).

In a discussion of Dr. Li's presentation, Dr. Jeff A. Sloan suggested the differences might have been statistically significant on all eight tests had the investigators chosen a less stringent definition of neurocognitive deterioration. The criterion used was a decline of two standard deviations from baseline on two consecutive measurements or on the last follow-up visit before death.

“Two standard deviations is a huge change, a profound change,” Dr. Sloan of the Mayo Clinic in Rochester, Minn., said, praising the study for its rigor. “… [T]he bar was set so high, it is not surprising that only three of these eight [findings] were significant.”

SCOTTSDALE, ARIZ. — Radiation exposure from the diagnostic imaging of children greatly increases their risk of cancer and death decades later, according to speakers at a pediatric update sponsored by Phoenix Children's Hospital.

Dr. Thomas L. Slovis and Dr. Alan H. Friedman urged pediatricians to be judicious, limiting their use of chest x-rays and computerized tomography to essential studies. They also called on pediatricians to insist that radiologists adjust radiation doses to minimize future harm to children.

Among the alarming statistics reported in their separate talks were the following:

▸ A 1-year-old infant is 10–15 times as likely to develop malignancy as is a 50-year-old adult given the same dose of radiation, according to the International Commission on Radiological Protection.

▸ The equivalent natural-radiation exposure ranges from 2.4 days of natural exposure during one chest x-ray to 4.3 years of natural exposure during one 30-minute cardiac catheterization. Within this range are one upper-gastrointestinal x-ray (equivalent to 1 year of natural exposure), one barium enema (equivalent to 2.3 years), and one abdominal CT scan (equivalent to 3.3 years).

▸ The risk of dying of complications from an abdominal CT scan performed in the first year of life is 1:1,000. This is greater than the risk of death from a bicycle accident, drowning, or a medical complication, according to the National Safety Council.

▸ Low doses of radiation comparable to a CT dose are associated with excess cancers and excess deaths in an ongoing 50-year study of 50,000 atomic bomb survivors (Radiation Research 2000:154:178–86).

The issue is not whether to image, but when and how often and which test to use, said Dr. Friedman, director of the pediatric echocardiography laboratory at Yale University, New Haven, Conn.

“If we're not careful and thoughtful in the use of the technology, we may be exposing our youngest and most vulnerable patients to potentially dangerous and worrisome doses of radiation,” he said in an interview. “It may not have an effect in the short term, but we may really start to realize deleterious effects decades down the road.”

Along with more judicious use of tests, pediatricians should ask radiologists whether they tailor radiation doses for children, said Dr. Slovis, of the division of pediatric imaging at Wayne State University, Detroit.

He advocated wider application of the concept of ALARA (“as low as reasonably achievable”) to radiation dosing in children. “You want the proper dose. If the dose is too low, you can't make the diagnosis,” he said.

Various factors make children more susceptible to radiation. Dr. Friedman listed tissue weighting, the exposure of more organs, longer life expectancy, and more rapid cell division.

Dr. Slovis said that children receive more radiation than do adults when the same dose of radiation is used. Radiation doses are measured with a phantom and set at a fixed midpoint, he said. This measurement is based on 14 slices, but is independent of the thickness of those slices.

Studies of the effects of radiation in the survivors of the atomic bombings of Hiroshima and Nagasaki include data specific to children.

Among the findings noted by Dr. Friedman is an increased incidence of leukemia, breast cancer, colon cancer, thyroid cancer, and lung cancer. These do not occur immediately, but at the times that would be expected for the specific cancer to develop.

Girls are more radiosensitive than boys, he said, and the risk of cancer development varies dramatically with the patient's age at exposure.

Dr. Slovis said some children with hereditary diseases—including ataxia-telangiectasia, basal cell nevus syndrome, Cockayne's syndrome, Down syndrome, Fanconi's anemia, Gardner's syndrome, Nijmegen breakage syndrome, and Usher's syndrome—are extremely sensitive to radiation and should not be exposed at all, if possible.

He also discouraged the use of radiation in children with hereditary syndromes that have been associated with childhood cancers.

Fetuses and premature babies are especially vulnerable, added Dr. Slovis. He hailed the late Dr. Alice Stewart's work for establishing that radiation in utero increases the relative risk of leukemia and other malignancies.

“How much radiation does a 25-week surviving preemie get?” he asked, comparing them to third-trimester fetuses and urging limited testing in infants. “I don't say don't get an indicated CT,” he said. “I say get the indications, and work it through.” Physicians should be sure each test they order is necessary, should use “the least invasive modality that gives a high certainty of success,” and should discuss the case with a pediatric radiologist whenever they are unsure.

'We may be exposing our … most vulnerable patients to dangerous doses of radiation. DR. FRIEDMAN

How to Lower the Risk of Radiation

▸ Reduce the number of multiple scans and procedures.

▸ Reduce the length of time the patient is in the scanner.

▸ Use bismuth shields, which reduce radiation exposure by up to 67% and don't significantly affect imaging.

▸ Limit exposure/coverage to the physical area necessary for addressing the clinical question.

▸ Do not repeat studies too early or too often.

▸ Discuss the risks with the patients and parents.

▸ Consider MRI or ultrasound studies whenever possible.

Source: Dr. Friedman

SCOTTSDALE, ARIZ. — Radiation exposure from the diagnostic imaging of children greatly increases their risk of cancer and death decades later, according to speakers at a pediatric update sponsored by Phoenix Children's Hospital.

Dr. Thomas L. Slovis and Dr. Alan H. Friedman urged pediatricians to be judicious, limiting their use of chest x-rays and computerized tomography to essential studies. They also called on pediatricians to insist that radiologists adjust radiation doses to minimize future harm to children.

Among the alarming statistics reported in their separate talks were the following:

▸ A 1-year-old infant is 10–15 times as likely to develop malignancy as is a 50-year-old adult given the same dose of radiation, according to the International Commission on Radiological Protection.

▸ The equivalent natural-radiation exposure ranges from 2.4 days of natural exposure during one chest x-ray to 4.3 years of natural exposure during one 30-minute cardiac catheterization. Within this range are one upper-gastrointestinal x-ray (equivalent to 1 year of natural exposure), one barium enema (equivalent to 2.3 years), and one abdominal CT scan (equivalent to 3.3 years).

▸ The risk of dying of complications from an abdominal CT scan performed in the first year of life is 1:1,000. This is greater than the risk of death from a bicycle accident, drowning, or a medical complication, according to the National Safety Council.

▸ Low doses of radiation comparable to a CT dose are associated with excess cancers and excess deaths in an ongoing 50-year study of 50,000 atomic bomb survivors (Radiation Research 2000:154:178–86).

The issue is not whether to image, but when and how often and which test to use, said Dr. Friedman, director of the pediatric echocardiography laboratory at Yale University, New Haven, Conn.

“If we're not careful and thoughtful in the use of the technology, we may be exposing our youngest and most vulnerable patients to potentially dangerous and worrisome doses of radiation,” he said in an interview. “It may not have an effect in the short term, but we may really start to realize deleterious effects decades down the road.”

Along with more judicious use of tests, pediatricians should ask radiologists whether they tailor radiation doses for children, said Dr. Slovis, of the division of pediatric imaging at Wayne State University, Detroit.

He advocated wider application of the concept of ALARA (“as low as reasonably achievable”) to radiation dosing in children. “You want the proper dose. If the dose is too low, you can't make the diagnosis,” he said.

Various factors make children more susceptible to radiation. Dr. Friedman listed tissue weighting, the exposure of more organs, longer life expectancy, and more rapid cell division.

Dr. Slovis said that children receive more radiation than do adults when the same dose of radiation is used. Radiation doses are measured with a phantom and set at a fixed midpoint, he said. This measurement is based on 14 slices, but is independent of the thickness of those slices.

Studies of the effects of radiation in the survivors of the atomic bombings of Hiroshima and Nagasaki include data specific to children.

Among the findings noted by Dr. Friedman is an increased incidence of leukemia, breast cancer, colon cancer, thyroid cancer, and lung cancer. These do not occur immediately, but at the times that would be expected for the specific cancer to develop.

Girls are more radiosensitive than boys, he said, and the risk of cancer development varies dramatically with the patient's age at exposure.

Dr. Slovis said some children with hereditary diseases—including ataxia-telangiectasia, basal cell nevus syndrome, Cockayne's syndrome, Down syndrome, Fanconi's anemia, Gardner's syndrome, Nijmegen breakage syndrome, and Usher's syndrome—are extremely sensitive to radiation and should not be exposed at all, if possible.

He also discouraged the use of radiation in children with hereditary syndromes that have been associated with childhood cancers.

Fetuses and premature babies are especially vulnerable, added Dr. Slovis. He hailed the late Dr. Alice Stewart's work for establishing that radiation in utero increases the relative risk of leukemia and other malignancies.

“How much radiation does a 25-week surviving preemie get?” he asked, comparing them to third-trimester fetuses and urging limited testing in infants. “I don't say don't get an indicated CT,” he said. “I say get the indications, and work it through.” Physicians should be sure each test they order is necessary, should use “the least invasive modality that gives a high certainty of success,” and should discuss the case with a pediatric radiologist whenever they are unsure.

'We may be exposing our … most vulnerable patients to dangerous doses of radiation. DR. FRIEDMAN

How to Lower the Risk of Radiation

▸ Reduce the number of multiple scans and procedures.

▸ Reduce the length of time the patient is in the scanner.

▸ Use bismuth shields, which reduce radiation exposure by up to 67% and don't significantly affect imaging.

▸ Limit exposure/coverage to the physical area necessary for addressing the clinical question.

▸ Do not repeat studies too early or too often.

▸ Discuss the risks with the patients and parents.

