Patrice Wendling

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, FLA. – Upper extremity deep vein thromboses accounted for a surprising 64% of 316 DVTs reported in a prospectively screened cohort of critically ill surgical and trauma patients.

Contrary to expectations, anticoagulation did not affect outcomes. In 77 patients with 123 upper extremity DVTs (UEDVTs), the clot resolution rate was 59% with no anticoagulation, 60% with prophylactic anticoagulation, and 61% with therapeutic anticoagulation (P = .976), Dr. Darren Malinoski said at the annual meeting of the Eastern Association for the Surgery of Trauma.

The American College of Chest Physicians (ACCP) recommends therapeutic anticoagulation for UEDVT, and recommends against the removal of a necessary, patent, central venous catheter. If a catheter is removed, however, the duration of anticoagulation should not be decreased.

Dr. Malinoski, director of the surgical ICU at the University of California Medical Center in Irvine, and his colleagues prospectively followed all surgical ICU patients from January 2008 to May 2010. A standardized DVT-prevention protocol was utilized, and screening duplex ultrasonography exams were obtained within 48 hours of admission and then weekly.

In all, 316 DVTs were identified in 198 patients, of which 201 (64%) occurred in the upper extremities of 129 patients, he said. Data from at least one follow-up duplex ultrasound was available in 77 patients with 123 UEDVTs, and these results formed the basis of the analysis.

The average number of UEDVTs in the 77 patients was 1.6 (range, 1-5), and average time to diagnosis was 19 days after admission. The internal jugular was the most common site and 72% were nonocclusive. Some 70% of UEDVTs occurred in men, 35% in trauma patients, and 11% in those with a history of cancer; 2% were associated with fractures. In all, 64% of the UEDVTs were catheter associated.

A total of 60% resolved prior to discharge, and only 2.4% embolized, Dr. Malinoski said. Notably, 46% of the catheter-associated UEDVTs were associated with double- and triple-lumen catheters, 30% with percutaneously inserted central catheters (PICCs), and 24% with Cordis or hemodialysis catheters.

A comparison of catheter-related vs. noncatheter-related DVTs found that line removal was significantly associated with clot improvement on the next duplex (55% vs. 17%; P = .04), he said.

In multivariate analysis, independent predictors of clot resolution on final duplex were DVT location in the arm (with an odds ratio of 4.1, compared with the internal jugular), and time between first and final duplex exam (OR, 1.05 per day), Dr. Malinoski said.

Invited discussant Dr. Susan Brundage of New York University Langone Medical Center asked how clinicians should reconcile the data with the ACCP guidelines and medical/legal pressures, and expressed surprise at the high rate of DVTs associated with PICC lines.

"We are using PICC lines much more often, as we think of them as having less morbidity and mortality," she said. "Given that one of your PEs [pulmonary embolisms] was actually associated with a PICC line, should we change our screening practices and our diligence in these PICC lines we are placing in our critically ill patients?’’

Dr. Malinoski responded that he does not like PICC lines for infection reasons, and recommended that surgical patients with upper extremity central venous catheters be screened for the presence of a clot.

"When you find a clot, I think the only thing you need to do is remove the catheter, as opposed to treating them with massive anticoagulation in this era and with these types of patients," he said.

Dr. Malinoski pointed out that ACCP’s recommendation for full anticoagulation is based on patients’ requiring long-term catheters, typically to deliver chemotherapy. Removing and replacing a catheter isn’t feasible in these patients, and also could put them at risk for a reclot.

Dr. Malinoski and Dr. Brundage disclosed no relevant conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

NAPLES, Fla. – About one-third of elderly patients who underwent a cranial operation for traumatic brain injury die in the hospital, and one-half are dead within a year, according to a retrospective analysis of 164 patients.

Long-term follow-up for a mean of 42 months, however, demonstrated that two-thirds of survivors had a "favorable" outcome, as indicated by a GOSE (Glasgow Outcome Scale–Extended) score of at least 5, Dr. Mark Cipolle and his colleagues reported at the annual meeting of the Eastern Association for the Surgery of Trauma.

