Patrice Wendling

MILAN – Targeting the epidermal growth factor receptor with cetuximab increased the overall response rate and time to disease progression in women with metastatic triple-negative breast cancer in the randomized phase II BALI-1 trial.

“This is the first randomized trial suggesting that cetuximab may be a potential addition to the treatment of patients with triple-negative breast cancer, and we believe this study makes a strong argument for studying EGFR targeting in this subgroup of breast cancer patients,” principal investigator Dr. José Baselga said during the Presidential Symposium at the annual congress of the European Society for Medical Oncology.

Cetuximab (Erbitux), a monoclonal antibody targets the epidermal growth factor receptor (EGFR), which is expressed in more than half of triple-negative disease, a difficult to treat subset that accounts for about 15% of all breast cancers but a disproportionate number of deaths.

Among the 173 evaluable patients, the overall response rate by investigator was 10.3% with cisplatin alone vs. 20% with cetuximab plus cisplatin (P = .11).

Progression-free survival more than doubled from a median of 1.5 months with cisplatin alone to 3.7 months with cetuximab plus cisplatin (hazard ratio 0.67, P = .03).

The study did not, however, meet its primary objective of an overall response rate would exceeding 20% in the experimental arm, said Dr. Baselga, chief of the division of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston. Although there is no standard treatment for triple-negative breast cancer, there were concerns in the design of the study about the suitability of cisplatin as a comparator, he explained.

Still, Dr. Baselga remained positive about the results, noting that the chance for response was twice as high for patients receiving cetuximab plus cisplatin (odds ratio 2.12).

Overall survival data are not yet available, but will be presented at a later date, he said.

Dr. Eric Winer, who was invited to discuss the findings, said the approach is worthy of pursuit, but that the modest differences between arms could be due to chance or that the unblinded nature of the trial could have affected progression-free survival and the overall response rate.

“The results are consistent with prior studies suggesting some limited activity of cetuximab in patients with triple-negative disease in combination with chemotherapy,” said Dr. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston.

He suggested that future trials could pair cetuximab with other chemotherapy partners or determine which tumor types benefit from cetuximab. “This regimen is not ready for use outside of a trial,” he said. “There appears to be a small subset that may derive benefit from the addition of cetuximab in additional trials, with extensive correlative, translational trials needed to identify patients more likely to respond.”

Subgroup analyses performed by the BALI-1 investigators found no significant differences in overall response rate with cetuximab plus cisplatin based on age, performance status, menopausal status, or lines of treatment, Dr. Baselga said.

Less than one-third of women in both arms were 60 years of age or older, two-thirds had an ECOG performance status of 0, and 27% had received second-line treatment. The median time from diagnosis to metastasis was short at 15 months, with lung metastases present in 55.7% of the experimental arm and 44.8% in the cisplatin-alone arm.

Centers in 11 countries randomly assigned 58 women to cisplatin 75 mg/m2 IV on day 1 for up to six 3-week cycles and 115 women to the same regimen plus cetuximab 400 mg/m2 for the initial dose then 250 mg/m2 weekly until progressive disease or unacceptable toxicity.

No new safety signals were observed in the study, Dr. Baselga said. Grade 3/4 adverse events that occurred in 5% or more of patients in either the experimental or cisplatin-only arms included neutropenia (9.6% vs. 5.3%), fatigue (8.8% vs. 7%), dyspnea (6.1% vs. 1.8%), and acne-like rash (14% vs. 0%).

Merck KGaA sponsored the study. Dr. Baselga disclosed no relevant conflicts of interest, but two of his coinvestigators are employees of Merck KGaA.

MILAN – Targeting the epidermal growth factor receptor with cetuximab increased the overall response rate and time to disease progression in women with metastatic triple-negative breast cancer in the randomized phase II BALI-1 trial.

“This is the first randomized trial suggesting that cetuximab may be a potential addition to the treatment of patients with triple-negative breast cancer, and we believe this study makes a strong argument for studying EGFR targeting in this subgroup of breast cancer patients,” principal investigator Dr. José Baselga said during the Presidential Symposium at the annual congress of the European Society for Medical Oncology.

Cetuximab (Erbitux), a monoclonal antibody targets the epidermal growth factor receptor (EGFR), which is expressed in more than half of triple-negative disease, a difficult to treat subset that accounts for about 15% of all breast cancers but a disproportionate number of deaths.

Among the 173 evaluable patients, the overall response rate by investigator was 10.3% with cisplatin alone vs. 20% with cetuximab plus cisplatin (P = .11).

Progression-free survival more than doubled from a median of 1.5 months with cisplatin alone to 3.7 months with cetuximab plus cisplatin (hazard ratio 0.67, P = .03).

The study did not, however, meet its primary objective of an overall response rate would exceeding 20% in the experimental arm, said Dr. Baselga, chief of the division of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston. Although there is no standard treatment for triple-negative breast cancer, there were concerns in the design of the study about the suitability of cisplatin as a comparator, he explained.

Still, Dr. Baselga remained positive about the results, noting that the chance for response was twice as high for patients receiving cetuximab plus cisplatin (odds ratio 2.12).

Overall survival data are not yet available, but will be presented at a later date, he said.

Dr. Eric Winer, who was invited to discuss the findings, said the approach is worthy of pursuit, but that the modest differences between arms could be due to chance or that the unblinded nature of the trial could have affected progression-free survival and the overall response rate.

“The results are consistent with prior studies suggesting some limited activity of cetuximab in patients with triple-negative disease in combination with chemotherapy,” said Dr. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston.

He suggested that future trials could pair cetuximab with other chemotherapy partners or determine which tumor types benefit from cetuximab. “This regimen is not ready for use outside of a trial,” he said. “There appears to be a small subset that may derive benefit from the addition of cetuximab in additional trials, with extensive correlative, translational trials needed to identify patients more likely to respond.”

Subgroup analyses performed by the BALI-1 investigators found no significant differences in overall response rate with cetuximab plus cisplatin based on age, performance status, menopausal status, or lines of treatment, Dr. Baselga said.

Less than one-third of women in both arms were 60 years of age or older, two-thirds had an ECOG performance status of 0, and 27% had received second-line treatment. The median time from diagnosis to metastasis was short at 15 months, with lung metastases present in 55.7% of the experimental arm and 44.8% in the cisplatin-alone arm.