▸ Consider MRI or ultrasound studies whenever possible.

Source: Dr. Friedman

SCOTTSDALE, ARIZ. — Radiation exposure from the diagnostic imaging of children greatly increases their risk of cancer and death decades later, according to speakers at a pediatric update sponsored by Phoenix Children's Hospital.

Dr. Thomas L. Slovis and Dr. Alan H. Friedman urged pediatricians to be judicious, limiting their use of chest x-rays and computerized tomography to essential studies. They also called on pediatricians to insist that radiologists adjust radiation doses to minimize future harm to children.

Among the alarming statistics reported in their separate talks were the following:

▸ A 1-year-old infant is 10–15 times as likely to develop malignancy as is a 50-year-old adult given the same dose of radiation, according to the International Commission on Radiological Protection.

▸ The equivalent natural-radiation exposure ranges from 2.4 days of natural exposure during one chest x-ray to 4.3 years of natural exposure during one 30-minute cardiac catheterization. Within this range are one upper-gastrointestinal x-ray (equivalent to 1 year of natural exposure), one barium enema (equivalent to 2.3 years), and one abdominal CT scan (equivalent to 3.3 years).

▸ The risk of dying of complications from an abdominal CT scan performed in the first year of life is 1:1,000. This is greater than the risk of death from a bicycle accident, drowning, or a medical complication, according to the National Safety Council.

▸ Low doses of radiation comparable to a CT dose are associated with excess cancers and excess deaths in an ongoing 50-year study of 50,000 atomic bomb survivors (Radiation Research 2000:154:178–86).

The issue is not whether to image, but when and how often and which test to use, said Dr. Friedman, director of the pediatric echocardiography laboratory at Yale University, New Haven, Conn.

“If we're not careful and thoughtful in the use of the technology, we may be exposing our youngest and most vulnerable patients to potentially dangerous and worrisome doses of radiation,” he said in an interview. “It may not have an effect in the short term, but we may really start to realize deleterious effects decades down the road.”

Along with more judicious use of tests, pediatricians should ask radiologists whether they tailor radiation doses for children, said Dr. Slovis, of the division of pediatric imaging at Wayne State University, Detroit.

He advocated wider application of the concept of ALARA (“as low as reasonably achievable”) to radiation dosing in children. “You want the proper dose. If the dose is too low, you can't make the diagnosis,” he said.

Various factors make children more susceptible to radiation. Dr. Friedman listed tissue weighting, the exposure of more organs, longer life expectancy, and more rapid cell division.

Dr. Slovis said that children receive more radiation than do adults when the same dose of radiation is used. Radiation doses are measured with a phantom and set at a fixed midpoint, he said. This measurement is based on 14 slices, but is independent of the thickness of those slices.

Studies of the effects of radiation in the survivors of the atomic bombings of Hiroshima and Nagasaki include data specific to children.

Among the findings noted by Dr. Friedman is an increased incidence of leukemia, breast cancer, colon cancer, thyroid cancer, and lung cancer. These do not occur immediately, but at the times that would be expected for the specific cancer to develop.

Girls are more radiosensitive than boys, he said, and the risk of cancer development varies dramatically with the patient's age at exposure.

Dr. Slovis said some children with hereditary diseases—including ataxia-telangiectasia, basal cell nevus syndrome, Cockayne's syndrome, Down syndrome, Fanconi's anemia, Gardner's syndrome, Nijmegen breakage syndrome, and Usher's syndrome—are extremely sensitive to radiation and should not be exposed at all, if possible.

He also discouraged the use of radiation in children with hereditary syndromes that have been associated with childhood cancers.

Fetuses and premature babies are especially vulnerable, added Dr. Slovis. He hailed the late Dr. Alice Stewart's work for establishing that radiation in utero increases the relative risk of leukemia and other malignancies.

“How much radiation does a 25-week surviving preemie get?” he asked, comparing them to third-trimester fetuses and urging limited testing in infants. “I don't say don't get an indicated CT,” he said. “I say get the indications, and work it through.” Physicians should be sure each test they order is necessary, should use “the least invasive modality that gives a high certainty of success,” and should discuss the case with a pediatric radiologist whenever they are unsure.

'We may be exposing our … most vulnerable patients to dangerous doses of radiation. DR. FRIEDMAN

How to Lower the Risk of Radiation

▸ Reduce the number of multiple scans and procedures.

▸ Reduce the length of time the patient is in the scanner.

▸ Use bismuth shields, which reduce radiation exposure by up to 67% and don't significantly affect imaging.

▸ Limit exposure/coverage to the physical area necessary for addressing the clinical question.

▸ Do not repeat studies too early or too often.

▸ Discuss the risks with the patients and parents.

▸ Consider MRI or ultrasound studies whenever possible.

Source: Dr. Friedman

SAN FRANCISCO — What health plans tell physicians can make a difference in the quality of care given to poor children with asthma, according to a study of about 4,500 children covered by 18 Medicaid managed care plans in Tennessee and Washington state.

Two types of communication significantly increased the proportion of children with severe asthma who filled their controller prescriptions, Dr. William O. Cooper reported at the annual meeting of the Pediatric Academic Societies.

The first was feedback about how the provider compared to other physicians with respect to quality-of-care benchmarks.

The other was provider notification of an asthma-related hospitalization or an asthma-related emergency room visit by a child in the physician's panel of patients.

“I think there are things that health plans do in the way they interface with providers that could potentially improve coverage for their children,” Dr. Cooper of Vanderbilt University, Nashville, Tenn., said in an interview at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The retrospective cohort study reviewed records from 2000 to 2002 for 3,058 children in Tennessee and for 1,440 children in Washington state. The children, who were aged 2–17 years, had moderate to severe asthma. They were covered by 11 health plans in Tennessee and 7 plans in Washington state.

Investigator interviews with the plans' medical directors determined that nine plans in Tennessee and five in Washington state provided feedback on quality of care to providers. Fewer plans, seven in Tennessee and three in Washington state, provided notification, Dr. Cooper said.

As an example of feedback, Dr. Cooper offered the following paraphrase of an insurer telling a physician, “In our health plan, 70% of children [with asthma] have controller medications. We looked at your panel of patients and only 30% [do]. Here's how you are doing compared to the other providers.”

All told, 1,413 children were in plans that provided neither feedback nor notification, 1,341 in plans that provided only feedback, 215 in plans that provided only notification, and 1,529 in plans that provided feedback and notification.

The study looked at the filling of prescriptions for asthma controllers (inhaled corticosteroids, cromolyn, or leukotriene modifiers) during a 365-day follow-up period.

Dr. Cooper and his coinvestigators at Vanderbilt and the University of Washington, Seattle, reported that children in plans with both components filled their controllers 17.6 days more on average than children in plans with no feedback.

If the plans had one component, either notification or feedback, the benefit was 10.3 more days of filled controllers.

Notification, by itself, resulted in more than 200 days that controllers were filled on average, the most of any option for the population as a whole.

The effects of feedback and notification were most pronounced for children with more severe asthma, as defined by the filling of three or more β-agonist prescriptions in the 6 months prior to their entering the study.

In this population, only 77.4% of children filled their controllers if their health plans did not provide feedback or notification.

The proportion increased to 81.6% with notification and 82.1% with feedback to physicians.

When feedback and notification were both used, 85.5% filled their controllers (odds ratio 1.7, compared with children in plans that provided neither form of communication).

The mean days that controllers were filled also increased from 144 with no communication to 181 with feedback to 327 with notification. On average, children in plans with feedback and notification filled their controllers for 225 days.

Children in plans with both components filled their controllers 17.6 days more on average. DR. COOPER

SAN FRANCISCO — What health plans tell physicians can make a difference in the quality of care given to poor children with asthma, according to a study of about 4,500 children covered by 18 Medicaid managed care plans in Tennessee and Washington state.

Two types of communication significantly increased the proportion of children with severe asthma who filled their controller prescriptions, Dr. William O. Cooper reported at the annual meeting of the Pediatric Academic Societies.

The first was feedback about how the provider compared to other physicians with respect to quality-of-care benchmarks.

The other was provider notification of an asthma-related hospitalization or an asthma-related emergency room visit by a child in the physician's panel of patients.

“I think there are things that health plans do in the way they interface with providers that could potentially improve coverage for their children,” Dr. Cooper of Vanderbilt University, Nashville, Tenn., said in an interview at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The retrospective cohort study reviewed records from 2000 to 2002 for 3,058 children in Tennessee and for 1,440 children in Washington state. The children, who were aged 2–17 years, had moderate to severe asthma. They were covered by 11 health plans in Tennessee and 7 plans in Washington state.

Investigator interviews with the plans' medical directors determined that nine plans in Tennessee and five in Washington state provided feedback on quality of care to providers. Fewer plans, seven in Tennessee and three in Washington state, provided notification, Dr. Cooper said.

As an example of feedback, Dr. Cooper offered the following paraphrase of an insurer telling a physician, “In our health plan, 70% of children [with asthma] have controller medications. We looked at your panel of patients and only 30% [do]. Here's how you are doing compared to the other providers.”

All told, 1,413 children were in plans that provided neither feedback nor notification, 1,341 in plans that provided only feedback, 215 in plans that provided only notification, and 1,529 in plans that provided feedback and notification.

The study looked at the filling of prescriptions for asthma controllers (inhaled corticosteroids, cromolyn, or leukotriene modifiers) during a 365-day follow-up period.

Dr. Cooper and his coinvestigators at Vanderbilt and the University of Washington, Seattle, reported that children in plans with both components filled their controllers 17.6 days more on average than children in plans with no feedback.

If the plans had one component, either notification or feedback, the benefit was 10.3 more days of filled controllers.

