Pulmonary Health Hub

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

A strategy for protecting the lungs in potential organ donors nearly doubled the number of lungs that were suitable for transplantation, according to a report in the Dec. 15 issue of JAMA.

The lung-protection strategy, which apparently forestalled much of the pulmonary damage associated with brain injury and mechanical ventilation, had no detrimental effects on other organs – hearts, livers, and kidneys – harvested from the same donors for transplantation, said Dr. Luciana Mascia of the departments of anesthesia and intensive care medicine at the University of Turin (Italy).

Potential organ donors who have relatively normal pulmonary function at the time of brain death often show marked declines in that function, so that only 15%-20% of these lungs are suitable for transplantation when organ harvesting commences.

Dr. Mascia and her colleagues studied 118 patients with brain death who were potential organ donors and were being treated at 12 intensive care units (ICUs) in Italy and Spain between 2004 and 2009. A total of 59 patients were randomly assigned to undergo conventional lung ventilation techniques, and the other 59 were assigned to a strategy of using lower tidal volumes, higher positive end-expiratory pressure (to prevent atelectasis), a closed system for any tracheal suctioning, alveolar recruitment maneuvers after any ventilator disconnections, and continuous positive airway pressure during apnea tests.

After a mandatory 6-hour interval before brain death could be officially declared, there were 49 potential donors in the conventional-care group and 51 in the lung-protection group. The number of patients who then were found to meet lung-donor eligibility criteria had decreased with the conventional ventilation strategy by 29% to only 32 patients. In contrast, the number in the lung-protection group had increased to 56 patients, a significant difference.

This means that of the original potential donors, only 54% in the conventional-care group met eligibility criteria, compared with 95% in the lung-protection group, Dr. Mascia and her associates said (JAMA 2010;304:2620-27).

The ultimate number of lungs that were successfully harvested was 27% of the conventional-care group (16 lungs), compared with 54% of the lung-protection group (32 lungs), also a significant difference.

For the lung recipients, the median ICU length of stay was 12 days for patients who received lungs from the conventional-care group and 8 days for those who received lungs from the lung-protection group. Six-month survival was 69% for patients who received lungs from the conventional-care group and 75% for those who received lungs from the lung-protection group, a nonsignificant difference.

The number of other organs harvested did not differ between the two study groups, and 6-month survival of those recipients also did not differ significantly.

The Protective Ventilatory Strategy in Potential Organ Donors Study (clinicaltrials.gov ID: NCT00260676) was stopped after 118 patients were enrolled, because of termination of funding.

This study was supported by the Ministero della Salute Programma Ricerca Finalizzata, the Regione Piemonte Programma Ricerca Finalizzata, and the Ministero dell’Universita Programma di Ricerca di Interesse Nazionale. No financial conflicts of interest were reported.

A strategy for protecting the lungs in potential organ donors nearly doubled the number of lungs that were suitable for transplantation, according to a report in the Dec. 15 issue of JAMA.

The lung-protection strategy, which apparently forestalled much of the pulmonary damage associated with brain injury and mechanical ventilation, had no detrimental effects on other organs – hearts, livers, and kidneys – harvested from the same donors for transplantation, said Dr. Luciana Mascia of the departments of anesthesia and intensive care medicine at the University of Turin (Italy).

Potential organ donors who have relatively normal pulmonary function at the time of brain death often show marked declines in that function, so that only 15%-20% of these lungs are suitable for transplantation when organ harvesting commences.

Dr. Mascia and her colleagues studied 118 patients with brain death who were potential organ donors and were being treated at 12 intensive care units (ICUs) in Italy and Spain between 2004 and 2009. A total of 59 patients were randomly assigned to undergo conventional lung ventilation techniques, and the other 59 were assigned to a strategy of using lower tidal volumes, higher positive end-expiratory pressure (to prevent atelectasis), a closed system for any tracheal suctioning, alveolar recruitment maneuvers after any ventilator disconnections, and continuous positive airway pressure during apnea tests.

After a mandatory 6-hour interval before brain death could be officially declared, there were 49 potential donors in the conventional-care group and 51 in the lung-protection group. The number of patients who then were found to meet lung-donor eligibility criteria had decreased with the conventional ventilation strategy by 29% to only 32 patients. In contrast, the number in the lung-protection group had increased to 56 patients, a significant difference.

This means that of the original potential donors, only 54% in the conventional-care group met eligibility criteria, compared with 95% in the lung-protection group, Dr. Mascia and her associates said (JAMA 2010;304:2620-27).

The ultimate number of lungs that were successfully harvested was 27% of the conventional-care group (16 lungs), compared with 54% of the lung-protection group (32 lungs), also a significant difference.

For the lung recipients, the median ICU length of stay was 12 days for patients who received lungs from the conventional-care group and 8 days for those who received lungs from the lung-protection group. Six-month survival was 69% for patients who received lungs from the conventional-care group and 75% for those who received lungs from the lung-protection group, a nonsignificant difference.

The number of other organs harvested did not differ between the two study groups, and 6-month survival of those recipients also did not differ significantly.

The Protective Ventilatory Strategy in Potential Organ Donors Study (clinicaltrials.gov ID: NCT00260676) was stopped after 118 patients were enrolled, because of termination of funding.

This study was supported by the Ministero della Salute Programma Ricerca Finalizzata, the Regione Piemonte Programma Ricerca Finalizzata, and the Ministero dell’Universita Programma di Ricerca di Interesse Nazionale. No financial conflicts of interest were reported.

A strategy for protecting the lungs in potential organ donors nearly doubled the number of lungs that were suitable for transplantation, according to a report in the Dec. 15 issue of JAMA.

The lung-protection strategy, which apparently forestalled much of the pulmonary damage associated with brain injury and mechanical ventilation, had no detrimental effects on other organs – hearts, livers, and kidneys – harvested from the same donors for transplantation, said Dr. Luciana Mascia of the departments of anesthesia and intensive care medicine at the University of Turin (Italy).

Potential organ donors who have relatively normal pulmonary function at the time of brain death often show marked declines in that function, so that only 15%-20% of these lungs are suitable for transplantation when organ harvesting commences.

Dr. Mascia and her colleagues studied 118 patients with brain death who were potential organ donors and were being treated at 12 intensive care units (ICUs) in Italy and Spain between 2004 and 2009. A total of 59 patients were randomly assigned to undergo conventional lung ventilation techniques, and the other 59 were assigned to a strategy of using lower tidal volumes, higher positive end-expiratory pressure (to prevent atelectasis), a closed system for any tracheal suctioning, alveolar recruitment maneuvers after any ventilator disconnections, and continuous positive airway pressure during apnea tests.

After a mandatory 6-hour interval before brain death could be officially declared, there were 49 potential donors in the conventional-care group and 51 in the lung-protection group. The number of patients who then were found to meet lung-donor eligibility criteria had decreased with the conventional ventilation strategy by 29% to only 32 patients. In contrast, the number in the lung-protection group had increased to 56 patients, a significant difference.

This means that of the original potential donors, only 54% in the conventional-care group met eligibility criteria, compared with 95% in the lung-protection group, Dr. Mascia and her associates said (JAMA 2010;304:2620-27).

The ultimate number of lungs that were successfully harvested was 27% of the conventional-care group (16 lungs), compared with 54% of the lung-protection group (32 lungs), also a significant difference.