Centers in 11 countries randomly assigned 58 women to cisplatin 75 mg/m2 IV on day 1 for up to six 3-week cycles and 115 women to the same regimen plus cetuximab 400 mg/m2 for the initial dose then 250 mg/m2 weekly until progressive disease or unacceptable toxicity.

No new safety signals were observed in the study, Dr. Baselga said. Grade 3/4 adverse events that occurred in 5% or more of patients in either the experimental or cisplatin-only arms included neutropenia (9.6% vs. 5.3%), fatigue (8.8% vs. 7%), dyspnea (6.1% vs. 1.8%), and acne-like rash (14% vs. 0%).

Merck KGaA sponsored the study. Dr. Baselga disclosed no relevant conflicts of interest, but two of his coinvestigators are employees of Merck KGaA.

MILAN – Targeting the epidermal growth factor receptor with cetuximab increased the overall response rate and time to disease progression in women with metastatic triple-negative breast cancer in the randomized phase II BALI-1 trial.

“This is the first randomized trial suggesting that cetuximab may be a potential addition to the treatment of patients with triple-negative breast cancer, and we believe this study makes a strong argument for studying EGFR targeting in this subgroup of breast cancer patients,” principal investigator Dr. José Baselga said during the Presidential Symposium at the annual congress of the European Society for Medical Oncology.

Cetuximab (Erbitux), a monoclonal antibody targets the epidermal growth factor receptor (EGFR), which is expressed in more than half of triple-negative disease, a difficult to treat subset that accounts for about 15% of all breast cancers but a disproportionate number of deaths.

Among the 173 evaluable patients, the overall response rate by investigator was 10.3% with cisplatin alone vs. 20% with cetuximab plus cisplatin (P = .11).

Progression-free survival more than doubled from a median of 1.5 months with cisplatin alone to 3.7 months with cetuximab plus cisplatin (hazard ratio 0.67, P = .03).

The study did not, however, meet its primary objective of an overall response rate would exceeding 20% in the experimental arm, said Dr. Baselga, chief of the division of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston. Although there is no standard treatment for triple-negative breast cancer, there were concerns in the design of the study about the suitability of cisplatin as a comparator, he explained.

Still, Dr. Baselga remained positive about the results, noting that the chance for response was twice as high for patients receiving cetuximab plus cisplatin (odds ratio 2.12).

Overall survival data are not yet available, but will be presented at a later date, he said.

Dr. Eric Winer, who was invited to discuss the findings, said the approach is worthy of pursuit, but that the modest differences between arms could be due to chance or that the unblinded nature of the trial could have affected progression-free survival and the overall response rate.

“The results are consistent with prior studies suggesting some limited activity of cetuximab in patients with triple-negative disease in combination with chemotherapy,” said Dr. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston.

He suggested that future trials could pair cetuximab with other chemotherapy partners or determine which tumor types benefit from cetuximab. “This regimen is not ready for use outside of a trial,” he said. “There appears to be a small subset that may derive benefit from the addition of cetuximab in additional trials, with extensive correlative, translational trials needed to identify patients more likely to respond.”

Subgroup analyses performed by the BALI-1 investigators found no significant differences in overall response rate with cetuximab plus cisplatin based on age, performance status, menopausal status, or lines of treatment, Dr. Baselga said.

Less than one-third of women in both arms were 60 years of age or older, two-thirds had an ECOG performance status of 0, and 27% had received second-line treatment. The median time from diagnosis to metastasis was short at 15 months, with lung metastases present in 55.7% of the experimental arm and 44.8% in the cisplatin-alone arm.

Centers in 11 countries randomly assigned 58 women to cisplatin 75 mg/m2 IV on day 1 for up to six 3-week cycles and 115 women to the same regimen plus cetuximab 400 mg/m2 for the initial dose then 250 mg/m2 weekly until progressive disease or unacceptable toxicity.

No new safety signals were observed in the study, Dr. Baselga said. Grade 3/4 adverse events that occurred in 5% or more of patients in either the experimental or cisplatin-only arms included neutropenia (9.6% vs. 5.3%), fatigue (8.8% vs. 7%), dyspnea (6.1% vs. 1.8%), and acne-like rash (14% vs. 0%).

Merck KGaA sponsored the study. Dr. Baselga disclosed no relevant conflicts of interest, but two of his coinvestigators are employees of Merck KGaA.

INDIANAPOLIS – The introduction of thoracic endovascular aortic repair increased the total number of aneurysm repairs, but did not replace conventional surgery, according to a population-based analysis.

The study, using the Nationwide Inpatient Sample (NIS) database, is the first to evaluate national trends in utilization of thoracic endovascular aortic repair (TEVAR) and to provide outcomes in the “real world,” according to principal investigator Dr. Jeffrey Jim. The NIS database is the largest all-payer inpatient care database in the United States and is designed to approximate a 20% sample of all U.S. hospitals.

Researchers at Washington University in St. Louis identified 18,267 hospitalizations for treatment of intact thoracic aortic aneurysms from October 2005, when the first ICD-9 procedural code for TEVAR became available, through December 2008, the latest data available.

A total of 4,649 patients (25%) underwent TEVAR and 13,618 (75%) underwent open aneurysm repair (OAR).

In terms of utilization, TEVAR was immediately adopted on a national basis, Dr. Jim said at the annual meeting of the Midwestern Vascular Surgical Society. The overall use of TEVAR in the study period was 25.6%.

The use of OAR, however, did not significantly decrease with the introduction of TEVAR. The number of OAR cases rose from 704 in the fourth quarter of 2005 to 1,264 cases in the fourth quarter of 2008. At the same time, the total number of thoracic aneurysm repairs jumped from 3,946 for all of 2005 to 6,628 for 2008.

“One thing that’s very surprising is that it [TEVAR] was rapidly adopted in the beginning, but really hasn’t changed over time,” said Dr. Jim, a vascular surgeon at Washington University.

Although sex did not significantly influence the use of TEVAR, age was a big factor, he said. Almost half (49%) of patients aged 80 years and older were treated with TEVAR, compared with 29.5% of those aged 65-79 years, and just 14% for those aged 50-64 years.