Notification, by itself, resulted in more than 200 days that controllers were filled on average, the most of any option for the population as a whole.

The effects of feedback and notification were most pronounced for children with more severe asthma, as defined by the filling of three or more β-agonist prescriptions in the 6 months prior to their entering the study.

In this population, only 77.4% of children filled their controllers if their health plans did not provide feedback or notification.

The proportion increased to 81.6% with notification and 82.1% with feedback to physicians.

When feedback and notification were both used, 85.5% filled their controllers (odds ratio 1.7, compared with children in plans that provided neither form of communication).

The mean days that controllers were filled also increased from 144 with no communication to 181 with feedback to 327 with notification. On average, children in plans with feedback and notification filled their controllers for 225 days.

Children in plans with both components filled their controllers 17.6 days more on average. DR. COOPER

SAN FRANCISCO — What health plans tell physicians can make a difference in the quality of care given to poor children with asthma, according to a study of about 4,500 children covered by 18 Medicaid managed care plans in Tennessee and Washington state.

Two types of communication significantly increased the proportion of children with severe asthma who filled their controller prescriptions, Dr. William O. Cooper reported at the annual meeting of the Pediatric Academic Societies.

The first was feedback about how the provider compared to other physicians with respect to quality-of-care benchmarks.

The other was provider notification of an asthma-related hospitalization or an asthma-related emergency room visit by a child in the physician's panel of patients.

“I think there are things that health plans do in the way they interface with providers that could potentially improve coverage for their children,” Dr. Cooper of Vanderbilt University, Nashville, Tenn., said in an interview at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The retrospective cohort study reviewed records from 2000 to 2002 for 3,058 children in Tennessee and for 1,440 children in Washington state. The children, who were aged 2–17 years, had moderate to severe asthma. They were covered by 11 health plans in Tennessee and 7 plans in Washington state.

Investigator interviews with the plans' medical directors determined that nine plans in Tennessee and five in Washington state provided feedback on quality of care to providers. Fewer plans, seven in Tennessee and three in Washington state, provided notification, Dr. Cooper said.

As an example of feedback, Dr. Cooper offered the following paraphrase of an insurer telling a physician, “In our health plan, 70% of children [with asthma] have controller medications. We looked at your panel of patients and only 30% [do]. Here's how you are doing compared to the other providers.”

All told, 1,413 children were in plans that provided neither feedback nor notification, 1,341 in plans that provided only feedback, 215 in plans that provided only notification, and 1,529 in plans that provided feedback and notification.

The study looked at the filling of prescriptions for asthma controllers (inhaled corticosteroids, cromolyn, or leukotriene modifiers) during a 365-day follow-up period.

Dr. Cooper and his coinvestigators at Vanderbilt and the University of Washington, Seattle, reported that children in plans with both components filled their controllers 17.6 days more on average than children in plans with no feedback.

If the plans had one component, either notification or feedback, the benefit was 10.3 more days of filled controllers.

Notification, by itself, resulted in more than 200 days that controllers were filled on average, the most of any option for the population as a whole.

The effects of feedback and notification were most pronounced for children with more severe asthma, as defined by the filling of three or more β-agonist prescriptions in the 6 months prior to their entering the study.

In this population, only 77.4% of children filled their controllers if their health plans did not provide feedback or notification.

The proportion increased to 81.6% with notification and 82.1% with feedback to physicians.

When feedback and notification were both used, 85.5% filled their controllers (odds ratio 1.7, compared with children in plans that provided neither form of communication).

The mean days that controllers were filled also increased from 144 with no communication to 181 with feedback to 327 with notification. On average, children in plans with feedback and notification filled their controllers for 225 days.

Children in plans with both components filled their controllers 17.6 days more on average. DR. COOPER

SAN FRANCISCO — Ceftriaxone by itself is not sufficient for acute or chronic pediatric mastoiditis, according to a group of emergency physicians who compared cases treated before and after adoption of the pneumococcal conjugate vaccine.

The proportion of Streptococcus pneumoniae isolates that were resistant to ceftriaxone increased from 7% in the pre-PCV era to 30% afterward, Dr. Dewesh Agrawal reported in a poster at the annual meeting of the Pediatric Academic Societies.

Although S. pneumoniae remained the most frequent cause of acute mastoiditis, Pseudomonas aeruginosa was found in five of seven chronic cases in which children had ear disease for more than 3 weeks before coming to the emergency department. In addition, P. aeruginosa was the second most common cause of acute mastoiditis.

“That's a really bad bug, and ceftriaxone isn't good enough for that,” Dr. Agrawal, of the Children's National Medical Center in Washington, said in an interview.

The study compared 68 cases seen from January 1995 through December 2000 with 54 cases seen from January 2005 through April 2005. Patients ranged in age from 30 days to 18.2 years with a median age of 5.4 years. Over half (54%) were female.

All told, 93 patients (76%) had acute mastoiditis, and 29 patients (24%) had chronic mastoiditis. In all, 75 children (61%) went on to have surgery; among these, myringotomy tubes were placed in ears (57 children) and/or mastoidectomy was performed (56 children).

The investigators were able to determine the etiologic agents causing mastoiditis in 60 children (49%). The other pathogens identified in the study were Staphylococcus aureus, Staphylococcus pyogenes, and Haemophilus influenzae (acute only).

Dr. Agrawal said the investigators were surprised to find that the proportion of mastoiditis cases caused by S. pneumoniae did not decrease in the PCV era. S. pneumoniae accounted for 21% (14 of 68) of the early cases and 19% (10 of 54) of the later cases. He speculated that the study may have been done “too soon” in that many of the older children in the post-PCV-era cohort turned out not to have been given the vaccine.

Physicians were much more likely to choose empirical parenteral combination therapy with ceftriaxone when treating acute mastoiditis: It was used in 49% of acute cases vs. 10% of chronic cases.

Empirical parenteral combination therapy with ceftriaxone was used more often in the post-PCV era as well (57% of the later cases vs. 24% in the earlier cohort). Clindamycin use, either alone or in combination, also increased from 12% of the early cases to 22% of later cases.

Even so, Dr. Agrawal and his colleagues reported that, based on the etiologic findings and antibiotic sensitivities, only 43% of the first-choice antibiotics were appropriate in the vaccine era. “In the post-PCV era, or in chronic mastoiditis, empirical antimicrobial therapy with ceftriaxone alone is not appropriate,” they concluded.

“With acute ear disease, you've got to add on other antibiotics,” Dr. Agrawal said.

'That's a really bad bug [Pseudomonas aeruginosa], and ceftriaxone isn't good enough for that.' DR. AGRAWAL

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Ceftriaxone by itself is not sufficient for acute or chronic pediatric mastoiditis, according to a group of emergency physicians who compared cases treated before and after adoption of the pneumococcal conjugate vaccine.

The proportion of Streptococcus pneumoniae isolates that were resistant to ceftriaxone increased from 7% in the pre-PCV era to 30% afterward, Dr. Dewesh Agrawal reported in a poster at the annual meeting of the Pediatric Academic Societies.

Although S. pneumoniae remained the most frequent cause of acute mastoiditis, Pseudomonas aeruginosa was found in five of seven chronic cases in which children had ear disease for more than 3 weeks before coming to the emergency department. In addition, P. aeruginosa was the second most common cause of acute mastoiditis.

“That's a really bad bug, and ceftriaxone isn't good enough for that,” Dr. Agrawal, of the Children's National Medical Center in Washington, said in an interview.

The study compared 68 cases seen from January 1995 through December 2000 with 54 cases seen from January 2005 through April 2005. Patients ranged in age from 30 days to 18.2 years with a median age of 5.4 years. Over half (54%) were female.

All told, 93 patients (76%) had acute mastoiditis, and 29 patients (24%) had chronic mastoiditis. In all, 75 children (61%) went on to have surgery; among these, myringotomy tubes were placed in ears (57 children) and/or mastoidectomy was performed (56 children).

The investigators were able to determine the etiologic agents causing mastoiditis in 60 children (49%). The other pathogens identified in the study were Staphylococcus aureus, Staphylococcus pyogenes, and Haemophilus influenzae (acute only).

Dr. Agrawal said the investigators were surprised to find that the proportion of mastoiditis cases caused by S. pneumoniae did not decrease in the PCV era. S. pneumoniae accounted for 21% (14 of 68) of the early cases and 19% (10 of 54) of the later cases. He speculated that the study may have been done “too soon” in that many of the older children in the post-PCV-era cohort turned out not to have been given the vaccine.

Physicians were much more likely to choose empirical parenteral combination therapy with ceftriaxone when treating acute mastoiditis: It was used in 49% of acute cases vs. 10% of chronic cases.

Empirical parenteral combination therapy with ceftriaxone was used more often in the post-PCV era as well (57% of the later cases vs. 24% in the earlier cohort). Clindamycin use, either alone or in combination, also increased from 12% of the early cases to 22% of later cases.

Even so, Dr. Agrawal and his colleagues reported that, based on the etiologic findings and antibiotic sensitivities, only 43% of the first-choice antibiotics were appropriate in the vaccine era. “In the post-PCV era, or in chronic mastoiditis, empirical antimicrobial therapy with ceftriaxone alone is not appropriate,” they concluded.

“With acute ear disease, you've got to add on other antibiotics,” Dr. Agrawal said.

'That's a really bad bug [Pseudomonas aeruginosa], and ceftriaxone isn't good enough for that.' DR. AGRAWAL

ELSEVIER GLOBAL MEDICAL NEWS

SAN FRANCISCO — Ceftriaxone by itself is not sufficient for acute or chronic pediatric mastoiditis, according to a group of emergency physicians who compared cases treated before and after adoption of the pneumococcal conjugate vaccine.