For the lung recipients, the median ICU length of stay was 12 days for patients who received lungs from the conventional-care group and 8 days for those who received lungs from the lung-protection group. Six-month survival was 69% for patients who received lungs from the conventional-care group and 75% for those who received lungs from the lung-protection group, a nonsignificant difference.

The number of other organs harvested did not differ between the two study groups, and 6-month survival of those recipients also did not differ significantly.

The Protective Ventilatory Strategy in Potential Organ Donors Study (clinicaltrials.gov ID: NCT00260676) was stopped after 118 patients were enrolled, because of termination of funding.

This study was supported by the Ministero della Salute Programma Ricerca Finalizzata, the Regione Piemonte Programma Ricerca Finalizzata, and the Ministero dell’Universita Programma di Ricerca di Interesse Nazionale. No financial conflicts of interest were reported.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

WASHINGTON – For the first time, there is evidence of immediate and direct harm done by smoking even one cigarette, according to the 30th annual United States Surgeon General’s Office report on smoking, issued Dec. 9.

© kutay tanir/iStockphoto.com

Surgeon General Regina M. Benjamin said at a press briefing that previous reports from her office honed in on the various diseases that smoking could cause. "This report focuses on how tobacco smoke causes damage to every organ in your body," she said.

When asked why this report could make a difference when so many previous warnings have not convinced all Americans to quit smoking, Dr. Benjamin said that she thinks that the direct evidence of harm will personalize the message.

"I believe it’s very important that every American knows what’s happening in their bodies, particularly those who are trying to quit." She said it might be helpful for people to know the various biological reasons why quitting is so hard.

Dr. Benjamin said she knew that even President Obama was trying very hard to quit and that she’d told him about the new findings.

The 700-page "Report of the Surgeon General: How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease" determined that tobacco smoke contains 7,000 chemicals, hundreds of which are known to be toxic and 70 of which are carcinogenic, she noted.

The report describes multiple insults to the body from those chemicals, including changes in DNA that can lead to cancer; damage to the lining of the lungs; obstructive pulmonary disease and bronchitis; stress on the vasculature and cardiovascular disease; and an increased risk of heart attack, stroke, and aortic aneurysm.

Smoking also interferes with the effectiveness of chemotherapy and the control of blood sugar and leads to fertility problems, including difficulty conceiving, miscarriage, and preterm birth.

Just one cigarette can trigger a heart attack or stroke, she said. In addition, the report examined the effects of secondhand smoke, finding that even brief exposure can cause cardiovascular disease and can also trigger acute cardiac events, such as heart attack. Babies exposed to secondhand smoke are more likely to die of sudden infant death syndrome.

The report highlights the increasingly addictive properties of today’s cigarettes, many of which are designed to enhance nicotine absorption and its crossing of the blood-brain barrier, Dr. Benjamin said. Some cigarettes also allow smokers to inhale more deeply into the lungs, increasing the disease risk.

Department of Health and Human Services Secretary Kathleen Sebelius said at the briefing that the report shows that "there is no safe level of exposure to tobacco smoke," and, she added, "If you’re a smoker, the best time to quit is right now."

John R. Seffrin, Ph.D., CEO of the American Cancer Society Cancer Action Network, agreed. "Today’s report makes it clear, once again, that there is no such thing as a safe cigarette and no such thing as a safe level of exposure to secondhand smoke for nonsmokers," he said in a statement.

Ms. Sebelius noted that, every day, 4,000 Americans under the age of 18 years try their first cigarette, and that 1,000 of them become daily smokers. Some 1,200 Americans die every day as a result of tobacco-related causes, she said, and the report is part of the Obama administration’s ongoing strategy to completely eliminate tobacco use.

Smoking rates declined until 2003, but since that time the rate has plateaued, with 20% of adults admitting they currently smoke. The administration has launched a multipronged attack, including giving the Food and Drug Administration the power to regulate tobacco and increasing funding to state and local programs for intervention and outreach programs. Medicare and the Federal Employees Health Benefits Program both now offer coverage of tobacco-cessation strategies, Ms. Sebelius said.

Tobacco-related disease is a big reason why America is less healthy than other countries, and that has consequences. "If we’re a less healthy nation, we’re not competitive in a global economy," she added.

The Surgeon General's office has created a consumer-friendly version of the new report and a printable, one-page fact sheet for physicians to use in discussing the report with their patients. [Also, read the full Surgeon General’s report.]

The report only focuses on smoking’s effects on adults. The office is working on another report on adolescents and teenagers, Dr. Benjamin said.

WASHINGTON – For the first time, there is evidence of immediate and direct harm done by smoking even one cigarette, according to the 30th annual United States Surgeon General’s Office report on smoking, issued Dec. 9.

© kutay tanir/iStockphoto.com

Surgeon General Regina M. Benjamin said at a press briefing that previous reports from her office honed in on the various diseases that smoking could cause. "This report focuses on how tobacco smoke causes damage to every organ in your body," she said.

When asked why this report could make a difference when so many previous warnings have not convinced all Americans to quit smoking, Dr. Benjamin said that she thinks that the direct evidence of harm will personalize the message.

"I believe it’s very important that every American knows what’s happening in their bodies, particularly those who are trying to quit." She said it might be helpful for people to know the various biological reasons why quitting is so hard.

Dr. Benjamin said she knew that even President Obama was trying very hard to quit and that she’d told him about the new findings.

The 700-page "Report of the Surgeon General: How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease" determined that tobacco smoke contains 7,000 chemicals, hundreds of which are known to be toxic and 70 of which are carcinogenic, she noted.

The report describes multiple insults to the body from those chemicals, including changes in DNA that can lead to cancer; damage to the lining of the lungs; obstructive pulmonary disease and bronchitis; stress on the vasculature and cardiovascular disease; and an increased risk of heart attack, stroke, and aortic aneurysm.

Smoking also interferes with the effectiveness of chemotherapy and the control of blood sugar and leads to fertility problems, including difficulty conceiving, miscarriage, and preterm birth.

Just one cigarette can trigger a heart attack or stroke, she said. In addition, the report examined the effects of secondhand smoke, finding that even brief exposure can cause cardiovascular disease and can also trigger acute cardiac events, such as heart attack. Babies exposed to secondhand smoke are more likely to die of sudden infant death syndrome.

The report highlights the increasingly addictive properties of today’s cigarettes, many of which are designed to enhance nicotine absorption and its crossing of the blood-brain barrier, Dr. Benjamin said. Some cigarettes also allow smokers to inhale more deeply into the lungs, increasing the disease risk.

Department of Health and Human Services Secretary Kathleen Sebelius said at the briefing that the report shows that "there is no safe level of exposure to tobacco smoke," and, she added, "If you’re a smoker, the best time to quit is right now."

John R. Seffrin, Ph.D., CEO of the American Cancer Society Cancer Action Network, agreed. "Today’s report makes it clear, once again, that there is no such thing as a safe cigarette and no such thing as a safe level of exposure to secondhand smoke for nonsmokers," he said in a statement.

Ms. Sebelius noted that, every day, 4,000 Americans under the age of 18 years try their first cigarette, and that 1,000 of them become daily smokers. Some 1,200 Americans die every day as a result of tobacco-related causes, she said, and the report is part of the Obama administration’s ongoing strategy to completely eliminate tobacco use.

