General Thoracic

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.

CHICAGO - Bevacizumab maintenance after first-line chemotherapy for advanced non-small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Multidiciplinary Symosium on Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.-affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

In order to control for survivorship and selection bias, the researchers excluded those patients who had disease progression or death within 30 days of their chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from the initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology-Baylor Sammons Cancer Center in Dallas.

The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).
 
Bevacizumab monotherapy was found to be associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide “significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research.”

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients' out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients.

Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

CHICAGO - Bevacizumab maintenance after first-line chemotherapy for advanced non-small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Multidiciplinary Symosium on Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.-affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

In order to control for survivorship and selection bias, the researchers excluded those patients who had disease progression or death within 30 days of their chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from the initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology-Baylor Sammons Cancer Center in Dallas.

The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).
 
Bevacizumab monotherapy was found to be associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide “significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research.”

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients' out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients.

Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

CHICAGO - Bevacizumab maintenance after first-line chemotherapy for advanced non-small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Multidiciplinary Symosium on Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.-affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

In order to control for survivorship and selection bias, the researchers excluded those patients who had disease progression or death within 30 days of their chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from the initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology-Baylor Sammons Cancer Center in Dallas.

The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).
 
Bevacizumab monotherapy was found to be associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide “significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research.”

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients' out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients.

Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

CHICAGO - Patients with previously treated, advanced non-small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy. These preliminary data suggest that “there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance,” Dr. Robert Jotte said at the symposium, where he presented the findings at the Multidiciplinary Symposium on Thoracic Oncology.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn't clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.
Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said.

The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO - Patients with previously treated, advanced non-small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy. These preliminary data suggest that “there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance,” Dr. Robert Jotte said at the symposium, where he presented the findings at the Multidiciplinary Symposium on Thoracic Oncology.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn't clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.
Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said.

The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO - Patients with previously treated, advanced non-small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy. These preliminary data suggest that “there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance,” Dr. Robert Jotte said at the symposium, where he presented the findings at the Multidiciplinary Symposium on Thoracic Oncology.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn't clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.
Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said.

The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with 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 at the Multidisciplinary Syposium on Thoracic Oncology.

The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, 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%, 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 clinician's 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 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 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 1 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,” she said.

The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (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.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.

CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with 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 at the Multidisciplinary Syposium on Thoracic Oncology.

The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, 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%, 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 clinician's 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 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 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 1 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,” she said.

The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (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.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.

CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with 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 at the Multidisciplinary Syposium on Thoracic Oncology.

The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, 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%, 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 clinician's 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 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 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 1 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,” she said.

The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (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.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.

An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.

The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.

In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).

"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.

Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.

The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.

Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.

One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).

In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.

"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.

The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.

The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.

Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”

Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.

Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.

Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.

"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.

The study authors and discussant said that they had no financial disclosures.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.

For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.

In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.

The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).

The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).

The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.

Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.

The complication rate was 6% for surgical staging, compared with 1% for endosonography.

These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.

They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.

This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.