The proportion of Streptococcus pneumoniae isolates that were resistant to ceftriaxone increased from 7% in the pre-PCV era to 30% afterward, Dr. Dewesh Agrawal reported in a poster at the annual meeting of the Pediatric Academic Societies.

Although S. pneumoniae remained the most frequent cause of acute mastoiditis, Pseudomonas aeruginosa was found in five of seven chronic cases in which children had ear disease for more than 3 weeks before coming to the emergency department. In addition, P. aeruginosa was the second most common cause of acute mastoiditis.

“That's a really bad bug, and ceftriaxone isn't good enough for that,” Dr. Agrawal, of the Children's National Medical Center in Washington, said in an interview.

The study compared 68 cases seen from January 1995 through December 2000 with 54 cases seen from January 2005 through April 2005. Patients ranged in age from 30 days to 18.2 years with a median age of 5.4 years. Over half (54%) were female.

All told, 93 patients (76%) had acute mastoiditis, and 29 patients (24%) had chronic mastoiditis. In all, 75 children (61%) went on to have surgery; among these, myringotomy tubes were placed in ears (57 children) and/or mastoidectomy was performed (56 children).

The investigators were able to determine the etiologic agents causing mastoiditis in 60 children (49%). The other pathogens identified in the study were Staphylococcus aureus, Staphylococcus pyogenes, and Haemophilus influenzae (acute only).

Dr. Agrawal said the investigators were surprised to find that the proportion of mastoiditis cases caused by S. pneumoniae did not decrease in the PCV era. S. pneumoniae accounted for 21% (14 of 68) of the early cases and 19% (10 of 54) of the later cases. He speculated that the study may have been done “too soon” in that many of the older children in the post-PCV-era cohort turned out not to have been given the vaccine.

Physicians were much more likely to choose empirical parenteral combination therapy with ceftriaxone when treating acute mastoiditis: It was used in 49% of acute cases vs. 10% of chronic cases.

Empirical parenteral combination therapy with ceftriaxone was used more often in the post-PCV era as well (57% of the later cases vs. 24% in the earlier cohort). Clindamycin use, either alone or in combination, also increased from 12% of the early cases to 22% of later cases.

Even so, Dr. Agrawal and his colleagues reported that, based on the etiologic findings and antibiotic sensitivities, only 43% of the first-choice antibiotics were appropriate in the vaccine era. “In the post-PCV era, or in chronic mastoiditis, empirical antimicrobial therapy with ceftriaxone alone is not appropriate,” they concluded.

“With acute ear disease, you've got to add on other antibiotics,” Dr. Agrawal said.

'That's a really bad bug [Pseudomonas aeruginosa], and ceftriaxone isn't good enough for that.' DR. AGRAWAL

ELSEVIER GLOBAL MEDICAL NEWS

ATLANTA — A year after bevacizumab proved that angiogenesis inhibition can help patients with non-small cell lung cancer live longer, a second generation of antiangiogenesis agents is showing activity against advanced, metastatic lung disease.

Phase II trials of sunitinib (Sutent), sorafenib (Nexavar), and an experimental drug called ZD6474 (Zactima) all reported progression-free survival rates of 11% or more at the annual meeting of the American Society of Clinical Oncology.

Because each drug hits more cellular targets than does bevacizumab (Avastin), investigators voiced hope that the new agents will be more effective. Two of the drugs—sunitinib and sorafenib—have already been approved for renal cell carcinoma. Sunitinib also has an indication for gastrointestinal stromal tumors that are refractory to imatinib (Gleevec).

Along with the possibility of better therapies, however, the three trials renewed concerns about the toxicity of antiangiogenic agents. Investigators reported cavitation and hemorrhage leading to treatment-related deaths. Rash, hand-foot syndrome, and controllable hypertension also were seen.

“More than ever, we need pulmonologists to look at the risk of bleeding and to look at cavitation,” Dr. Roy S. Herbst said in an interview after presenting a review of the new drugs and the state of antiangiogenic therapy against lung cancer.

“We need to find some sort of risk factors to stratify these patients,” said Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston and the senior investigator of a series of lung cancer trials testing the combination of bevacizumab and erlotinib (Tarceva).

Dr. Herbst cited the survival advantages reported last year in a phase III trial combining bevacizumab with chemotherapy as well as early results from his study. “Despite these advances, few, if any, metastatic patients are cured,” he cautioned.

He called the three new agents “quite comparable” and noted that “signs of early activity are seen,” but cautioned that whether the new multitargeted tyrosine kinase inhibitors are more effective than single-targeted bevacizumab is “not clear yet” in non-small cell lung cancer.

Among the potential advantages of multitargeted agents, Dr. Herbst cited convenience, single-agent activity, the ability to act on both tumor and blood vessels, and the potential to lower the cost of treatment. He cautioned, however, that the inhibition of each target may not be equally effective with just one drug.

Sunitinib

Dr. Mark A. Socinski reported that sunitinib controlled tumor growth in more than half of 63 patients who had failed previous regimens for advanced non-small cell lung cancer.

Six patients (9.5%) had partial responses, and 27 patients (42.9%) had stable disease in the study. Median progression-free survival reached 11.3 weeks and overall survival 23.9 weeks.

Three patients died of hemorrhages, however: Two were pulmonary—only one of which was attributed to treatment—and one was cerebral.

Patients received 50 mg of sunitinib daily for 4 weeks followed by 2 weeks off therapy before starting another cycle in the trial. Dr. Socinski, director of the multidisciplinary thoracic oncology program at the University of North Carolina at Chapel Hill, announced that the study has been extended and 47 additional patients enrolled on a revised dosing schedule of 37.5 mg daily.

Sorafenib

Dr. Ulrich Gatzemeier reported that 30 (59%) of 51 patients with advanced non-small cell lung cancer had stable disease while they were treated with 400 mg twice a day of sorafenib. No partial responses were recorded in the study.

Another 18 patients (35%) progressed, and three patients died before they could be evaluated.

Median progression-free survival reached 11.3 months, and median survival 29.5 weeks. Two patients have been on therapy for 2 years, according to Dr. Gatzemeier, head of thoracic oncology at Grosshansdorf Hospital in Hamburg, Germany.

Dr. Gatzemeier announced that a phase III trial has already started. It is to randomize 900 patients to a carboplatin/paclitaxel regimen with sorafenib or a placebo.

ZD6474

Dr. Ronald B. Natale reported that 83 patients achieved a median progression-free survival of 11 weeks on 300 mg per day of ZD6474. In comparison, only 8.1 weeks was reached by a control arm of 85 patients treated with 250 mg of gefitinib (Iressa) daily. The response rates were 8% and 1%, respectively.

The trial allowed patients who had progressed to cross over to the other agent. There were no additional responses, but 16 of 37 patients who switched from gefitinib to ZD6474 achieved more than 8 weeks' disease control vs. 7 of 29 patients who switched to gefitinib from ZD6474.

Dr. Natale, a medical oncologist at the Cedars-Sinai Comprehensive Cancer Center in Los Angeles, concluded that the data support further investigation of ZD6474 as monotherapy.

Convenience and the potential to lower treatment costs are among the advantages of these agents. DR. HERBST

ATLANTA — A year after bevacizumab proved that angiogenesis inhibition can help patients with non-small cell lung cancer live longer, a second generation of antiangiogenesis agents is showing activity against advanced, metastatic lung disease.

Phase II trials of sunitinib (Sutent), sorafenib (Nexavar), and an experimental drug called ZD6474 (Zactima) all reported progression-free survival rates of 11% or more at the annual meeting of the American Society of Clinical Oncology.

Because each drug hits more cellular targets than does bevacizumab (Avastin), investigators voiced hope that the new agents will be more effective. Two of the drugs—sunitinib and sorafenib—have already been approved for renal cell carcinoma. Sunitinib also has an indication for gastrointestinal stromal tumors that are refractory to imatinib (Gleevec).

Along with the possibility of better therapies, however, the three trials renewed concerns about the toxicity of antiangiogenic agents. Investigators reported cavitation and hemorrhage leading to treatment-related deaths. Rash, hand-foot syndrome, and controllable hypertension also were seen.

“More than ever, we need pulmonologists to look at the risk of bleeding and to look at cavitation,” Dr. Roy S. Herbst said in an interview after presenting a review of the new drugs and the state of antiangiogenic therapy against lung cancer.

“We need to find some sort of risk factors to stratify these patients,” said Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston and the senior investigator of a series of lung cancer trials testing the combination of bevacizumab and erlotinib (Tarceva).

Dr. Herbst cited the survival advantages reported last year in a phase III trial combining bevacizumab with chemotherapy as well as early results from his study. “Despite these advances, few, if any, metastatic patients are cured,” he cautioned.

He called the three new agents “quite comparable” and noted that “signs of early activity are seen,” but cautioned that whether the new multitargeted tyrosine kinase inhibitors are more effective than single-targeted bevacizumab is “not clear yet” in non-small cell lung cancer.

Among the potential advantages of multitargeted agents, Dr. Herbst cited convenience, single-agent activity, the ability to act on both tumor and blood vessels, and the potential to lower the cost of treatment. He cautioned, however, that the inhibition of each target may not be equally effective with just one drug.

Sunitinib

Dr. Mark A. Socinski reported that sunitinib controlled tumor growth in more than half of 63 patients who had failed previous regimens for advanced non-small cell lung cancer.

Six patients (9.5%) had partial responses, and 27 patients (42.9%) had stable disease in the study. Median progression-free survival reached 11.3 weeks and overall survival 23.9 weeks.

Three patients died of hemorrhages, however: Two were pulmonary—only one of which was attributed to treatment—and one was cerebral.