Smoking rates declined until 2003, but since that time the rate has plateaued, with 20% of adults admitting they currently smoke. The administration has launched a multipronged attack, including giving the Food and Drug Administration the power to regulate tobacco and increasing funding to state and local programs for intervention and outreach programs. Medicare and the Federal Employees Health Benefits Program both now offer coverage of tobacco-cessation strategies, Ms. Sebelius said.

Tobacco-related disease is a big reason why America is less healthy than other countries, and that has consequences. "If we’re a less healthy nation, we’re not competitive in a global economy," she added.

The Surgeon General's office has created a consumer-friendly version of the new report and a printable, one-page fact sheet for physicians to use in discussing the report with their patients. [Also, read the full Surgeon General’s report.]

The report only focuses on smoking’s effects on adults. The office is working on another report on adolescents and teenagers, Dr. Benjamin said.

WASHINGTON – For the first time, there is evidence of immediate and direct harm done by smoking even one cigarette, according to the 30th annual United States Surgeon General’s Office report on smoking, issued Dec. 9.

© kutay tanir/iStockphoto.com

Surgeon General Regina M. Benjamin said at a press briefing that previous reports from her office honed in on the various diseases that smoking could cause. "This report focuses on how tobacco smoke causes damage to every organ in your body," she said.

When asked why this report could make a difference when so many previous warnings have not convinced all Americans to quit smoking, Dr. Benjamin said that she thinks that the direct evidence of harm will personalize the message.

"I believe it’s very important that every American knows what’s happening in their bodies, particularly those who are trying to quit." She said it might be helpful for people to know the various biological reasons why quitting is so hard.

Dr. Benjamin said she knew that even President Obama was trying very hard to quit and that she’d told him about the new findings.

The 700-page "Report of the Surgeon General: How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease" determined that tobacco smoke contains 7,000 chemicals, hundreds of which are known to be toxic and 70 of which are carcinogenic, she noted.

The report describes multiple insults to the body from those chemicals, including changes in DNA that can lead to cancer; damage to the lining of the lungs; obstructive pulmonary disease and bronchitis; stress on the vasculature and cardiovascular disease; and an increased risk of heart attack, stroke, and aortic aneurysm.

Smoking also interferes with the effectiveness of chemotherapy and the control of blood sugar and leads to fertility problems, including difficulty conceiving, miscarriage, and preterm birth.

Just one cigarette can trigger a heart attack or stroke, she said. In addition, the report examined the effects of secondhand smoke, finding that even brief exposure can cause cardiovascular disease and can also trigger acute cardiac events, such as heart attack. Babies exposed to secondhand smoke are more likely to die of sudden infant death syndrome.

The report highlights the increasingly addictive properties of today’s cigarettes, many of which are designed to enhance nicotine absorption and its crossing of the blood-brain barrier, Dr. Benjamin said. Some cigarettes also allow smokers to inhale more deeply into the lungs, increasing the disease risk.

Department of Health and Human Services Secretary Kathleen Sebelius said at the briefing that the report shows that "there is no safe level of exposure to tobacco smoke," and, she added, "If you’re a smoker, the best time to quit is right now."

John R. Seffrin, Ph.D., CEO of the American Cancer Society Cancer Action Network, agreed. "Today’s report makes it clear, once again, that there is no such thing as a safe cigarette and no such thing as a safe level of exposure to secondhand smoke for nonsmokers," he said in a statement.

Ms. Sebelius noted that, every day, 4,000 Americans under the age of 18 years try their first cigarette, and that 1,000 of them become daily smokers. Some 1,200 Americans die every day as a result of tobacco-related causes, she said, and the report is part of the Obama administration’s ongoing strategy to completely eliminate tobacco use.

Smoking rates declined until 2003, but since that time the rate has plateaued, with 20% of adults admitting they currently smoke. The administration has launched a multipronged attack, including giving the Food and Drug Administration the power to regulate tobacco and increasing funding to state and local programs for intervention and outreach programs. Medicare and the Federal Employees Health Benefits Program both now offer coverage of tobacco-cessation strategies, Ms. Sebelius said.

Tobacco-related disease is a big reason why America is less healthy than other countries, and that has consequences. "If we’re a less healthy nation, we’re not competitive in a global economy," she added.

The Surgeon General's office has created a consumer-friendly version of the new report and a printable, one-page fact sheet for physicians to use in discussing the report with their patients. [Also, read the full Surgeon General’s report.]

The report only focuses on smoking’s effects on adults. The office is working on another report on adolescents and teenagers, Dr. Benjamin said.

DENVER — Asthma may be a risk factor for lung cancer, according to two new meta-analyses.

The public health implications of such an association would be enormous. Asthma affects at least 15 million Americans, 40% of them children. Its prevalence has been climbing steadily for decades in developed countries, more than doubling in the United States during a recent 20-year period. And lung cancer is the second most common noncutaneous malignancy in this country, with 10% of lung cancer deaths not attributable to smoking, Chanis Mercado said at the annual meeting of the American Public Health Association.

One of the two meta-analyses she performed as a Ph.D. candidate in public health at the Ponce (P.R.) School of Medicine involved 17 high-quality case-control studies with a total of 54,238 subjects. The conclusion was that individuals with asthma had 34% greater odds of having lung cancer, compared with matched controls without asthma.

A separate meta-analysis that included 16 high-quality cohort studies and 1,384,824 subjects showed that those with asthma were 46% more likely to develop lung cancer than were subjects without asthma.

These results were statistically robust. Eliminating any individual study didn’t substantially change the results. Tests for the existence of publication bias proved reassuringly negative.

One biologically plausible possible mechanism for the observed asthma–lung cancer link is that the persistent chronic inflammation that is a defining feature of asthma causes DNA damage to cells in the airway. Another possibility is that asthma patients have defective clearance of toxins in the bronchioalveolar epithelium, resulting in prolonged local exposure to carcinogens, she said.

The clinical implication of these two meta-analyses is that asthma patients ought to be screened earlier and more often for signs and symptoms of lung cancer, Ms. Mercado continued. This screening might take the form of chest x-rays, sputum cytology tests, and/or a low threshold for acting on symptoms of weight loss or hemoptysis.

Ms. Mercado declared having no relevant financial interests.

DENVER — Asthma may be a risk factor for lung cancer, according to two new meta-analyses.

The public health implications of such an association would be enormous. Asthma affects at least 15 million Americans, 40% of them children. Its prevalence has been climbing steadily for decades in developed countries, more than doubling in the United States during a recent 20-year period. And lung cancer is the second most common noncutaneous malignancy in this country, with 10% of lung cancer deaths not attributable to smoking, Chanis Mercado said at the annual meeting of the American Public Health Association.

One of the two meta-analyses she performed as a Ph.D. candidate in public health at the Ponce (P.R.) School of Medicine involved 17 high-quality case-control studies with a total of 54,238 subjects. The conclusion was that individuals with asthma had 34% greater odds of having lung cancer, compared with matched controls without asthma.

A separate meta-analysis that included 16 high-quality cohort studies and 1,384,824 subjects showed that those with asthma were 46% more likely to develop lung cancer than were subjects without asthma.

These results were statistically robust. Eliminating any individual study didn’t substantially change the results. Tests for the existence of publication bias proved reassuringly negative.