Overall mortality rates were similar: 3.2% for TEVAR and 2.6% for OAR. While TEVAR conferred no mortality benefit, it was associated with a significantly shorter length of stay (mean, 7.4 days vs. 9.1 days for OAR patients) and significantly fewer patients with any complication (38% vs. 51%), Dr. Jim said.

The use of TEVAR vs. OAR was associated with significantly lower rates of cardiac (5.4% vs. 17%), pulmonary (3% vs. 5%) and respiratory (5.5% vs. 7.5%) complications, but a significantly higher rate of neurologic complications (0.7% vs. 0.1%). This was true even though TEVAR patients had a significantly higher prevalence of comorbid conditions than did OAR patients, including cerebral (10% vs. 4.4%), peripheral vascular disease (18% vs. 6%), chronic obstructive pulmonary disease (35.5% vs. 18%), and renal insufficiency (14% vs. 6.5%).

Dr. Jim acknowledged the study was limited by the inherent variability in the accuracy of coding, the lack of anatomical information and operative details, and the inability to perform a longitudinal analysis or to accurately evaluate the rate of spinal cord ischemic injuries/paraplegia.

Still, the analysis is more inclusive than are institution reports, state databases, and even Medicare databases, which cover only about two-thirds of this population, he said.

While one attendee questioned the accuracy of the NIS database, the most pointed comment came from Dr. Alexander Shepard, codirector of the Edith and Benson Ford Heart & Vascular Institute in Detroit: “I rise to challenge all of us to look at these results and ask ourselves what we are really accomplishing with some of these patients.”

He noted that clinical trials show a 1-year mortality rate approaching 25% for patients who undergo thoracic repairs, whether open or endovascular. In addition, there is the issue of quality of life in relation to the outlay of reimbursement and financing.

“Just because it can be done, should it be done?” he asked. “I would challenge all of us, as we look at these older patients that we’re subjecting to these procedures – are we really getting the bang for our buck?”

Dr. Jim reported no conflicts or study support. Coinvestigator Dr. Luis Sanchez stated that he has consulting agreements with Aptus Endosystems Inc., Cook Medical Inc., Endologix Inc., W.L. Gore & Associates Inc., Medtronic Inc., and Trivascular Inc.

INDIANAPOLIS – The introduction of thoracic endovascular aortic repair increased the total number of aneurysm repairs, but did not replace conventional surgery, according to a population-based analysis.

The study, using the Nationwide Inpatient Sample (NIS) database, is the first to evaluate national trends in utilization of thoracic endovascular aortic repair (TEVAR) and to provide outcomes in the “real world,” according to principal investigator Dr. Jeffrey Jim. The NIS database is the largest all-payer inpatient care database in the United States and is designed to approximate a 20% sample of all U.S. hospitals.

Researchers at Washington University in St. Louis identified 18,267 hospitalizations for treatment of intact thoracic aortic aneurysms from October 2005, when the first ICD-9 procedural code for TEVAR became available, through December 2008, the latest data available.

A total of 4,649 patients (25%) underwent TEVAR and 13,618 (75%) underwent open aneurysm repair (OAR).

In terms of utilization, TEVAR was immediately adopted on a national basis, Dr. Jim said at the annual meeting of the Midwestern Vascular Surgical Society. The overall use of TEVAR in the study period was 25.6%.

The use of OAR, however, did not significantly decrease with the introduction of TEVAR. The number of OAR cases rose from 704 in the fourth quarter of 2005 to 1,264 cases in the fourth quarter of 2008. At the same time, the total number of thoracic aneurysm repairs jumped from 3,946 for all of 2005 to 6,628 for 2008.

“One thing that’s very surprising is that it [TEVAR] was rapidly adopted in the beginning, but really hasn’t changed over time,” said Dr. Jim, a vascular surgeon at Washington University.

Although sex did not significantly influence the use of TEVAR, age was a big factor, he said. Almost half (49%) of patients aged 80 years and older were treated with TEVAR, compared with 29.5% of those aged 65-79 years, and just 14% for those aged 50-64 years.

Overall mortality rates were similar: 3.2% for TEVAR and 2.6% for OAR. While TEVAR conferred no mortality benefit, it was associated with a significantly shorter length of stay (mean, 7.4 days vs. 9.1 days for OAR patients) and significantly fewer patients with any complication (38% vs. 51%), Dr. Jim said.

The use of TEVAR vs. OAR was associated with significantly lower rates of cardiac (5.4% vs. 17%), pulmonary (3% vs. 5%) and respiratory (5.5% vs. 7.5%) complications, but a significantly higher rate of neurologic complications (0.7% vs. 0.1%). This was true even though TEVAR patients had a significantly higher prevalence of comorbid conditions than did OAR patients, including cerebral (10% vs. 4.4%), peripheral vascular disease (18% vs. 6%), chronic obstructive pulmonary disease (35.5% vs. 18%), and renal insufficiency (14% vs. 6.5%).

Dr. Jim acknowledged the study was limited by the inherent variability in the accuracy of coding, the lack of anatomical information and operative details, and the inability to perform a longitudinal analysis or to accurately evaluate the rate of spinal cord ischemic injuries/paraplegia.

Still, the analysis is more inclusive than are institution reports, state databases, and even Medicare databases, which cover only about two-thirds of this population, he said.

While one attendee questioned the accuracy of the NIS database, the most pointed comment came from Dr. Alexander Shepard, codirector of the Edith and Benson Ford Heart & Vascular Institute in Detroit: “I rise to challenge all of us to look at these results and ask ourselves what we are really accomplishing with some of these patients.”

He noted that clinical trials show a 1-year mortality rate approaching 25% for patients who undergo thoracic repairs, whether open or endovascular. In addition, there is the issue of quality of life in relation to the outlay of reimbursement and financing.

“Just because it can be done, should it be done?” he asked. “I would challenge all of us, as we look at these older patients that we’re subjecting to these procedures – are we really getting the bang for our buck?”

Dr. Jim reported no conflicts or study support. Coinvestigator Dr. Luis Sanchez stated that he has consulting agreements with Aptus Endosystems Inc., Cook Medical Inc., Endologix Inc., W.L. Gore & Associates Inc., Medtronic Inc., and Trivascular Inc.