The study demonstrates that in-hospital mortality is not an adequate measure of outcome and reflects an increasing willingness to operate on the growing elderly patient population. The patients, who were at least 65 years old, had an average age of 79.

"One thing that’s very important to understand as clinicians is that these patients don’t get operated on and immediately do better," he said. "They often don’t do better and often have a decline after surgery.

"We were not thrilled with what we were seeing at 1 year, but we were fairly happy with what we saw with the patients who did survive long term."

The cohort represents 20% of the 823 patients aged at least 65 years with a head AIS (Abbreviated Injury Scale) score of 4 (severe) or 5 (critical) who were admitted in 2004-2008 to the Christiana Care Health Care System in Newark, Del. Falls were the most common mechanism of injury.

Roughly half (51%) of patients were men, 25% were taking warfarin, and 20% were on clopidogrel. Their average international normalized ratio was 2.7.

Craniotomy was the most common operation, performed in 146 patients, followed by a burr hole in 14 and craniectomy in 4, said Dr. Cipolle, chief of trauma surgery at Christiana. In all, 156 primary procedures were performed for subdural hematoma and 8 for intraparenchymal hemorrhage. Secondary procedures in 10 patients included seven craniotomies, one burr hole, and two craniectomies.

There were 46 in-hospital deaths, with 118 patients surviving until discharge to a skilled nursing facility (51%), rehabilitation (45%), or home (4%). Within 1 year, 33 of the 118 patients died.

The study, led by general surgery resident Dr. Kevin Geffe, classified 51 patients as having a favorable outcome. They included 29 patients who died more than 1 year after discharge and 22 patients with a GOSE score of at least 5 on a follow-up scripted telephone interview.

The 89 patients with an unfavorable outcome included the 46 in-hospital deaths, the 33 patients who died within a year of discharge, and 10 survivors who had a GOSE score of less than 5. Seven patients refused the GOSE interview, and 17 were lost to follow-up.

Of several factors examined by multivariate analysis, only functional independence at discharge and prehospital warfarin – but not clopidogrel (Plavix) – use were associated with outcome, Dr. Cipolle said. Not surprisingly, patients who were awake when they came in were nearly 2.5 times more likely to have a favorable outcome (odds ratio, 2.42).

The time to the operating room was 23.6 hours among patients with a favorable outcome and 27.8 hours among those with an unfavorable outcome.

"The long [operating room] times are obviously, I think, a reflection of the chronicity of many of these hemorrhages," he said. "One of the reasons we really are interested in this problem is that we can’t help but think there’s got to be a better way to deal with these patients than waiting for them to decline to decide to start operating on them."

An analysis of in-hospital mortality found that patients with a head AIS score of 4 were less likely to undergo surgery and did significantly worse with surgery than without surgery (29% vs. 7%). Dr. Cipolle pointed out, however, that patients with an AIS score of 5 were operated on at about the same rate, and there was no significant difference in mortality between the operated and nonoperated groups (28% vs. 33.5%).

Invited discussant Dr. Gary Marshall of the University of Pittsburgh Medical Center remarked that grouping the patients as favorable vs. unfavorable seemed arbitrary. Dr. Cipolle acknowledged that they struggled with the classification scheme and said they plan to more closely determine cause of death to take away additional assumptions made in the analysis.

When asked whether the hospital has reversal strategies for warfarin and clopidogrel, Dr. Cipolle responded that a statewide reversal policy for warfarin directs that patients on the anticoagulant who have a positive CT scan be given vitamin K and fresh frozen plasma, with small doses of activated factor VII therapy for those going directly to surgery. Patients on clopidogrel or aspirin with a small amount of bleeding are not treated, whereas those with substantial bleeding are given platelets. The researchers have submitted a proposal to the National Trauma Institute to conduct a pilot study evaluating reversal of antiplatelet therapy in patients with intracranial hemorrhage, Dr. Cipolle said.

The authors and Dr. Marshall reported no conflicts of interest.

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.

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.

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.