One biologically plausible possible mechanism for the observed asthma–lung cancer link is that the persistent chronic inflammation that is a defining feature of asthma causes DNA damage to cells in the airway. Another possibility is that asthma patients have defective clearance of toxins in the bronchioalveolar epithelium, resulting in prolonged local exposure to carcinogens, she said.

The clinical implication of these two meta-analyses is that asthma patients ought to be screened earlier and more often for signs and symptoms of lung cancer, Ms. Mercado continued. This screening might take the form of chest x-rays, sputum cytology tests, and/or a low threshold for acting on symptoms of weight loss or hemoptysis.

Ms. Mercado declared having no relevant financial interests.

DENVER — Asthma may be a risk factor for lung cancer, according to two new meta-analyses.

The public health implications of such an association would be enormous. Asthma affects at least 15 million Americans, 40% of them children. Its prevalence has been climbing steadily for decades in developed countries, more than doubling in the United States during a recent 20-year period. And lung cancer is the second most common noncutaneous malignancy in this country, with 10% of lung cancer deaths not attributable to smoking, Chanis Mercado said at the annual meeting of the American Public Health Association.

One of the two meta-analyses she performed as a Ph.D. candidate in public health at the Ponce (P.R.) School of Medicine involved 17 high-quality case-control studies with a total of 54,238 subjects. The conclusion was that individuals with asthma had 34% greater odds of having lung cancer, compared with matched controls without asthma.

A separate meta-analysis that included 16 high-quality cohort studies and 1,384,824 subjects showed that those with asthma were 46% more likely to develop lung cancer than were subjects without asthma.

These results were statistically robust. Eliminating any individual study didn’t substantially change the results. Tests for the existence of publication bias proved reassuringly negative.

One biologically plausible possible mechanism for the observed asthma–lung cancer link is that the persistent chronic inflammation that is a defining feature of asthma causes DNA damage to cells in the airway. Another possibility is that asthma patients have defective clearance of toxins in the bronchioalveolar epithelium, resulting in prolonged local exposure to carcinogens, she said.

The clinical implication of these two meta-analyses is that asthma patients ought to be screened earlier and more often for signs and symptoms of lung cancer, Ms. Mercado continued. This screening might take the form of chest x-rays, sputum cytology tests, and/or a low threshold for acting on symptoms of weight loss or hemoptysis.

Ms. Mercado declared having no relevant financial interests.

ORLANDO – Oral apixaban reduced the incidence of major venous thromboembolism after joint replacement surgery by approximately half compared with enoxaparin, with no increased risk of bleeding, investigators have reported.

Of approximately 7,000 patients who underwent thromboprophylaxis after surgery, major VTE occurred in 0.68% of those who had received apixaban, compared with 1.50% who had been given enoxaparin. This was a statistically significant difference, study investigator Gary E. Raskob, Ph.D., said in a press conference at the annual meeting of the American Society of Hematology.

Prevention of major venous thromboembolism (VTE) is "a significant issue in health care in the United States," where the number of knee and hip replacements is expected to increase, said Dr. Raskob, dean of the College of Public Health at the University of Oklahoma Health Sciences Center in Oklahoma City.

Previous studies have demonstrated the potential for an increased risk of bleeding with new anticoagulants. To provide more precise estimates of the incidence of major VTE and safety outcomes, the investigators combined data from two phase III, randomized, double-blind clinical trials of patients who had undergone knee (ADVANCE-2 study) or hip replacement (ADVANCE-3). A total of 8,464 were randomized to receive apixaban, a novel orally administered factor Xa inhibitor (4,236 patients), or enoxaparin (4,228 patients).

Efficacy results related to VTE were based on 3,394 patients in each group. Major VTE occurred in 23 patients in the apixaban group (0.68%), compared with 51 patients in the enoxaparin group (1.50%).

Bleeding results were based on 4,174 apixaban patients and 4,228 enoxaparin patients. Major bleeding occurred in 31 patients in the apixaban group and 32 in the enoxaparin group (0.74% vs. 0.77%). Major bleeding at the surgical site occurred in 26 in the apixaban group and 27 in the enoxaparin group. Overall, major or clinically relevant nonmajor bleeding occurred in 182 apixaban patients and 206 enoxaparin patients (4.4% vs. 4.9%).

The patients received 2.5 mg of apixaban twice daily or 40 mg of enoxaparin once daily. Apixaban was started 12-24 hours after wound closure, and enoxaparin was started approximately 12 hours before surgery and resumed 12-24 hours after wound closure. Both medications were continued for 10-14 days in the knee replacement group and 32-38 days in the hip replacement group. Patients were followed up at 30 days and 60 days after their last doses of either study medication.

Myocardial infarction or stroke occurred in 13 apixaban patients and 10 enoxaparin patients during the course of the study and follow-up period.

Dr. Raskob has served as a consultant or member of the board of directors or advisory committee for multiple companies, including Bristol-Meyers Squibb, Pfizer, Bayer, Johnson & Johnson, Sanofi Aventis, and Daiichi Sankyo.

ORLANDO – Oral apixaban reduced the incidence of major venous thromboembolism after joint replacement surgery by approximately half compared with enoxaparin, with no increased risk of bleeding, investigators have reported.

Of approximately 7,000 patients who underwent thromboprophylaxis after surgery, major VTE occurred in 0.68% of those who had received apixaban, compared with 1.50% who had been given enoxaparin. This was a statistically significant difference, study investigator Gary E. Raskob, Ph.D., said in a press conference at the annual meeting of the American Society of Hematology.

Prevention of major venous thromboembolism (VTE) is "a significant issue in health care in the United States," where the number of knee and hip replacements is expected to increase, said Dr. Raskob, dean of the College of Public Health at the University of Oklahoma Health Sciences Center in Oklahoma City.

Previous studies have demonstrated the potential for an increased risk of bleeding with new anticoagulants. To provide more precise estimates of the incidence of major VTE and safety outcomes, the investigators combined data from two phase III, randomized, double-blind clinical trials of patients who had undergone knee (ADVANCE-2 study) or hip replacement (ADVANCE-3). A total of 8,464 were randomized to receive apixaban, a novel orally administered factor Xa inhibitor (4,236 patients), or enoxaparin (4,228 patients).

Efficacy results related to VTE were based on 3,394 patients in each group. Major VTE occurred in 23 patients in the apixaban group (0.68%), compared with 51 patients in the enoxaparin group (1.50%).

Bleeding results were based on 4,174 apixaban patients and 4,228 enoxaparin patients. Major bleeding occurred in 31 patients in the apixaban group and 32 in the enoxaparin group (0.74% vs. 0.77%). Major bleeding at the surgical site occurred in 26 in the apixaban group and 27 in the enoxaparin group. Overall, major or clinically relevant nonmajor bleeding occurred in 182 apixaban patients and 206 enoxaparin patients (4.4% vs. 4.9%).

The patients received 2.5 mg of apixaban twice daily or 40 mg of enoxaparin once daily. Apixaban was started 12-24 hours after wound closure, and enoxaparin was started approximately 12 hours before surgery and resumed 12-24 hours after wound closure. Both medications were continued for 10-14 days in the knee replacement group and 32-38 days in the hip replacement group. Patients were followed up at 30 days and 60 days after their last doses of either study medication.