INDIANAPOLIS – The introduction of thoracic endovascular aortic repair increased the total number of aneurysm repairs, but did not replace conventional surgery, according to a population-based analysis.

The study, using the Nationwide Inpatient Sample (NIS) database, is the first to evaluate national trends in utilization of thoracic endovascular aortic repair (TEVAR) and to provide outcomes in the “real world,” according to principal investigator Dr. Jeffrey Jim. The NIS database is the largest all-payer inpatient care database in the United States and is designed to approximate a 20% sample of all U.S. hospitals.

Researchers at Washington University in St. Louis identified 18,267 hospitalizations for treatment of intact thoracic aortic aneurysms from October 2005, when the first ICD-9 procedural code for TEVAR became available, through December 2008, the latest data available.

A total of 4,649 patients (25%) underwent TEVAR and 13,618 (75%) underwent open aneurysm repair (OAR).

In terms of utilization, TEVAR was immediately adopted on a national basis, Dr. Jim said at the annual meeting of the Midwestern Vascular Surgical Society. The overall use of TEVAR in the study period was 25.6%.

The use of OAR, however, did not significantly decrease with the introduction of TEVAR. The number of OAR cases rose from 704 in the fourth quarter of 2005 to 1,264 cases in the fourth quarter of 2008. At the same time, the total number of thoracic aneurysm repairs jumped from 3,946 for all of 2005 to 6,628 for 2008.

“One thing that’s very surprising is that it [TEVAR] was rapidly adopted in the beginning, but really hasn’t changed over time,” said Dr. Jim, a vascular surgeon at Washington University.

Although sex did not significantly influence the use of TEVAR, age was a big factor, he said. Almost half (49%) of patients aged 80 years and older were treated with TEVAR, compared with 29.5% of those aged 65-79 years, and just 14% for those aged 50-64 years.

Overall mortality rates were similar: 3.2% for TEVAR and 2.6% for OAR. While TEVAR conferred no mortality benefit, it was associated with a significantly shorter length of stay (mean, 7.4 days vs. 9.1 days for OAR patients) and significantly fewer patients with any complication (38% vs. 51%), Dr. Jim said.

The use of TEVAR vs. OAR was associated with significantly lower rates of cardiac (5.4% vs. 17%), pulmonary (3% vs. 5%) and respiratory (5.5% vs. 7.5%) complications, but a significantly higher rate of neurologic complications (0.7% vs. 0.1%). This was true even though TEVAR patients had a significantly higher prevalence of comorbid conditions than did OAR patients, including cerebral (10% vs. 4.4%), peripheral vascular disease (18% vs. 6%), chronic obstructive pulmonary disease (35.5% vs. 18%), and renal insufficiency (14% vs. 6.5%).

Dr. Jim acknowledged the study was limited by the inherent variability in the accuracy of coding, the lack of anatomical information and operative details, and the inability to perform a longitudinal analysis or to accurately evaluate the rate of spinal cord ischemic injuries/paraplegia.

Still, the analysis is more inclusive than are institution reports, state databases, and even Medicare databases, which cover only about two-thirds of this population, he said.

While one attendee questioned the accuracy of the NIS database, the most pointed comment came from Dr. Alexander Shepard, codirector of the Edith and Benson Ford Heart & Vascular Institute in Detroit: “I rise to challenge all of us to look at these results and ask ourselves what we are really accomplishing with some of these patients.”

He noted that clinical trials show a 1-year mortality rate approaching 25% for patients who undergo thoracic repairs, whether open or endovascular. In addition, there is the issue of quality of life in relation to the outlay of reimbursement and financing.

“Just because it can be done, should it be done?” he asked. “I would challenge all of us, as we look at these older patients that we’re subjecting to these procedures – are we really getting the bang for our buck?”

Dr. Jim reported no conflicts or study support. Coinvestigator Dr. Luis Sanchez stated that he has consulting agreements with Aptus Endosystems Inc., Cook Medical Inc., Endologix Inc., W.L. Gore & Associates Inc., Medtronic Inc., and Trivascular Inc.

CHICAGO – A past psychiatric history, depressive disorder diagnosis, and current use of psychotropic medications were significantly associated with a higher potential for suicidal behavior.

“Suicide risk in patients with epilepsy reflects the higher incidence of psychiatric comorbidity in this population rather than any neurologic or demographic factor,” reported Robert C. Doss, Psy.D., and Dr. Patricia E. Penovich, of the Minnesota Epilepsy Group in St. Paul. This finding confirms what has been established in previous research.

About 30% of people with epilepsy have a major depressive disorder, and research suggests that about 50% of the time they are never treated for the problem, according to the Epilepsy Foundation.

Moreover, the suicide rate in persons with epilepsy is on average 12%, compared with about 1% in the general population (Epilepsy Behav. 2003;4:[Suppl. 3]S31-8). Given the prevalence of this problem and the 2008 warning by the Food and Drug Administration regarding the association between suicidality and antiepileptic drugs, further understanding of this matter is urgently needed, Dr. Doss and Dr. Penovich reported in a poster at the 2010 Epilepsy and Depressive Disorders Conference (EDDC).

Upon admission, the 58 patients in the sample underwent long-term video-EEG, neuropsychological testing, personality assessment using the Personality Assessment Inventory, social work evaluation, and if indicated, psychology and/or psychiatry consultation.

Ten patients (mean age, 36 years) showed clinical elevations on the inventory’s Suicide Potential Index (SPI) and 48 patients (mean age, 38 years) did not. The SPI consists of 20 features on the inventory that tap what are described as key risk factors for completed suicide in the suicidality literature.

Patients with a positive SPI were significantly more likely than were those with a negative SPI to have a depressive disorder diagnosis (80% vs. 19%, respectively), previous psychiatric history (90% vs. 27%), and to currently use psychotropic medications (50% vs. 13%), Dr. Doss and Dr. Penovich reported.

No other variables, including age, gender, education, duration of epilepsy, temporal lobe epilepsy, complex partial seizures, other neurologic history, epilepsy surgery, number of anti-epileptic drugs, seizure frequency, anxiety disorder diagnosis or cognitive status were found to significantly differentiate the two groups.