Patients received 50 mg of sunitinib daily for 4 weeks followed by 2 weeks off therapy before starting another cycle in the trial. Dr. Socinski, director of the multidisciplinary thoracic oncology program at the University of North Carolina at Chapel Hill, announced that the study has been extended and 47 additional patients enrolled on a revised dosing schedule of 37.5 mg daily.

Sorafenib

Dr. Ulrich Gatzemeier reported that 30 (59%) of 51 patients with advanced non-small cell lung cancer had stable disease while they were treated with 400 mg twice a day of sorafenib. No partial responses were recorded in the study.

Another 18 patients (35%) progressed, and three patients died before they could be evaluated.

Median progression-free survival reached 11.3 months, and median survival 29.5 weeks. Two patients have been on therapy for 2 years, according to Dr. Gatzemeier, head of thoracic oncology at Grosshansdorf Hospital in Hamburg, Germany.

Dr. Gatzemeier announced that a phase III trial has already started. It is to randomize 900 patients to a carboplatin/paclitaxel regimen with sorafenib or a placebo.

ZD6474

Dr. Ronald B. Natale reported that 83 patients achieved a median progression-free survival of 11 weeks on 300 mg per day of ZD6474. In comparison, only 8.1 weeks was reached by a control arm of 85 patients treated with 250 mg of gefitinib (Iressa) daily. The response rates were 8% and 1%, respectively.

The trial allowed patients who had progressed to cross over to the other agent. There were no additional responses, but 16 of 37 patients who switched from gefitinib to ZD6474 achieved more than 8 weeks' disease control vs. 7 of 29 patients who switched to gefitinib from ZD6474.

Dr. Natale, a medical oncologist at the Cedars-Sinai Comprehensive Cancer Center in Los Angeles, concluded that the data support further investigation of ZD6474 as monotherapy.

Convenience and the potential to lower treatment costs are among the advantages of these agents. DR. HERBST

ATLANTA — A year after bevacizumab proved that angiogenesis inhibition can help patients with non-small cell lung cancer live longer, a second generation of antiangiogenesis agents is showing activity against advanced, metastatic lung disease.

Phase II trials of sunitinib (Sutent), sorafenib (Nexavar), and an experimental drug called ZD6474 (Zactima) all reported progression-free survival rates of 11% or more at the annual meeting of the American Society of Clinical Oncology.

Because each drug hits more cellular targets than does bevacizumab (Avastin), investigators voiced hope that the new agents will be more effective. Two of the drugs—sunitinib and sorafenib—have already been approved for renal cell carcinoma. Sunitinib also has an indication for gastrointestinal stromal tumors that are refractory to imatinib (Gleevec).

Along with the possibility of better therapies, however, the three trials renewed concerns about the toxicity of antiangiogenic agents. Investigators reported cavitation and hemorrhage leading to treatment-related deaths. Rash, hand-foot syndrome, and controllable hypertension also were seen.

“More than ever, we need pulmonologists to look at the risk of bleeding and to look at cavitation,” Dr. Roy S. Herbst said in an interview after presenting a review of the new drugs and the state of antiangiogenic therapy against lung cancer.

“We need to find some sort of risk factors to stratify these patients,” said Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston and the senior investigator of a series of lung cancer trials testing the combination of bevacizumab and erlotinib (Tarceva).

Dr. Herbst cited the survival advantages reported last year in a phase III trial combining bevacizumab with chemotherapy as well as early results from his study. “Despite these advances, few, if any, metastatic patients are cured,” he cautioned.

He called the three new agents “quite comparable” and noted that “signs of early activity are seen,” but cautioned that whether the new multitargeted tyrosine kinase inhibitors are more effective than single-targeted bevacizumab is “not clear yet” in non-small cell lung cancer.

Among the potential advantages of multitargeted agents, Dr. Herbst cited convenience, single-agent activity, the ability to act on both tumor and blood vessels, and the potential to lower the cost of treatment. He cautioned, however, that the inhibition of each target may not be equally effective with just one drug.

Sunitinib

Dr. Mark A. Socinski reported that sunitinib controlled tumor growth in more than half of 63 patients who had failed previous regimens for advanced non-small cell lung cancer.

Six patients (9.5%) had partial responses, and 27 patients (42.9%) had stable disease in the study. Median progression-free survival reached 11.3 weeks and overall survival 23.9 weeks.

Three patients died of hemorrhages, however: Two were pulmonary—only one of which was attributed to treatment—and one was cerebral.

Patients received 50 mg of sunitinib daily for 4 weeks followed by 2 weeks off therapy before starting another cycle in the trial. Dr. Socinski, director of the multidisciplinary thoracic oncology program at the University of North Carolina at Chapel Hill, announced that the study has been extended and 47 additional patients enrolled on a revised dosing schedule of 37.5 mg daily.

Sorafenib

Dr. Ulrich Gatzemeier reported that 30 (59%) of 51 patients with advanced non-small cell lung cancer had stable disease while they were treated with 400 mg twice a day of sorafenib. No partial responses were recorded in the study.

Another 18 patients (35%) progressed, and three patients died before they could be evaluated.

Median progression-free survival reached 11.3 months, and median survival 29.5 weeks. Two patients have been on therapy for 2 years, according to Dr. Gatzemeier, head of thoracic oncology at Grosshansdorf Hospital in Hamburg, Germany.

Dr. Gatzemeier announced that a phase III trial has already started. It is to randomize 900 patients to a carboplatin/paclitaxel regimen with sorafenib or a placebo.

ZD6474

Dr. Ronald B. Natale reported that 83 patients achieved a median progression-free survival of 11 weeks on 300 mg per day of ZD6474. In comparison, only 8.1 weeks was reached by a control arm of 85 patients treated with 250 mg of gefitinib (Iressa) daily. The response rates were 8% and 1%, respectively.

The trial allowed patients who had progressed to cross over to the other agent. There were no additional responses, but 16 of 37 patients who switched from gefitinib to ZD6474 achieved more than 8 weeks' disease control vs. 7 of 29 patients who switched to gefitinib from ZD6474.

Dr. Natale, a medical oncologist at the Cedars-Sinai Comprehensive Cancer Center in Los Angeles, concluded that the data support further investigation of ZD6474 as monotherapy.

Convenience and the potential to lower treatment costs are among the advantages of these agents. DR. HERBST

ATLANTA — Bevacizumab (Avastin) in combination with erlotinib (Tarceva) was associated with promising preliminary results in the treatment of refractory non-small cell lung cancer in data presented at the annual meeting of the American Society of Clinical Oncology.

The 17.9% response rate with the bevacizumab-erlotinib combination was better than the 12.5% rate seen in patients treated with bevacizumab and chemotherapy and the 12.2% rate seen in those treated chemotherapy alone.

Dr. Louis Fehrenbacher reported that 31 of 39 patients treated with bevacizumab and erlotinib were alive at 6 months. With bevacizumab and chemotherapy, 29 of 40 were still alive at 6 months.

The two bevacizumab arms also had similar progression-free survival: 4.8 months when the angiogenesis inhibitor was combined with chemotherapy and 4.4 months when it was used with erlotinib.

A control arm of 41 patients treated only with chemotherapy (either pemetrexed or docetaxel) had the worst outcomes. Only 26 of those patients were alive at 6 months. Median progression-free survival was just 3 months.

Dr. Fehrenbacher of Kaiser Permanente Vallejo Medical Center in California and his coinvestigators reported that about one-third of both bevacizumab arms and about one-fifth of the chemotherapy-only patients were progression free at 6 months. The investigators calculated adjusted hazard ratios of 0.66 for bevacizumab with chemotherapy and 0.72 for bevacizumab with erlotinib, compared with the chemotherapy arm.

“Overall I think this is a very encouraging finding that the [bevacizumab-erlotinib] combination may actually work in a refractory situation,” Dr. Tony Mok said in a discussion of the poster.

Dr. Mok, of the Chinese University of Hong Kong, said the results challenge the belief that combining agents is not worthwhile for second-line treatment of non-small cell lung cancer. It also raises questions, he said, about how bevacizumab works and how bevacizumab and chemotherapy work together. Instead of treating chemotherapies as interchangeable with bevacizumab, he said, clinicians need to find the best combination.

One-year data are not yet available for the trial, which enrolled patients with locally advanced or metastatic (stages IIb-IV), nonsquamous non-small cell lung cancer. The study excluded patients with brain metastases.

Bevacizumab, a monoclonal antibody marketed by Genentech in the United States and by Roche worldwide, helps to cut off blood supply to tumors by inhibiting vascular endothelial growth factor. It is approved for use in combination with chemotherapy for the treatment of metastatic colorectal cancer.

Erlotinib, produced by OSI Pharmaceuticals, targets the human epidermal growth factor receptor pathway, which also plays a role in promoting tumor growth. It is approved for use as monotherapy in patients with locally advanced or metastatic non-small cell lung cancer that has progressed on chemotherapy.

Beyond the juggling of similar benefits in the two bevacizumab arms, the much-anticipated phase II trial showed less toxicity overall when patients were treated with two targeted therapies instead of chemotherapy alone or in combination.

Only four patients (10%) in the bevacizumab-erlotinib arm discontinued treatment because of adverse events, compared with 10 patients in each of the chemotherapy arms. The trial reported serious events in 13 bevacizumab-erlotinib patients (33%), 16 bevacizumab-chemotherapy patients (40%), and 22 chemotherapy-only patients (54%). One chemotherapy-only patient died of cardiopulmonary arrest. No chemotherapy-only patients had pulmonary hemorrhage, a growing concern for patients treated with angiogenic inhibitors.

Two fatal pulmonary hemorrhages and a fatal gastrointestinal bleed occurred in patients treated with bevacizumab and chemotherapy. One patient in the bevacizumab-erlotinib arm died of a pulmonary hemorrhage.