Myocardial infarction or stroke occurred in 13 apixaban patients and 10 enoxaparin patients during the course of the study and follow-up period.

Dr. Raskob has served as a consultant or member of the board of directors or advisory committee for multiple companies, including Bristol-Meyers Squibb, Pfizer, Bayer, Johnson & Johnson, Sanofi Aventis, and Daiichi Sankyo.

ORLANDO – Oral apixaban reduced the incidence of major venous thromboembolism after joint replacement surgery by approximately half compared with enoxaparin, with no increased risk of bleeding, investigators have reported.

Of approximately 7,000 patients who underwent thromboprophylaxis after surgery, major VTE occurred in 0.68% of those who had received apixaban, compared with 1.50% who had been given enoxaparin. This was a statistically significant difference, study investigator Gary E. Raskob, Ph.D., said in a press conference at the annual meeting of the American Society of Hematology.

Prevention of major venous thromboembolism (VTE) is "a significant issue in health care in the United States," where the number of knee and hip replacements is expected to increase, said Dr. Raskob, dean of the College of Public Health at the University of Oklahoma Health Sciences Center in Oklahoma City.

Previous studies have demonstrated the potential for an increased risk of bleeding with new anticoagulants. To provide more precise estimates of the incidence of major VTE and safety outcomes, the investigators combined data from two phase III, randomized, double-blind clinical trials of patients who had undergone knee (ADVANCE-2 study) or hip replacement (ADVANCE-3). A total of 8,464 were randomized to receive apixaban, a novel orally administered factor Xa inhibitor (4,236 patients), or enoxaparin (4,228 patients).

Efficacy results related to VTE were based on 3,394 patients in each group. Major VTE occurred in 23 patients in the apixaban group (0.68%), compared with 51 patients in the enoxaparin group (1.50%).

Bleeding results were based on 4,174 apixaban patients and 4,228 enoxaparin patients. Major bleeding occurred in 31 patients in the apixaban group and 32 in the enoxaparin group (0.74% vs. 0.77%). Major bleeding at the surgical site occurred in 26 in the apixaban group and 27 in the enoxaparin group. Overall, major or clinically relevant nonmajor bleeding occurred in 182 apixaban patients and 206 enoxaparin patients (4.4% vs. 4.9%).

The patients received 2.5 mg of apixaban twice daily or 40 mg of enoxaparin once daily. Apixaban was started 12-24 hours after wound closure, and enoxaparin was started approximately 12 hours before surgery and resumed 12-24 hours after wound closure. Both medications were continued for 10-14 days in the knee replacement group and 32-38 days in the hip replacement group. Patients were followed up at 30 days and 60 days after their last doses of either study medication.

Myocardial infarction or stroke occurred in 13 apixaban patients and 10 enoxaparin patients during the course of the study and follow-up period.

Dr. Raskob has served as a consultant or member of the board of directors or advisory committee for multiple companies, including Bristol-Meyers Squibb, Pfizer, Bayer, Johnson & Johnson, Sanofi Aventis, and Daiichi Sankyo.

ORLANDO – The investigational oral anticoagulant rivaroxaban was not inferior to a combination of the low-molecular-weight heparin enoxaparin and a vitamin K antagonist for reducing risk of recurrent deep venous thromboembolism for up to 1 year, reported investigators with the EINSTEIN Acute DVT study.

In an open-label study, venous thromboembolism (VTE) or pulmonary embolism recurred in 2.1% of 1,731 patients randomized to rivaroxaban and in 3.0% of 1,718 patients randomized to enoxaparin (Lovenox) followed by either warfarin or acenocoumarol. The data were reported by Harry R. Büller, M.D., Ph.D., at the annual meeting of the American Society of Hematology and online in the New England Journal of Medicine (Dec. 4, 2010 [10.1056/NEJMoa1007903]).

Incidence of major bleeding or clinically relevant nonmajor bleeding was identical in the two groups, at 8.1%. Additionally, rivaroxaban, a factor Xa inhibitor in late-stage clinical development, was superior in efficacy to placebo in a randomized double-blind extension study in patients who had completed 6-12 months of thromboprophylaxis.

"This regimen of 15 mg [rivaroxaban] twice a day for the first 3 weeks followed by 20 mg for the remainder period provides clinicians and patients, I think, with an attractive and simple treatment option for venous thrombosis, not only in the acute phase, but also when prolonged treatment is indicated," Dr. Büller of the Academic Medical Center in Amsterdam, the Netherlands, said in a media briefing.

The EINSTEIN Acute-DVT trial compared oral rivaroxaban alone with enoxaparin followed by a vitamin K antagonist for prophylaxis of recurrent VTE or pulmonary embolism in 3,449 patients. Rivaroxaban was delivered orally 15 mg twice daily for 3 weeks, followed by 20 mg orally once daily for 3, 6, or 12 months. Duration of treatment was at the discretion of the treating physician at the time of randomization.

The EINSTEIN-extension study compared rivaroxaban with placebo in 1,197 patients who had completed 6-12 months of rivaroxaban in the EINSTEIN studies or 6-12 months of a vitamin K antagonist, either in the EINSTEIN studies or in routine care.

The primary efficacy end point for both studies was the incidence of recurrent VTE. The primary safety outcome for the acute DVT trial was major bleeding or clinically relevant minor bleeding. The major safety outcome in the extension trial was major bleeding.

In the acute trial, there were 36 VTE events in the rivaroxaban group, compared with 51 in the enoxaparin/vitamin K antagonist group (hazard ratio, 0.68; P less than .001). A total of 8.1% of patients in each group experienced a recurrent VTE.

In the continuation trial, there were 8 events among 602 patients (1.3%) treated with rivaroxaban, compared with 42 of 594 patients (7.1%) treated with the enoxaparin/vitamin K antagonist regimen (hazard ratio, 0.18; P less than .001). There were four nonfatal major bleeding events among patients treated with rivaroxaban, versus none in those who received placebo.

Both trials were sponsored by Bayer Schering Pharma and Ortho-McNeil.

ORLANDO – The investigational oral anticoagulant rivaroxaban was not inferior to a combination of the low-molecular-weight heparin enoxaparin and a vitamin K antagonist for reducing risk of recurrent deep venous thromboembolism for up to 1 year, reported investigators with the EINSTEIN Acute DVT study.

In an open-label study, venous thromboembolism (VTE) or pulmonary embolism recurred in 2.1% of 1,731 patients randomized to rivaroxaban and in 3.0% of 1,718 patients randomized to enoxaparin (Lovenox) followed by either warfarin or acenocoumarol. The data were reported by Harry R. Büller, M.D., Ph.D., at the annual meeting of the American Society of Hematology and online in the New England Journal of Medicine (Dec. 4, 2010 [10.1056/NEJMoa1007903]).

Incidence of major bleeding or clinically relevant nonmajor bleeding was identical in the two groups, at 8.1%. Additionally, rivaroxaban, a factor Xa inhibitor in late-stage clinical development, was superior in efficacy to placebo in a randomized double-blind extension study in patients who had completed 6-12 months of thromboprophylaxis.

"This regimen of 15 mg [rivaroxaban] twice a day for the first 3 weeks followed by 20 mg for the remainder period provides clinicians and patients, I think, with an attractive and simple treatment option for venous thrombosis, not only in the acute phase, but also when prolonged treatment is indicated," Dr. Büller of the Academic Medical Center in Amsterdam, the Netherlands, said in a media briefing.