The lifetime prevalence rate of suicide and suicide attempts has been reported to be particularly high in patients with temporal lobe epilepsy and those who have had epilepsy surgery when compared with the general population, but neither risk factor stood out in the current analysis. Temporal lobe epilepsy was present in 30% of the SPI-positive group, compared with 55% of the SPI-negative group, and epilepsy surgery in 20%, compared with 10%. Also, the number of antiepileptic drugs was similar in both groups at 2.0 and 1.8.

“Routine care of persons with epilepsy should include screening for both current and past psychiatric symptoms,” the authors concluded. “Particular attention should be paid to persons with epilepsy with a clear psychiatric history.”

The authors disclosed no conflicts of interest. The conference was jointly sponsored by the EDDC and the office of continuing education of Elsevier, which owns this news organization.

CHICAGO – A past psychiatric history, depressive disorder diagnosis, and current use of psychotropic medications were significantly associated with a higher potential for suicidal behavior.

“Suicide risk in patients with epilepsy reflects the higher incidence of psychiatric comorbidity in this population rather than any neurologic or demographic factor,” reported Robert C. Doss, Psy.D., and Dr. Patricia E. Penovich, of the Minnesota Epilepsy Group in St. Paul. This finding confirms what has been established in previous research.

About 30% of people with epilepsy have a major depressive disorder, and research suggests that about 50% of the time they are never treated for the problem, according to the Epilepsy Foundation.

Moreover, the suicide rate in persons with epilepsy is on average 12%, compared with about 1% in the general population (Epilepsy Behav. 2003;4:[Suppl. 3]S31-8). Given the prevalence of this problem and the 2008 warning by the Food and Drug Administration regarding the association between suicidality and antiepileptic drugs, further understanding of this matter is urgently needed, Dr. Doss and Dr. Penovich reported in a poster at the 2010 Epilepsy and Depressive Disorders Conference (EDDC).

Upon admission, the 58 patients in the sample underwent long-term video-EEG, neuropsychological testing, personality assessment using the Personality Assessment Inventory, social work evaluation, and if indicated, psychology and/or psychiatry consultation.

Ten patients (mean age, 36 years) showed clinical elevations on the inventory’s Suicide Potential Index (SPI) and 48 patients (mean age, 38 years) did not. The SPI consists of 20 features on the inventory that tap what are described as key risk factors for completed suicide in the suicidality literature.

Patients with a positive SPI were significantly more likely than were those with a negative SPI to have a depressive disorder diagnosis (80% vs. 19%, respectively), previous psychiatric history (90% vs. 27%), and to currently use psychotropic medications (50% vs. 13%), Dr. Doss and Dr. Penovich reported.

No other variables, including age, gender, education, duration of epilepsy, temporal lobe epilepsy, complex partial seizures, other neurologic history, epilepsy surgery, number of anti-epileptic drugs, seizure frequency, anxiety disorder diagnosis or cognitive status were found to significantly differentiate the two groups.

The lifetime prevalence rate of suicide and suicide attempts has been reported to be particularly high in patients with temporal lobe epilepsy and those who have had epilepsy surgery when compared with the general population, but neither risk factor stood out in the current analysis. Temporal lobe epilepsy was present in 30% of the SPI-positive group, compared with 55% of the SPI-negative group, and epilepsy surgery in 20%, compared with 10%. Also, the number of antiepileptic drugs was similar in both groups at 2.0 and 1.8.

“Routine care of persons with epilepsy should include screening for both current and past psychiatric symptoms,” the authors concluded. “Particular attention should be paid to persons with epilepsy with a clear psychiatric history.”

The authors disclosed no conflicts of interest. The conference was jointly sponsored by the EDDC and the office of continuing education of Elsevier, which owns this news organization.

CHICAGO – A past psychiatric history, depressive disorder diagnosis, and current use of psychotropic medications were significantly associated with a higher potential for suicidal behavior.

“Suicide risk in patients with epilepsy reflects the higher incidence of psychiatric comorbidity in this population rather than any neurologic or demographic factor,” reported Robert C. Doss, Psy.D., and Dr. Patricia E. Penovich, of the Minnesota Epilepsy Group in St. Paul. This finding confirms what has been established in previous research.

About 30% of people with epilepsy have a major depressive disorder, and research suggests that about 50% of the time they are never treated for the problem, according to the Epilepsy Foundation.

Moreover, the suicide rate in persons with epilepsy is on average 12%, compared with about 1% in the general population (Epilepsy Behav. 2003;4:[Suppl. 3]S31-8). Given the prevalence of this problem and the 2008 warning by the Food and Drug Administration regarding the association between suicidality and antiepileptic drugs, further understanding of this matter is urgently needed, Dr. Doss and Dr. Penovich reported in a poster at the 2010 Epilepsy and Depressive Disorders Conference (EDDC).

Upon admission, the 58 patients in the sample underwent long-term video-EEG, neuropsychological testing, personality assessment using the Personality Assessment Inventory, social work evaluation, and if indicated, psychology and/or psychiatry consultation.

Ten patients (mean age, 36 years) showed clinical elevations on the inventory’s Suicide Potential Index (SPI) and 48 patients (mean age, 38 years) did not. The SPI consists of 20 features on the inventory that tap what are described as key risk factors for completed suicide in the suicidality literature.

Patients with a positive SPI were significantly more likely than were those with a negative SPI to have a depressive disorder diagnosis (80% vs. 19%, respectively), previous psychiatric history (90% vs. 27%), and to currently use psychotropic medications (50% vs. 13%), Dr. Doss and Dr. Penovich reported.

No other variables, including age, gender, education, duration of epilepsy, temporal lobe epilepsy, complex partial seizures, other neurologic history, epilepsy surgery, number of anti-epileptic drugs, seizure frequency, anxiety disorder diagnosis or cognitive status were found to significantly differentiate the two groups.

The lifetime prevalence rate of suicide and suicide attempts has been reported to be particularly high in patients with temporal lobe epilepsy and those who have had epilepsy surgery when compared with the general population, but neither risk factor stood out in the current analysis. Temporal lobe epilepsy was present in 30% of the SPI-positive group, compared with 55% of the SPI-negative group, and epilepsy surgery in 20%, compared with 10%. Also, the number of antiepileptic drugs was similar in both groups at 2.0 and 1.8.