Dr. Roy S. Herbst, senior author of the trial, noted that two much larger studies are already exploring the bevacizumab-erlotinib combination as first- and second-line therapies in non-small cell lung cancer. Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston, said about 1,800 patients are to be enrolled in these studies, which will test the targeted agents alone and in combination against chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

ATLANTA — Bevacizumab (Avastin) in combination with erlotinib (Tarceva) was associated with promising preliminary results in the treatment of refractory non-small cell lung cancer in data presented at the annual meeting of the American Society of Clinical Oncology.

The 17.9% response rate with the bevacizumab-erlotinib combination was better than the 12.5% rate seen in patients treated with bevacizumab and chemotherapy and the 12.2% rate seen in those treated chemotherapy alone.

Dr. Louis Fehrenbacher reported that 31 of 39 patients treated with bevacizumab and erlotinib were alive at 6 months. With bevacizumab and chemotherapy, 29 of 40 were still alive at 6 months.

The two bevacizumab arms also had similar progression-free survival: 4.8 months when the angiogenesis inhibitor was combined with chemotherapy and 4.4 months when it was used with erlotinib.

A control arm of 41 patients treated only with chemotherapy (either pemetrexed or docetaxel) had the worst outcomes. Only 26 of those patients were alive at 6 months. Median progression-free survival was just 3 months.

Dr. Fehrenbacher of Kaiser Permanente Vallejo Medical Center in California and his coinvestigators reported that about one-third of both bevacizumab arms and about one-fifth of the chemotherapy-only patients were progression free at 6 months. The investigators calculated adjusted hazard ratios of 0.66 for bevacizumab with chemotherapy and 0.72 for bevacizumab with erlotinib, compared with the chemotherapy arm.

“Overall I think this is a very encouraging finding that the [bevacizumab-erlotinib] combination may actually work in a refractory situation,” Dr. Tony Mok said in a discussion of the poster.

Dr. Mok, of the Chinese University of Hong Kong, said the results challenge the belief that combining agents is not worthwhile for second-line treatment of non-small cell lung cancer. It also raises questions, he said, about how bevacizumab works and how bevacizumab and chemotherapy work together. Instead of treating chemotherapies as interchangeable with bevacizumab, he said, clinicians need to find the best combination.

One-year data are not yet available for the trial, which enrolled patients with locally advanced or metastatic (stages IIb-IV), nonsquamous non-small cell lung cancer. The study excluded patients with brain metastases.

Bevacizumab, a monoclonal antibody marketed by Genentech in the United States and by Roche worldwide, helps to cut off blood supply to tumors by inhibiting vascular endothelial growth factor. It is approved for use in combination with chemotherapy for the treatment of metastatic colorectal cancer.

Erlotinib, produced by OSI Pharmaceuticals, targets the human epidermal growth factor receptor pathway, which also plays a role in promoting tumor growth. It is approved for use as monotherapy in patients with locally advanced or metastatic non-small cell lung cancer that has progressed on chemotherapy.

Beyond the juggling of similar benefits in the two bevacizumab arms, the much-anticipated phase II trial showed less toxicity overall when patients were treated with two targeted therapies instead of chemotherapy alone or in combination.

Only four patients (10%) in the bevacizumab-erlotinib arm discontinued treatment because of adverse events, compared with 10 patients in each of the chemotherapy arms. The trial reported serious events in 13 bevacizumab-erlotinib patients (33%), 16 bevacizumab-chemotherapy patients (40%), and 22 chemotherapy-only patients (54%). One chemotherapy-only patient died of cardiopulmonary arrest. No chemotherapy-only patients had pulmonary hemorrhage, a growing concern for patients treated with angiogenic inhibitors.

Two fatal pulmonary hemorrhages and a fatal gastrointestinal bleed occurred in patients treated with bevacizumab and chemotherapy. One patient in the bevacizumab-erlotinib arm died of a pulmonary hemorrhage.

Dr. Roy S. Herbst, senior author of the trial, noted that two much larger studies are already exploring the bevacizumab-erlotinib combination as first- and second-line therapies in non-small cell lung cancer. Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston, said about 1,800 patients are to be enrolled in these studies, which will test the targeted agents alone and in combination against chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

ATLANTA — Bevacizumab (Avastin) in combination with erlotinib (Tarceva) was associated with promising preliminary results in the treatment of refractory non-small cell lung cancer in data presented at the annual meeting of the American Society of Clinical Oncology.

The 17.9% response rate with the bevacizumab-erlotinib combination was better than the 12.5% rate seen in patients treated with bevacizumab and chemotherapy and the 12.2% rate seen in those treated chemotherapy alone.

Dr. Louis Fehrenbacher reported that 31 of 39 patients treated with bevacizumab and erlotinib were alive at 6 months. With bevacizumab and chemotherapy, 29 of 40 were still alive at 6 months.

The two bevacizumab arms also had similar progression-free survival: 4.8 months when the angiogenesis inhibitor was combined with chemotherapy and 4.4 months when it was used with erlotinib.

A control arm of 41 patients treated only with chemotherapy (either pemetrexed or docetaxel) had the worst outcomes. Only 26 of those patients were alive at 6 months. Median progression-free survival was just 3 months.

Dr. Fehrenbacher of Kaiser Permanente Vallejo Medical Center in California and his coinvestigators reported that about one-third of both bevacizumab arms and about one-fifth of the chemotherapy-only patients were progression free at 6 months. The investigators calculated adjusted hazard ratios of 0.66 for bevacizumab with chemotherapy and 0.72 for bevacizumab with erlotinib, compared with the chemotherapy arm.

“Overall I think this is a very encouraging finding that the [bevacizumab-erlotinib] combination may actually work in a refractory situation,” Dr. Tony Mok said in a discussion of the poster.

Dr. Mok, of the Chinese University of Hong Kong, said the results challenge the belief that combining agents is not worthwhile for second-line treatment of non-small cell lung cancer. It also raises questions, he said, about how bevacizumab works and how bevacizumab and chemotherapy work together. Instead of treating chemotherapies as interchangeable with bevacizumab, he said, clinicians need to find the best combination.

One-year data are not yet available for the trial, which enrolled patients with locally advanced or metastatic (stages IIb-IV), nonsquamous non-small cell lung cancer. The study excluded patients with brain metastases.

Bevacizumab, a monoclonal antibody marketed by Genentech in the United States and by Roche worldwide, helps to cut off blood supply to tumors by inhibiting vascular endothelial growth factor. It is approved for use in combination with chemotherapy for the treatment of metastatic colorectal cancer.

Erlotinib, produced by OSI Pharmaceuticals, targets the human epidermal growth factor receptor pathway, which also plays a role in promoting tumor growth. It is approved for use as monotherapy in patients with locally advanced or metastatic non-small cell lung cancer that has progressed on chemotherapy.

Beyond the juggling of similar benefits in the two bevacizumab arms, the much-anticipated phase II trial showed less toxicity overall when patients were treated with two targeted therapies instead of chemotherapy alone or in combination.

Only four patients (10%) in the bevacizumab-erlotinib arm discontinued treatment because of adverse events, compared with 10 patients in each of the chemotherapy arms. The trial reported serious events in 13 bevacizumab-erlotinib patients (33%), 16 bevacizumab-chemotherapy patients (40%), and 22 chemotherapy-only patients (54%). One chemotherapy-only patient died of cardiopulmonary arrest. No chemotherapy-only patients had pulmonary hemorrhage, a growing concern for patients treated with angiogenic inhibitors.

Two fatal pulmonary hemorrhages and a fatal gastrointestinal bleed occurred in patients treated with bevacizumab and chemotherapy. One patient in the bevacizumab-erlotinib arm died of a pulmonary hemorrhage.

Dr. Roy S. Herbst, senior author of the trial, noted that two much larger studies are already exploring the bevacizumab-erlotinib combination as first- and second-line therapies in non-small cell lung cancer. Dr. Herbst, chief of thoracic medical oncology at M.D. Anderson Cancer Center in Houston, said about 1,800 patients are to be enrolled in these studies, which will test the targeted agents alone and in combination against chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use].”

Dr. Buzdar, professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. They noted that cardiovascular adverse events were no worse with anastrozole than with tamoxifen, whereas the other studies have raised concern about cardiovascular safety.

“Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said. “We can't assume the other aromatase inhibitors will have the same safety data.”

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 participating centers in 21 countries. A combination arm in which women were randomized to tamoxifen and anastrozole was dropped after an initial analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). Dr. Buzdar noted that this is significantly longer than the follow-up so far in ongoing letrozole and exemestane trials. Only 8% of patients were still on their trial medication, with less than a year of treatment remaining.

Efficacy measures were based on the intent-to-treat population, but safety was based on the treatment of 3,092 women on anastrozole and 3,094 women on tamoxifen.

Women in the anastrozole group had fewer treatment-related adverse events (61% vs. 68%) and fewer serious adverse events that were treatment related (5% vs. 9%). They also were less likely to withdraw because of adverse events (11% vs. 14%).

About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%).

The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

In both groups, the women who died of breast cancer tended to be younger, with a median age 68 years vs. 74 years for those who died of other causes.

“There are a lot more women free of cancer down the line,” Dr. Buzdar said, adding that the fact that they are dying older and of other causes “means we can prevent cancer in a much larger population, and they are having a normal life span.”

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Eyes Inhibitor Issues

The International Aromatase Inhibitor Expert Panel of 24 breast cancer experts reviewed the major randomized trials of adjuvant treatment and concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85). The panel also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use].”

Dr. Buzdar, professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. They noted that cardiovascular adverse events were no worse with anastrozole than with tamoxifen, whereas the other studies have raised concern about cardiovascular safety.

“Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said. “We can't assume the other aromatase inhibitors will have the same safety data.”

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 participating centers in 21 countries. A combination arm in which women were randomized to tamoxifen and anastrozole was dropped after an initial analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). Dr. Buzdar noted that this is significantly longer than the follow-up so far in ongoing letrozole and exemestane trials. Only 8% of patients were still on their trial medication, with less than a year of treatment remaining.

Efficacy measures were based on the intent-to-treat population, but safety was based on the treatment of 3,092 women on anastrozole and 3,094 women on tamoxifen.

Women in the anastrozole group had fewer treatment-related adverse events (61% vs. 68%) and fewer serious adverse events that were treatment related (5% vs. 9%). They also were less likely to withdraw because of adverse events (11% vs. 14%).

About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%).

The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

In both groups, the women who died of breast cancer tended to be younger, with a median age 68 years vs. 74 years for those who died of other causes.

“There are a lot more women free of cancer down the line,” Dr. Buzdar said, adding that the fact that they are dying older and of other causes “means we can prevent cancer in a much larger population, and they are having a normal life span.”

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Eyes Inhibitor Issues

The International Aromatase Inhibitor Expert Panel of 24 breast cancer experts reviewed the major randomized trials of adjuvant treatment and concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85). The panel also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

Investigators of a key international trial comparing anastrozole to tamoxifen have concluded that their long-term safety results support up-front use of the aromatase inhibitor as an adjuvant treatment for hormone-sensitive early-stage breast cancer in postmenopausal women.

Risk-benefit analysis of adverse event and recurrence data from more than 6,000 women, most of whom had completed 5 years of hormonal therapy, demonstrated a significant advantage for anastrozole (Arimidex) over tamoxifen (Nolvadex), according to the Armidex, Tamoxifen, Alone or in Combination (ATAC) trialists' group.

“This benefit was greatest at 1–2 years of treatment, which indicates that a prospective strategy to start tamoxifen treatment but switch to an aromatase inhibitor afterward puts patients at risk of preventable recurrences and excess adverse events during the initial period of tamoxifen treatment,” the investigators said (Lancet Oncol. 2006;7:633–43).

In an interview, Dr. Aman U. Buzdar, the principal investigator, said he did not think the ATAC findings would be the last word in the quandary over up-front vs. sequential use of aromatase inhibitors after a number of years of tamoxifen therapy. “I don't think it is resolved, but the evidence points to [up-front use].”

Dr. Buzdar, professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, said that the risk of recurrence peaks 2–3 years after treatment in women with either node-negative or node-positive breast cancer. “We can't predict which one will not get disease up front,” he said in support of starting the more effective therapy immediately in all patients.

Current guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network state that aromatase inhibitors alone or in combination with tamoxifen are better than tamoxifen alone. They recommend specific up-front and sequential strategies without stating a preference.

Category 1 evidence from randomized trials comparing aromatase inhibitors with tamoxifen supports up-front and sequential approaches, according to Dr. J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society in Atlanta. Without a head-to-head comparison of strategies in a randomized clinical trial, the decision remains up to clinician judgment, he said in an interview.

“There are obvious questions people will ask to which there are not obvious answers available,” he said.

That the ATAC long-term analysis did not introduce any late side effects is perhaps its most salient contribution to the literature, according to the physicians interviewed.

“If there were any skeptics at the first ATAC report, the data have held up over time,” Dr. Lichtenfeld said.

“Nothing new has emerged from that data,” Dr. Buzdar said. “It is reassuring that there is nothing in the back that is lurking and may show up.”

The ATAC investigators warned that their safety findings should not be extrapolated to letrozole and exemestane, the other two aromatase inhibitors in large clinical trials as adjuvant treatments for early-stage hormone-sensitive breast cancer. They noted that cardiovascular adverse events were no worse with anastrozole than with tamoxifen, whereas the other studies have raised concern about cardiovascular safety.

“Even though their efficacy may be the same, their safety may be different,” Dr. Buzdar said. “We can't assume the other aromatase inhibitors will have the same safety data.”

The ATAC trial and many of the investigators, including Dr. Buzdar, received financial support from AstraZeneca, maker of anastrozole and of Nolvadex, a trademarked form of tamoxifen, which recently became a generic drug.

Clinicians enrolled 9,366 postmenopausal women at 381 participating centers in 21 countries. A combination arm in which women were randomized to tamoxifen and anastrozole was dropped after an initial analysis showed no benefit over tamoxifen as a single agent.

In the latest analysis, 3,125 women assigned to monotherapy with anastrozole and 3,116 women on tamoxifen were followed for a median of 68 months (range 1–90 months). Dr. Buzdar noted that this is significantly longer than the follow-up so far in ongoing letrozole and exemestane trials. Only 8% of patients were still on their trial medication, with less than a year of treatment remaining.

Efficacy measures were based on the intent-to-treat population, but safety was based on the treatment of 3,092 women on anastrozole and 3,094 women on tamoxifen.

Women in the anastrozole group had fewer treatment-related adverse events (61% vs. 68%) and fewer serious adverse events that were treatment related (5% vs. 9%). They also were less likely to withdraw because of adverse events (11% vs. 14%).

About 13% of both cohorts had died, but the tamoxifen patients were more likely to have died of breast cancer (9% vs. 8% of the anastrozole arm) and less likely to die without a recurrence of breast cancer (5% vs. 6%).

The analysis calculated the hazard ratio of death from breast cancer as 0.88 for anastrozole in comparison with tamoxifen.

In both groups, the women who died of breast cancer tended to be younger, with a median age 68 years vs. 74 years for those who died of other causes.

“There are a lot more women free of cancer down the line,” Dr. Buzdar said, adding that the fact that they are dying older and of other causes “means we can prevent cancer in a much larger population, and they are having a normal life span.”

ELSEVIER GLOBAL MEDICAL NEWS

Expert Panel Eyes Inhibitor Issues

The International Aromatase Inhibitor Expert Panel of 24 breast cancer experts reviewed the major randomized trials of adjuvant treatment and concluded that aromatase inhibitors are superior to tamoxifen, whether given as an initial hormonal therapy or sequentially in patients who started on tamoxifen (Curr. Med. Res. Opin. 2006;22:1575–85). The panel also found, however, that the best way to use aromatase inhibitors is yet to be determined.

Among the issues addressed by the panel, which was supported by an unrestricted grant from AstraZeneca, are:

▸ Patient populations. Patients who were switched to aromatase inhibitors after they did not recur while on tamoxifen are not the same as patients who were randomized to a sequence of tamoxifen followed by an aromatase inhibitor. “Switching-study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment,” the panel wrote.

▸ No direct comparisons. Until the Breast International Group-98 trial publishes mature data comparing 5 years of letrozole therapy with sequence therapy, no data are available from trials comparing a sequential strategy with monotherapy. For now, the panel found that the best researchers can do is to construct models based on existing data.

▸ Duration of therapy. Although the optimal duration of tamoxifen therapy is 5 years, and 5 years has been adopted as the standard for endocrine therapy, the optimal duration of aromatase inhibition is not known.

▸ Cardiac, stroke, and endometrial cancer risk. Data on patients with preexisting coronary heart disease are not available for tamoxifen or aromatase inhibitors, according to the panel. Although there is no evidence that these patients should be excluded from treatment with aromatase inhibitors, this needs to be studied.

SAN FRANCISCO — The live attenuated influenza vaccine known as FluMist is as safe as an inactivated virus vaccine for children with HIV who have CD4 percentages of 15% or greater, according to the findings of a randomized, controlled trial.

Investigators recorded similar toxicity profiles for FluMist and the trivalent inactivated virus (TIV) vaccine that is standard for this population, Dr. Sharon Nachman reported at the annual meeting of the Pediatric Academic Societies.

Prolonged shedding, a major concern, was not observed in either arm of the phase I-II trial, according to Dr. Nachman, chief of pediatric infectious diseases, department of pediatrics, State University of New York at Stony Brook.

“There were no unexpected toxicities or adverse events associated with administration of LAIV [live attenuated influenza virus] or TIV in HIV-positive children in this study,” she said, summarizing 6 months of follow-up on behalf of the Pediatric AIDS Clinical Trials Group.

The investigators randomized 243 HIV-positive children aged 5–18 years at the start of the 2004–2005 flu season: 122 to intranasal LAIV and 121 to injected TIV. The LAIV arm received the FluMist formulation that is currently approved for healthy children and adults aged 5–49 years.

Entry criteria included a current viral load below 60,000 copies/mL. All participants had at least 16 weeks of stable antiretroviral therapy with three different antiretroviral agents from at least two therapeutic classes. All had been vaccinated with TIV in at least one of the two previous years as well.

“Ethnicity looks exactly like [the] demographic of perinatally infected children across the United States,” Dr. Nachman said. The study arms were evenly matched with respect to mean age (11.4–11.9 years), CD4 percentage (33%–34%), and viral load (2.9 copies/mL in both groups).

Vaccine administration did not lead to clinically significant changes in CD4 count, viral load, or changes in antiretroviral therapy during the study.

Investigators detected influenza shedding in 31 of 115 LAIV recipients (27%) 3 days after they received the vaccine. By day 28 only one of 119 subjects (0.9%) was shedding virus, and the results of a follow-up culture on day 56 were negative.

During the first 28 days, eight children in the LAIV arm had nine events that may have been related to FluMist administration, including fever, conjunctivitis, sinusitis, and pharyngitis.

One child was hospitalized and recovered with antibiotic therapy, Dr. Nachman reported at the meeting, sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

A coinvestigator on the study is an employee of MedImmune Inc., manufacturer of FluMist.