The EINSTEIN Acute-DVT trial compared oral rivaroxaban alone with enoxaparin followed by a vitamin K antagonist for prophylaxis of recurrent VTE or pulmonary embolism in 3,449 patients. Rivaroxaban was delivered orally 15 mg twice daily for 3 weeks, followed by 20 mg orally once daily for 3, 6, or 12 months. Duration of treatment was at the discretion of the treating physician at the time of randomization.

The EINSTEIN-extension study compared rivaroxaban with placebo in 1,197 patients who had completed 6-12 months of rivaroxaban in the EINSTEIN studies or 6-12 months of a vitamin K antagonist, either in the EINSTEIN studies or in routine care.

The primary efficacy end point for both studies was the incidence of recurrent VTE. The primary safety outcome for the acute DVT trial was major bleeding or clinically relevant minor bleeding. The major safety outcome in the extension trial was major bleeding.

In the acute trial, there were 36 VTE events in the rivaroxaban group, compared with 51 in the enoxaparin/vitamin K antagonist group (hazard ratio, 0.68; P less than .001). A total of 8.1% of patients in each group experienced a recurrent VTE.

In the continuation trial, there were 8 events among 602 patients (1.3%) treated with rivaroxaban, compared with 42 of 594 patients (7.1%) treated with the enoxaparin/vitamin K antagonist regimen (hazard ratio, 0.18; P less than .001). There were four nonfatal major bleeding events among patients treated with rivaroxaban, versus none in those who received placebo.

Both trials were sponsored by Bayer Schering Pharma and Ortho-McNeil.

ORLANDO – The investigational oral anticoagulant rivaroxaban was not inferior to a combination of the low-molecular-weight heparin enoxaparin and a vitamin K antagonist for reducing risk of recurrent deep venous thromboembolism for up to 1 year, reported investigators with the EINSTEIN Acute DVT study.

In an open-label study, venous thromboembolism (VTE) or pulmonary embolism recurred in 2.1% of 1,731 patients randomized to rivaroxaban and in 3.0% of 1,718 patients randomized to enoxaparin (Lovenox) followed by either warfarin or acenocoumarol. The data were reported by Harry R. Büller, M.D., Ph.D., at the annual meeting of the American Society of Hematology and online in the New England Journal of Medicine (Dec. 4, 2010 [10.1056/NEJMoa1007903]).

Incidence of major bleeding or clinically relevant nonmajor bleeding was identical in the two groups, at 8.1%. Additionally, rivaroxaban, a factor Xa inhibitor in late-stage clinical development, was superior in efficacy to placebo in a randomized double-blind extension study in patients who had completed 6-12 months of thromboprophylaxis.

"This regimen of 15 mg [rivaroxaban] twice a day for the first 3 weeks followed by 20 mg for the remainder period provides clinicians and patients, I think, with an attractive and simple treatment option for venous thrombosis, not only in the acute phase, but also when prolonged treatment is indicated," Dr. Büller of the Academic Medical Center in Amsterdam, the Netherlands, said in a media briefing.

The EINSTEIN Acute-DVT trial compared oral rivaroxaban alone with enoxaparin followed by a vitamin K antagonist for prophylaxis of recurrent VTE or pulmonary embolism in 3,449 patients. Rivaroxaban was delivered orally 15 mg twice daily for 3 weeks, followed by 20 mg orally once daily for 3, 6, or 12 months. Duration of treatment was at the discretion of the treating physician at the time of randomization.

The EINSTEIN-extension study compared rivaroxaban with placebo in 1,197 patients who had completed 6-12 months of rivaroxaban in the EINSTEIN studies or 6-12 months of a vitamin K antagonist, either in the EINSTEIN studies or in routine care.

The primary efficacy end point for both studies was the incidence of recurrent VTE. The primary safety outcome for the acute DVT trial was major bleeding or clinically relevant minor bleeding. The major safety outcome in the extension trial was major bleeding.

In the acute trial, there were 36 VTE events in the rivaroxaban group, compared with 51 in the enoxaparin/vitamin K antagonist group (hazard ratio, 0.68; P less than .001). A total of 8.1% of patients in each group experienced a recurrent VTE.

In the continuation trial, there were 8 events among 602 patients (1.3%) treated with rivaroxaban, compared with 42 of 594 patients (7.1%) treated with the enoxaparin/vitamin K antagonist regimen (hazard ratio, 0.18; P less than .001). There were four nonfatal major bleeding events among patients treated with rivaroxaban, versus none in those who received placebo.

Both trials were sponsored by Bayer Schering Pharma and Ortho-McNeil.

VANCOUVER, B.C.– A live, interactive, cased-based educational initiative improved primary care physicians’ knowledge of chronic obstructive pulmonary disease, according to study results reported at the annual meeting of the American College of Chest Physicians.

In a cross-sectional study of 50 primary care physicians who participated in the initiative and 50 similar nonparticipants, the former were more likely to know that alveolar destruction is a pathophysiologic feature of COPD (94% vs. 74%) and that women have greater susceptibility to the harmful effects of smoking (90% vs. 54%), according to Dr. Nicola A. Hanania and his coinvestigators.

Additionally, when presented with case vignettes, the participants were more likely to recognize the presence of COPD in dyspnea patients (90% vs. 74%).

"Even though this was sort of a one-time ... cross-sectional survey, we believe that educational initiatives such as this one may at least improve the knowledge about COPD – both diagnosis and management," commented Dr. Hanania, an associate professor of medicine at Baylor College of Medicine, Houston.

Explaining the need for primary care–focused efforts, he noted that "the majority of COPD patients are [seen] in the primary care arena."

But statistics show that "COPD remains under-recognized and underdiagnosed in about 50% of the population out there, not only in the United States but in other countries as well. It also remains undertreated," even though the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines now stress that it is a treatable disease.

The initiative studied – called Improving COPD Patient Outcomes: Breaking Down the Barriers to Optimal Care – was designed to improve primary care providers’ knowledge and competency in the guideline-based diagnosis, staging, and management of COPD, Dr. Hanania said.

It consisted of a series of live half-day meetings conducted over a 3-month period that included short lectures, a video on correct use of inhaler devices, and small-group workshops that incorporated detailed case discussions and hands-on demonstrations and practice in the use of spirometry.

A total of 769 physicians attended the meetings. The investigators assessed the initiative’s effectiveness with a case vignette–based survey, given to a randomly selected subset of 50 participants and 50 nonparticipants with similar demographics and practice characteristics.

The number of patients with COPD seen weekly was 11 for participants and 15 for nonparticipants. The mean number of years in practice was 28 and 24, respectively. And both groups were about equally divided between family physicians and internal medicine physicians. Participants were somewhat more likely to be in solo practice (45% vs. 38%) or work in a government facility (25% vs. 0%), and less likely to be in group practice (31% vs. 58%).

Survey results showed that in the area of diagnosis, the participants were more likely than the nonparticipants to recognize COPD in case vignettes of patients with dyspnea (90% vs. 74%, P = .007) and to be aware of the greater susceptibility of women compared with men to the harmful effects of smoking (90% vs. 54%, P less than .001).

Also, when asked which of several pathophysiologic features was one of COPD, participants were more likely to correctly answer alveolar destruction (94% vs. 74%, P = .007). (The other options were muscular deconditioning, synovial inflammation, and increased ventricular filling pressure.)