“Routine care of persons with epilepsy should include screening for both current and past psychiatric symptoms,” the authors concluded. “Particular attention should be paid to persons with epilepsy with a clear psychiatric history.”

The authors disclosed no conflicts of interest. The conference was jointly sponsored by the EDDC and the office of continuing education of Elsevier, which owns this news organization.

MILAN – Final results from an open-label phase II study confirm the survival advantage of adding an investigational PARP inhibitor to gemcitabine and carboplatin chemotherapy in metastatic triple-negative breast cancer.

Although not a prespecified outcome, median overall survival increased from 7.7 months to 12.3 months (hazard ratio, 0.57; P = .014,), lead author Dr. Joyce O’Shaughnessy reported in a late-breaking abstract at the the annual congress of the European Society for Medical Oncology. Median survival in this aggressive form of breast cancer is about 13 months after developing metastases.

Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin alone to 5.9 months with the addition of iniparib, a poly (adenosine diphosphate–ribose) polymerase-1 (PARP1) inhibitor also known as BSI-201 (HR, 0.59; P =.012).

The clinical benefit rate rose as well from 33.9% in the chemotherapy-alone arm to 55.7% in the iniparib arm (P = .015). This seemed to be driven by the overall response rate, which was 32.3% with chemotherapy alone and 52.5% with the addition of iniparib (P = .023). The clinical benefit rate (complete or partial response or stable disease for at least 6 months) was a coprimary end point with safety and tolerability.

Thirty of the 62 patients in the gemcitabine-carboplatin arm crossed over to receive iniparib plus chemotherapy. An unconfirmed partial response was reported in 1, stable disease in 4, and progressive disease in 18, while 7 were not evaluable.

The study’s rationale was that inhibiting PARP, an enzyme that helps the cell to repair DNA damage, would enhance the effectiveness of chemotherapy damaging DNA.

Dr. O’Shaughnessy reported on 123 women with estrogen receptor–, progesterone receptor– and HER2-negative breast cancer and a median of three metastatic sites who had received not more than two prior cytotoxic regimens. Of these, 62 were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (AUC = 2) IV on days 1 and 8 every 3 weeks, and 61 to the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11.

In a special PARP symposium at the meeting, chair Dr. Johann de Bono of the Royal Marsden Hospital and Institute of Cancer Research in Sutton, England, took issue with the study’s dosing. “I’m concerned that it was an insufficient dose of carboplatin in the control arm; was that the right dose to do – maybe. [But] was it even ethical?” he asked. “I think that’s a real key issue.”

When this concern was raised during the discussion of the study, Dr. O’Shaughnessy said they didn’t know for sure whether carboplatin AUC 5 or 6 given every 3 weeks in metastatic breast cancer would be superior. Indirect evidence from two phase II trials in unselected breast cancer patients showed response rates of 30% with carboplatin AUC 5 given every 3 weeks and with AUC 2.5 given every other week with gemcitabine 1,500 mg/m2.

“When we gave 2.5 every other week, after about two [to] three cycles, patients went down on their AUC to 2; that’s why we choose 2 as opposed to 2.5,” she said. “We couldn’t get the 2.5 in consistently.”

Invited discussant Dr. Richard Bell of the Andrew Love Cancer Centre in Geelong, Australia, said the difference in progression-free survival between study arms is clinically meaningful, but urged caution as the outcomes were investigator reported and other enthusiastically received phase II trials have fallen short in phase III evaluation.

“The big issue is would this work in other breast cancer types or in other cancer types,” he said.

A confirmatory phase III trial using the same schema has completed enrollment of 500 patients with triple-negative breast cancer, including women with BRCA mutations, said Dr. O’Shaughnessy. She noted that a recent study from M.D. Anderson Cancer Center found that 20% of 77 unselected triple-negative breast cancer patients carried a BRCA1/2 mutation.

Predictive biomarker evaluation is underway to identify subsets of triple-negative breast cancer patients likely to benefit from iniparib. Preoperative and adjuvant trials of iniparib in this setting are planned. Iniparib is also being studied in phase II and III trials in ovarian, uterine, and brain tumors.

Dr. Bell expressed surprise at the lack of toxicity reported with the addition of iniparib to chemotherapy. Although there is great excitement over the use of PARP inhibitors, with no less than 49 trials now in various stages, most have the potential to enhance toxicity, particularly hematologic toxicity, when used in combination with other drugs.

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, said Dr. O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas. Grade 3 or 4 adverse events, mainly hematologic toxicity, were similar at 81% in the chemotherapy alone arm and 86% in the iniparib arm.

Grade 4 neutropenia occurred in 16 patients in each group; grade 4 thrombocytopenia in 10 in the chemotherapy group vs. 11 in the iniparib group. There were no grade 4 anemia or leukopenia events in either arm.

Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression, Dr. O’Shaughnessy said. In all, 14% in the iniparib group and 27% in the chemotherapy alone group discontinued treatment because of adverse events. Dose reductions were similar between study arms.

Dr. O’Shaughnessy reported no conflicts of interest. Several coinvestigators are employees of study sponsor Bipar Sciences Inc., which is developing iniparib with its parent company, Sanofi-Aventis.

MILAN – Final results from an open-label phase II study confirm the survival advantage of adding an investigational PARP inhibitor to gemcitabine and carboplatin chemotherapy in metastatic triple-negative breast cancer.

Although not a prespecified outcome, median overall survival increased from 7.7 months to 12.3 months (hazard ratio, 0.57; P = .014,), lead author Dr. Joyce O’Shaughnessy reported in a late-breaking abstract at the the annual congress of the European Society for Medical Oncology. Median survival in this aggressive form of breast cancer is about 13 months after developing metastases.

Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin alone to 5.9 months with the addition of iniparib, a poly (adenosine diphosphate–ribose) polymerase-1 (PARP1) inhibitor also known as BSI-201 (HR, 0.59; P =.012).