SAN FRANCISCO — The live attenuated influenza vaccine known as FluMist is as safe as an inactivated virus vaccine for children with HIV who have CD4 percentages of 15% or greater, according to the findings of a randomized, controlled trial.

Investigators recorded similar toxicity profiles for FluMist and the trivalent inactivated virus (TIV) vaccine that is standard for this population, Dr. Sharon Nachman reported at the annual meeting of the Pediatric Academic Societies.

Prolonged shedding, a major concern, was not observed in either arm of the phase I-II trial, according to Dr. Nachman, chief of pediatric infectious diseases, department of pediatrics, State University of New York at Stony Brook.

“There were no unexpected toxicities or adverse events associated with administration of LAIV [live attenuated influenza virus] or TIV in HIV-positive children in this study,” she said, summarizing 6 months of follow-up on behalf of the Pediatric AIDS Clinical Trials Group.

The investigators randomized 243 HIV-positive children aged 5–18 years at the start of the 2004–2005 flu season: 122 to intranasal LAIV and 121 to injected TIV. The LAIV arm received the FluMist formulation that is currently approved for healthy children and adults aged 5–49 years.

Entry criteria included a current viral load below 60,000 copies/mL. All participants had at least 16 weeks of stable antiretroviral therapy with three different antiretroviral agents from at least two therapeutic classes. All had been vaccinated with TIV in at least one of the two previous years as well.

“Ethnicity looks exactly like [the] demographic of perinatally infected children across the United States,” Dr. Nachman said. The study arms were evenly matched with respect to mean age (11.4–11.9 years), CD4 percentage (33%–34%), and viral load (2.9 copies/mL in both groups).

Vaccine administration did not lead to clinically significant changes in CD4 count, viral load, or changes in antiretroviral therapy during the study.

Investigators detected influenza shedding in 31 of 115 LAIV recipients (27%) 3 days after they received the vaccine. By day 28 only one of 119 subjects (0.9%) was shedding virus, and the results of a follow-up culture on day 56 were negative.

During the first 28 days, eight children in the LAIV arm had nine events that may have been related to FluMist administration, including fever, conjunctivitis, sinusitis, and pharyngitis.

One child was hospitalized and recovered with antibiotic therapy, Dr. Nachman reported at the meeting, sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

A coinvestigator on the study is an employee of MedImmune Inc., manufacturer of FluMist.

SAN FRANCISCO — The live attenuated influenza vaccine known as FluMist is as safe as an inactivated virus vaccine for children with HIV who have CD4 percentages of 15% or greater, according to the findings of a randomized, controlled trial.

Investigators recorded similar toxicity profiles for FluMist and the trivalent inactivated virus (TIV) vaccine that is standard for this population, Dr. Sharon Nachman reported at the annual meeting of the Pediatric Academic Societies.

Prolonged shedding, a major concern, was not observed in either arm of the phase I-II trial, according to Dr. Nachman, chief of pediatric infectious diseases, department of pediatrics, State University of New York at Stony Brook.

“There were no unexpected toxicities or adverse events associated with administration of LAIV [live attenuated influenza virus] or TIV in HIV-positive children in this study,” she said, summarizing 6 months of follow-up on behalf of the Pediatric AIDS Clinical Trials Group.

The investigators randomized 243 HIV-positive children aged 5–18 years at the start of the 2004–2005 flu season: 122 to intranasal LAIV and 121 to injected TIV. The LAIV arm received the FluMist formulation that is currently approved for healthy children and adults aged 5–49 years.

Entry criteria included a current viral load below 60,000 copies/mL. All participants had at least 16 weeks of stable antiretroviral therapy with three different antiretroviral agents from at least two therapeutic classes. All had been vaccinated with TIV in at least one of the two previous years as well.

“Ethnicity looks exactly like [the] demographic of perinatally infected children across the United States,” Dr. Nachman said. The study arms were evenly matched with respect to mean age (11.4–11.9 years), CD4 percentage (33%–34%), and viral load (2.9 copies/mL in both groups).

Vaccine administration did not lead to clinically significant changes in CD4 count, viral load, or changes in antiretroviral therapy during the study.

Investigators detected influenza shedding in 31 of 115 LAIV recipients (27%) 3 days after they received the vaccine. By day 28 only one of 119 subjects (0.9%) was shedding virus, and the results of a follow-up culture on day 56 were negative.

During the first 28 days, eight children in the LAIV arm had nine events that may have been related to FluMist administration, including fever, conjunctivitis, sinusitis, and pharyngitis.

One child was hospitalized and recovered with antibiotic therapy, Dr. Nachman reported at the meeting, sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

A coinvestigator on the study is an employee of MedImmune Inc., manufacturer of FluMist.

SAN FRANCISCO — A Finnish trial testing an investigational, refrigerator-stable version of the FluMist vaccine in healthy infants aged 6 weeks to 6 months suggests it might be given safely to babies below the recommended age of influenza immunization in the United States.

Irritability and runny nose/nasal congestion were more common in the younger half of the trial's infant population, but these and other reactogenicity events were mild, Dr. Timo Vesikari reported at the annual meeting of the Pediatric Academic Societies.

Adverse events, including fever, were similar for babies in intranasal vaccine and placebo groups.

“I believe further investigation of CAIV-T [cold-adapted influenza vaccine, trivalent] in young infants is warranted, but we should consider the present finding in the 6- to 16-week-olds,” Dr. Vesikari of the University of Tampere, Finland, said at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The study enrolled 120 healthy infants from May to December 2002. Dr. Vesikari and his colleagues stratified the population into two groups: 59 babies in a 6- to 16-week-old cohort and 61 babies in a 16- to 24-week-old cohort.

Each cohort was randomized to receive two doses of CAIV-T or placebo about 35 days apart.

Monitoring for reactogenicity 11 days after the first dose showed the 6- to 16-week-old cohort experienced nearly twice as much irritability (66.7% vs. 35.7%) and runny nose/nasal congestion (63.3% vs. 33.3%) as the placebo group. No differences were seen after the second dose. Among the older infants, the only difference seen after the second dose was that cough occurred more with the placebo group (39.3%) than with the children given CAIV-T (10.7%).

Dr. Vesikari said the investigators accepted Wyeth's invitation to do the trial in part because studies have found FluMist to be more effective than trivalent, inactive vaccine in children.

SAN FRANCISCO — A Finnish trial testing an investigational, refrigerator-stable version of the FluMist vaccine in healthy infants aged 6 weeks to 6 months suggests it might be given safely to babies below the recommended age of influenza immunization in the United States.

Irritability and runny nose/nasal congestion were more common in the younger half of the trial's infant population, but these and other reactogenicity events were mild, Dr. Timo Vesikari reported at the annual meeting of the Pediatric Academic Societies.

Adverse events, including fever, were similar for babies in intranasal vaccine and placebo groups.

“I believe further investigation of CAIV-T [cold-adapted influenza vaccine, trivalent] in young infants is warranted, but we should consider the present finding in the 6- to 16-week-olds,” Dr. Vesikari of the University of Tampere, Finland, said at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The study enrolled 120 healthy infants from May to December 2002. Dr. Vesikari and his colleagues stratified the population into two groups: 59 babies in a 6- to 16-week-old cohort and 61 babies in a 16- to 24-week-old cohort.

Each cohort was randomized to receive two doses of CAIV-T or placebo about 35 days apart.

Monitoring for reactogenicity 11 days after the first dose showed the 6- to 16-week-old cohort experienced nearly twice as much irritability (66.7% vs. 35.7%) and runny nose/nasal congestion (63.3% vs. 33.3%) as the placebo group. No differences were seen after the second dose. Among the older infants, the only difference seen after the second dose was that cough occurred more with the placebo group (39.3%) than with the children given CAIV-T (10.7%).

Dr. Vesikari said the investigators accepted Wyeth's invitation to do the trial in part because studies have found FluMist to be more effective than trivalent, inactive vaccine in children.

SAN FRANCISCO — A Finnish trial testing an investigational, refrigerator-stable version of the FluMist vaccine in healthy infants aged 6 weeks to 6 months suggests it might be given safely to babies below the recommended age of influenza immunization in the United States.

Irritability and runny nose/nasal congestion were more common in the younger half of the trial's infant population, but these and other reactogenicity events were mild, Dr. Timo Vesikari reported at the annual meeting of the Pediatric Academic Societies.

Adverse events, including fever, were similar for babies in intranasal vaccine and placebo groups.

“I believe further investigation of CAIV-T [cold-adapted influenza vaccine, trivalent] in young infants is warranted, but we should consider the present finding in the 6- to 16-week-olds,” Dr. Vesikari of the University of Tampere, Finland, said at the meeting, which was sponsored by the American Pediatric Society, Society for Pediatric Research, Ambulatory Pediatric Association, and American Academy of Pediatrics.

The study enrolled 120 healthy infants from May to December 2002. Dr. Vesikari and his colleagues stratified the population into two groups: 59 babies in a 6- to 16-week-old cohort and 61 babies in a 16- to 24-week-old cohort.

Each cohort was randomized to receive two doses of CAIV-T or placebo about 35 days apart.

Monitoring for reactogenicity 11 days after the first dose showed the 6- to 16-week-old cohort experienced nearly twice as much irritability (66.7% vs. 35.7%) and runny nose/nasal congestion (63.3% vs. 33.3%) as the placebo group. No differences were seen after the second dose. Among the older infants, the only difference seen after the second dose was that cough occurred more with the placebo group (39.3%) than with the children given CAIV-T (10.7%).

Dr. Vesikari said the investigators accepted Wyeth's invitation to do the trial in part because studies have found FluMist to be more effective than trivalent, inactive vaccine in children.