While the groups did not differ significantly in terms of how likely they were to use spirometry for diagnosis and staging of COPD, participants were more likely than nonparticipants to indicate that difficulty in obtaining spirometry results in the office setting was a very significant barrier to COPD management (27% vs. 12%). "Maybe they acknowledged that it is an important tool, but they cannot do it," he commented.

The groups were statistically indistinguishable with respect to their approaches to caring for patients with repeated exacerbations and improving adherence, and their selection of appropriate maintenance therapy.

The survey also asked about barriers to managing COPD, which may help in designing future initiatives, Dr. Hanania said.

In addition to difficulty with spirometry, the groups were similarly likely to rate as very significant a patient’s nonadherence to a recommendation to stop smoking, the complexity of the medical regimen, and a lack of clarity about the staging of COPD severity.

A calculation of the initiative’s quality of education index showed that participants were 50% more likely than nonparticipants to provide evidence-based, guideline-driven COPD care, Dr. Hanania reported. "We estimate that participation in this half-day program can potentially improve the care of many patients per week, but this needs to be further tested," he commented.

"We did not attempt to look at long-term [outcomes] – retention of knowledge or practice change – which are very important," Dr. Hanania acknowledged. But a similar, ongoing initiative, being conducted by the ACCP, is currently assessing impact on real-life practice.

That initiative is including not only physicians but also physician assistants and nurse practitioners, Dr. Hanania noted. "In our primary care setting in the U.S., nonphysician extenders – PAs, nurse practitioners – play a major role in encountering COPD, and those are people we like to target," he explained. Furthermore, their role will likely increase if health care reform proceeds and primary care physicians are overwhelmed by demand.

The initiative meetings were supported by an educational grant from Novartis Pharmaceuticals. Dr. Hanania had no relevant conflicts of interest.

VANCOUVER, B.C.– A live, interactive, cased-based educational initiative improved primary care physicians’ knowledge of chronic obstructive pulmonary disease, according to study results reported at the annual meeting of the American College of Chest Physicians.

In a cross-sectional study of 50 primary care physicians who participated in the initiative and 50 similar nonparticipants, the former were more likely to know that alveolar destruction is a pathophysiologic feature of COPD (94% vs. 74%) and that women have greater susceptibility to the harmful effects of smoking (90% vs. 54%), according to Dr. Nicola A. Hanania and his coinvestigators.

Additionally, when presented with case vignettes, the participants were more likely to recognize the presence of COPD in dyspnea patients (90% vs. 74%).

"Even though this was sort of a one-time ... cross-sectional survey, we believe that educational initiatives such as this one may at least improve the knowledge about COPD – both diagnosis and management," commented Dr. Hanania, an associate professor of medicine at Baylor College of Medicine, Houston.

Explaining the need for primary care–focused efforts, he noted that "the majority of COPD patients are [seen] in the primary care arena."

But statistics show that "COPD remains under-recognized and underdiagnosed in about 50% of the population out there, not only in the United States but in other countries as well. It also remains undertreated," even though the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines now stress that it is a treatable disease.

The initiative studied – called Improving COPD Patient Outcomes: Breaking Down the Barriers to Optimal Care – was designed to improve primary care providers’ knowledge and competency in the guideline-based diagnosis, staging, and management of COPD, Dr. Hanania said.

It consisted of a series of live half-day meetings conducted over a 3-month period that included short lectures, a video on correct use of inhaler devices, and small-group workshops that incorporated detailed case discussions and hands-on demonstrations and practice in the use of spirometry.

A total of 769 physicians attended the meetings. The investigators assessed the initiative’s effectiveness with a case vignette–based survey, given to a randomly selected subset of 50 participants and 50 nonparticipants with similar demographics and practice characteristics.

The number of patients with COPD seen weekly was 11 for participants and 15 for nonparticipants. The mean number of years in practice was 28 and 24, respectively. And both groups were about equally divided between family physicians and internal medicine physicians. Participants were somewhat more likely to be in solo practice (45% vs. 38%) or work in a government facility (25% vs. 0%), and less likely to be in group practice (31% vs. 58%).

Survey results showed that in the area of diagnosis, the participants were more likely than the nonparticipants to recognize COPD in case vignettes of patients with dyspnea (90% vs. 74%, P = .007) and to be aware of the greater susceptibility of women compared with men to the harmful effects of smoking (90% vs. 54%, P less than .001).

Also, when asked which of several pathophysiologic features was one of COPD, participants were more likely to correctly answer alveolar destruction (94% vs. 74%, P = .007). (The other options were muscular deconditioning, synovial inflammation, and increased ventricular filling pressure.)

While the groups did not differ significantly in terms of how likely they were to use spirometry for diagnosis and staging of COPD, participants were more likely than nonparticipants to indicate that difficulty in obtaining spirometry results in the office setting was a very significant barrier to COPD management (27% vs. 12%). "Maybe they acknowledged that it is an important tool, but they cannot do it," he commented.

The groups were statistically indistinguishable with respect to their approaches to caring for patients with repeated exacerbations and improving adherence, and their selection of appropriate maintenance therapy.

The survey also asked about barriers to managing COPD, which may help in designing future initiatives, Dr. Hanania said.

In addition to difficulty with spirometry, the groups were similarly likely to rate as very significant a patient’s nonadherence to a recommendation to stop smoking, the complexity of the medical regimen, and a lack of clarity about the staging of COPD severity.

A calculation of the initiative’s quality of education index showed that participants were 50% more likely than nonparticipants to provide evidence-based, guideline-driven COPD care, Dr. Hanania reported. "We estimate that participation in this half-day program can potentially improve the care of many patients per week, but this needs to be further tested," he commented.

"We did not attempt to look at long-term [outcomes] – retention of knowledge or practice change – which are very important," Dr. Hanania acknowledged. But a similar, ongoing initiative, being conducted by the ACCP, is currently assessing impact on real-life practice.

That initiative is including not only physicians but also physician assistants and nurse practitioners, Dr. Hanania noted. "In our primary care setting in the U.S., nonphysician extenders – PAs, nurse practitioners – play a major role in encountering COPD, and those are people we like to target," he explained. Furthermore, their role will likely increase if health care reform proceeds and primary care physicians are overwhelmed by demand.

The initiative meetings were supported by an educational grant from Novartis Pharmaceuticals. Dr. Hanania had no relevant conflicts of interest.

VANCOUVER, B.C.– A live, interactive, cased-based educational initiative improved primary care physicians’ knowledge of chronic obstructive pulmonary disease, according to study results reported at the annual meeting of the American College of Chest Physicians.

In a cross-sectional study of 50 primary care physicians who participated in the initiative and 50 similar nonparticipants, the former were more likely to know that alveolar destruction is a pathophysiologic feature of COPD (94% vs. 74%) and that women have greater susceptibility to the harmful effects of smoking (90% vs. 54%), according to Dr. Nicola A. Hanania and his coinvestigators.

Additionally, when presented with case vignettes, the participants were more likely to recognize the presence of COPD in dyspnea patients (90% vs. 74%).

"Even though this was sort of a one-time ... cross-sectional survey, we believe that educational initiatives such as this one may at least improve the knowledge about COPD – both diagnosis and management," commented Dr. Hanania, an associate professor of medicine at Baylor College of Medicine, Houston.