The clinical benefit rate rose as well from 33.9% in the chemotherapy-alone arm to 55.7% in the iniparib arm (P = .015). This seemed to be driven by the overall response rate, which was 32.3% with chemotherapy alone and 52.5% with the addition of iniparib (P = .023). The clinical benefit rate (complete or partial response or stable disease for at least 6 months) was a coprimary end point with safety and tolerability.

Thirty of the 62 patients in the gemcitabine-carboplatin arm crossed over to receive iniparib plus chemotherapy. An unconfirmed partial response was reported in 1, stable disease in 4, and progressive disease in 18, while 7 were not evaluable.

The study’s rationale was that inhibiting PARP, an enzyme that helps the cell to repair DNA damage, would enhance the effectiveness of chemotherapy damaging DNA.

Dr. O’Shaughnessy reported on 123 women with estrogen receptor–, progesterone receptor– and HER2-negative breast cancer and a median of three metastatic sites who had received not more than two prior cytotoxic regimens. Of these, 62 were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (AUC = 2) IV on days 1 and 8 every 3 weeks, and 61 to the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11.

In a special PARP symposium at the meeting, chair Dr. Johann de Bono of the Royal Marsden Hospital and Institute of Cancer Research in Sutton, England, took issue with the study’s dosing. “I’m concerned that it was an insufficient dose of carboplatin in the control arm; was that the right dose to do – maybe. [But] was it even ethical?” he asked. “I think that’s a real key issue.”

When this concern was raised during the discussion of the study, Dr. O’Shaughnessy said they didn’t know for sure whether carboplatin AUC 5 or 6 given every 3 weeks in metastatic breast cancer would be superior. Indirect evidence from two phase II trials in unselected breast cancer patients showed response rates of 30% with carboplatin AUC 5 given every 3 weeks and with AUC 2.5 given every other week with gemcitabine 1,500 mg/m2.

“When we gave 2.5 every other week, after about two [to] three cycles, patients went down on their AUC to 2; that’s why we choose 2 as opposed to 2.5,” she said. “We couldn’t get the 2.5 in consistently.”

Invited discussant Dr. Richard Bell of the Andrew Love Cancer Centre in Geelong, Australia, said the difference in progression-free survival between study arms is clinically meaningful, but urged caution as the outcomes were investigator reported and other enthusiastically received phase II trials have fallen short in phase III evaluation.

“The big issue is would this work in other breast cancer types or in other cancer types,” he said.

A confirmatory phase III trial using the same schema has completed enrollment of 500 patients with triple-negative breast cancer, including women with BRCA mutations, said Dr. O’Shaughnessy. She noted that a recent study from M.D. Anderson Cancer Center found that 20% of 77 unselected triple-negative breast cancer patients carried a BRCA1/2 mutation.

Predictive biomarker evaluation is underway to identify subsets of triple-negative breast cancer patients likely to benefit from iniparib. Preoperative and adjuvant trials of iniparib in this setting are planned. Iniparib is also being studied in phase II and III trials in ovarian, uterine, and brain tumors.

Dr. Bell expressed surprise at the lack of toxicity reported with the addition of iniparib to chemotherapy. Although there is great excitement over the use of PARP inhibitors, with no less than 49 trials now in various stages, most have the potential to enhance toxicity, particularly hematologic toxicity, when used in combination with other drugs.

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, said Dr. O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas. Grade 3 or 4 adverse events, mainly hematologic toxicity, were similar at 81% in the chemotherapy alone arm and 86% in the iniparib arm.

Grade 4 neutropenia occurred in 16 patients in each group; grade 4 thrombocytopenia in 10 in the chemotherapy group vs. 11 in the iniparib group. There were no grade 4 anemia or leukopenia events in either arm.

Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression, Dr. O’Shaughnessy said. In all, 14% in the iniparib group and 27% in the chemotherapy alone group discontinued treatment because of adverse events. Dose reductions were similar between study arms.

Dr. O’Shaughnessy reported no conflicts of interest. Several coinvestigators are employees of study sponsor Bipar Sciences Inc., which is developing iniparib with its parent company, Sanofi-Aventis.

MILAN – Final results from an open-label phase II study confirm the survival advantage of adding an investigational PARP inhibitor to gemcitabine and carboplatin chemotherapy in metastatic triple-negative breast cancer.

Although not a prespecified outcome, median overall survival increased from 7.7 months to 12.3 months (hazard ratio, 0.57; P = .014,), lead author Dr. Joyce O’Shaughnessy reported in a late-breaking abstract at the the annual congress of the European Society for Medical Oncology. Median survival in this aggressive form of breast cancer is about 13 months after developing metastases.

Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin alone to 5.9 months with the addition of iniparib, a poly (adenosine diphosphate–ribose) polymerase-1 (PARP1) inhibitor also known as BSI-201 (HR, 0.59; P =.012).

The clinical benefit rate rose as well from 33.9% in the chemotherapy-alone arm to 55.7% in the iniparib arm (P = .015). This seemed to be driven by the overall response rate, which was 32.3% with chemotherapy alone and 52.5% with the addition of iniparib (P = .023). The clinical benefit rate (complete or partial response or stable disease for at least 6 months) was a coprimary end point with safety and tolerability.

Thirty of the 62 patients in the gemcitabine-carboplatin arm crossed over to receive iniparib plus chemotherapy. An unconfirmed partial response was reported in 1, stable disease in 4, and progressive disease in 18, while 7 were not evaluable.

The study’s rationale was that inhibiting PARP, an enzyme that helps the cell to repair DNA damage, would enhance the effectiveness of chemotherapy damaging DNA.

Dr. O’Shaughnessy reported on 123 women with estrogen receptor–, progesterone receptor– and HER2-negative breast cancer and a median of three metastatic sites who had received not more than two prior cytotoxic regimens. Of these, 62 were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (AUC = 2) IV on days 1 and 8 every 3 weeks, and 61 to the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11.

In a special PARP symposium at the meeting, chair Dr. Johann de Bono of the Royal Marsden Hospital and Institute of Cancer Research in Sutton, England, took issue with the study’s dosing. “I’m concerned that it was an insufficient dose of carboplatin in the control arm; was that the right dose to do – maybe. [But] was it even ethical?” he asked. “I think that’s a real key issue.”