Explaining the need for primary care–focused efforts, he noted that "the majority of COPD patients are [seen] in the primary care arena."

But statistics show that "COPD remains under-recognized and underdiagnosed in about 50% of the population out there, not only in the United States but in other countries as well. It also remains undertreated," even though the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines now stress that it is a treatable disease.

The initiative studied – called Improving COPD Patient Outcomes: Breaking Down the Barriers to Optimal Care – was designed to improve primary care providers’ knowledge and competency in the guideline-based diagnosis, staging, and management of COPD, Dr. Hanania said.

It consisted of a series of live half-day meetings conducted over a 3-month period that included short lectures, a video on correct use of inhaler devices, and small-group workshops that incorporated detailed case discussions and hands-on demonstrations and practice in the use of spirometry.

A total of 769 physicians attended the meetings. The investigators assessed the initiative’s effectiveness with a case vignette–based survey, given to a randomly selected subset of 50 participants and 50 nonparticipants with similar demographics and practice characteristics.

The number of patients with COPD seen weekly was 11 for participants and 15 for nonparticipants. The mean number of years in practice was 28 and 24, respectively. And both groups were about equally divided between family physicians and internal medicine physicians. Participants were somewhat more likely to be in solo practice (45% vs. 38%) or work in a government facility (25% vs. 0%), and less likely to be in group practice (31% vs. 58%).

Survey results showed that in the area of diagnosis, the participants were more likely than the nonparticipants to recognize COPD in case vignettes of patients with dyspnea (90% vs. 74%, P = .007) and to be aware of the greater susceptibility of women compared with men to the harmful effects of smoking (90% vs. 54%, P less than .001).

Also, when asked which of several pathophysiologic features was one of COPD, participants were more likely to correctly answer alveolar destruction (94% vs. 74%, P = .007). (The other options were muscular deconditioning, synovial inflammation, and increased ventricular filling pressure.)

While the groups did not differ significantly in terms of how likely they were to use spirometry for diagnosis and staging of COPD, participants were more likely than nonparticipants to indicate that difficulty in obtaining spirometry results in the office setting was a very significant barrier to COPD management (27% vs. 12%). "Maybe they acknowledged that it is an important tool, but they cannot do it," he commented.

The groups were statistically indistinguishable with respect to their approaches to caring for patients with repeated exacerbations and improving adherence, and their selection of appropriate maintenance therapy.

The survey also asked about barriers to managing COPD, which may help in designing future initiatives, Dr. Hanania said.

In addition to difficulty with spirometry, the groups were similarly likely to rate as very significant a patient’s nonadherence to a recommendation to stop smoking, the complexity of the medical regimen, and a lack of clarity about the staging of COPD severity.

A calculation of the initiative’s quality of education index showed that participants were 50% more likely than nonparticipants to provide evidence-based, guideline-driven COPD care, Dr. Hanania reported. "We estimate that participation in this half-day program can potentially improve the care of many patients per week, but this needs to be further tested," he commented.

"We did not attempt to look at long-term [outcomes] – retention of knowledge or practice change – which are very important," Dr. Hanania acknowledged. But a similar, ongoing initiative, being conducted by the ACCP, is currently assessing impact on real-life practice.

That initiative is including not only physicians but also physician assistants and nurse practitioners, Dr. Hanania noted. "In our primary care setting in the U.S., nonphysician extenders – PAs, nurse practitioners – play a major role in encountering COPD, and those are people we like to target," he explained. Furthermore, their role will likely increase if health care reform proceeds and primary care physicians are overwhelmed by demand.

The initiative meetings were supported by an educational grant from Novartis Pharmaceuticals. Dr. Hanania had no relevant conflicts of interest.

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.

The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.

In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.

The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.

“The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come,” Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.

Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.

At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.

NCI director Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.

“Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease,” he said. “But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases.”

Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.

[Editor's note: In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.]

Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.

“What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public,” Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.

A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published by the journal Radiology.

The National Cancer Institute sponsored the study.

A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.

The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.

In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.

The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.

“The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come,” Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.

Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.

At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.

NCI director Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.

“Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease,” he said. “But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases.”

Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.

[Editor's note: In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.]

Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.

“What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public,” Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.

A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published by the journal Radiology.

The National Cancer Institute sponsored the study.

A large randomized national trial has provided the first evidence of a significant reduction in lung cancer deaths with a screening test.

The National Lung Screening Trial (NLST) reported a 20.3% reduction in lung cancer mortality among heavy smokers screened with low-dose helical computed tomography (CT), as compared with those given standard chest x-rays. The trial enrolled more than 53,000 older, high-risk individuals.

In addition, deaths from any cause, including lung cancer, were 7% lower among participants screened with low-dose helical CT, also known as spiral CT.

The initial results were released today by the study sponsor, the National Cancer Institute, after the study's independent data and safety monitoring board recommended halting the trial.

“The fact that low-dose helical CT provides a decided benefit is a result that will have implications for screening and management of lung cancer for many years to come,” Dr. Christine Berg, project officer for the lung screening study at the NCI, said in a statement.

Beginning in 2002, the NLST recruited about 53,500 American men and women, aged 55-74 years, who were current or former smokers with a smoking history of at least 30 pack-years. It randomly assigned them to receive three annual screens with low-dose helical CT or chest x-ray. Helical CT uses x-rays to obtain a multiple-image scan of the entire chest during a 7- to 15-second breath-hold, whereas a standard chest x-ray produces only a single image of the chest from a sub-second breath-hold.

At the time of the Oct. 20, 2010 analysis, 354 deaths from lung cancer had occurred in the CT arm vs. 442 in the chest x-ray group. Approximately 25% of deaths in the NLST were due to lung cancer.

NCI director Harold E. Varmus said the well-designed study used rigorous scientific methods and that its findings could spare countless lives.

“Lung cancer is the leading cause of cancer mortality in the U.S. and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease,” he said. “But these findings should in no way distract us from continued effort to curtail the use of tobacco, which will remain the major causative factor for lung cancer and several other diseases.”

Like other screening strategies, the use of low-dose helical CT has disadvantages including the cumulative effects of radiation from multiple CT scans, complications among patients who need additional testing to make a definitive lung cancer diagnosis, and the anxiety and added cost associated with investigating incidental findings picked up on CT.

[Editor's note: In 2009, investigators reported that low-dose CT screening was associated with twice the rate of false positives and more unneeded interventions, compared with chest x-ray, in a randomized feasibility trial that preceded the NLST. But low-dose CT also detected twice as many lung cancers as did chest x-ray screens in that study.]

Although the NLST trial cohort was ethnically representative of the high-risk U.S. population, the researchers noted that participants were highly motivated and screened at major medical centers. Thus, the results may not accurately predict the effect of CT screening for other populations.

“What has happened here is that the technology shows you can cut down on lung cancer deaths, the leading cause of cancer mortality, and save nearly as many lives as the number of people who die from breast cancer per year. We as a medical community now need to figure out how to do this in a way that the cost is acceptable to the public,” Dr. Bruce E. Johnson, an official with the American Society of Clinical Oncology and director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, said in a statement.

A more detailed analysis of the NLST results is expected to be published in the coming months, although a paper describing its design and protocol was published by the journal Radiology.

The National Cancer Institute sponsored the study.