When this concern was raised during the discussion of the study, Dr. O’Shaughnessy said they didn’t know for sure whether carboplatin AUC 5 or 6 given every 3 weeks in metastatic breast cancer would be superior. Indirect evidence from two phase II trials in unselected breast cancer patients showed response rates of 30% with carboplatin AUC 5 given every 3 weeks and with AUC 2.5 given every other week with gemcitabine 1,500 mg/m2.

“When we gave 2.5 every other week, after about two [to] three cycles, patients went down on their AUC to 2; that’s why we choose 2 as opposed to 2.5,” she said. “We couldn’t get the 2.5 in consistently.”

Invited discussant Dr. Richard Bell of the Andrew Love Cancer Centre in Geelong, Australia, said the difference in progression-free survival between study arms is clinically meaningful, but urged caution as the outcomes were investigator reported and other enthusiastically received phase II trials have fallen short in phase III evaluation.

“The big issue is would this work in other breast cancer types or in other cancer types,” he said.

A confirmatory phase III trial using the same schema has completed enrollment of 500 patients with triple-negative breast cancer, including women with BRCA mutations, said Dr. O’Shaughnessy. She noted that a recent study from M.D. Anderson Cancer Center found that 20% of 77 unselected triple-negative breast cancer patients carried a BRCA1/2 mutation.

Predictive biomarker evaluation is underway to identify subsets of triple-negative breast cancer patients likely to benefit from iniparib. Preoperative and adjuvant trials of iniparib in this setting are planned. Iniparib is also being studied in phase II and III trials in ovarian, uterine, and brain tumors.

Dr. Bell expressed surprise at the lack of toxicity reported with the addition of iniparib to chemotherapy. Although there is great excitement over the use of PARP inhibitors, with no less than 49 trials now in various stages, most have the potential to enhance toxicity, particularly hematologic toxicity, when used in combination with other drugs.

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, said Dr. O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas. Grade 3 or 4 adverse events, mainly hematologic toxicity, were similar at 81% in the chemotherapy alone arm and 86% in the iniparib arm.

Grade 4 neutropenia occurred in 16 patients in each group; grade 4 thrombocytopenia in 10 in the chemotherapy group vs. 11 in the iniparib group. There were no grade 4 anemia or leukopenia events in either arm.

Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression, Dr. O’Shaughnessy said. In all, 14% in the iniparib group and 27% in the chemotherapy alone group discontinued treatment because of adverse events. Dose reductions were similar between study arms.

Dr. O’Shaughnessy reported no conflicts of interest. Several coinvestigators are employees of study sponsor Bipar Sciences Inc., which is developing iniparib with its parent company, Sanofi-Aventis.

MILAN – First-line erlotinib nearly tripled progression-free survival when compared with platinum-based chemotherapy in patients with advanced lung cancer carrying mutations activating the epidermal growth factor receptor.

Median progression-free survival in the randomized, phase III OPTIMAL trial from China reached 13.1 months in patients given erlotinib (Tarceva), compared with 4.6 months in those given gemcitabine (Gemzar) plus carboplatin chemotherapy (hazard ratio 0.16, P less than .0001).

After a median follow-up of 15.6 months, 31 patients on erlotinib are still on the study, compared with only one on chemotherapy, lead author Dr. Caicun Zhou reported in a late-breaking abstract at the 35th Congress of the European Society for Medical Oncology. There was also much less toxicity with erlotinib.

OPTIMAL is the first phase III prospective study demonstrating that erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is superior to standard platinum-based chemotherapy in Asian patients with EGFR mutation-positive non–small cell lung cancer (NSCLC).

Treatment with erlotinib more than doubled the objective response rate from 36% with chemotherapy to 83% (P less than .0001). The disease control rate also was superior at 96% vs. 82% (P = .002). Overall survival data were not available.

Subgroup analysis showed a consistent benefit with erlotinib regardless of histology, smoking history, age, sex, and disease stage, said Dr. Zhou, director of medical oncology at the Shanghai Pulmonary Hospital and of the Cancer Institute at Tongji University, Shanghai.

“A greater benefit was observed in patients with good performance status, indicating that Tarceva should be used as early as possible in this disease setting,” he told reporters at a press briefing.

Invited discussant Dr. Federico Cappuzzo said the 13-month progression-free survival is consistent with what has been observed in previous phase II erlotinib trials and seems better than results observed with gefitinib (Iressa), another EGFR inhibitor used first-line in this setting in some countries.

“Although these data could potentially suggest that erlotinib is superior to gefitinib, we don’t have a demonstration of that because we don’t have any trial directly comparing gefitinib with erlotinib and [that] therefore would allow us to conclude that one drug is superior to another,” he said.

At least four trials including the Iressa Pan-Asia Study (IPASS) have shown superior progression-free survival and response rates for gefitinib, compared with chemotherapy in Asian patients with EGFR-mutation–positive NSCLC. The problem for clinicians is the lack information on its efficacy, and that of erlotinib, in Caucasians, said Dr. Cappuzzo, director of medical oncology, Ospedale Civile-Livorno, Italy. EGFR mutations occur in about 40% of NSCLC patients from Asia, compared with about 10% of those in Western countries.

Two ongoing trials may address this knowledge gap: a single-arm study of gefitinib in Caucasians and the prospective phase III EURTAC trial evaluating the efficacy of erlotinib, compared with chemotherapy in patients in Spain, Italy, and France. The final results of EURTAC are expected next year, he said.

The first biomarker analysis from OPTIMAL also was presented at the meeting, and did not identify any additional markers (including c-MET amplification status) that predicted greater benefit with erlotinib. There was, however, a trend in the erlotinib arm for longer progression-free survival in patients with EGFR exon 19 deletions, compared with those with EGFR L858R mutations (15.3 months vs. 12.5 months, respectively, HR 0.58), reported Dr. Yi-long Wu from Guangdong General Hospital and Guangdong Academy of Medical Sciences in China.

“Exon 19 is probably the best predictor that we can use in our clinical practice,” Dr. Cappuzzo said.

OPTIMAL, also known as CTONG 0802, randomized 83 patients to receive erlotinib 150 mg per day until disease progression or unacceptable toxicity and 82 to receive gemcitabine/carboplatin administered in standard fashion for up to four cycles.

Erlotinib had less severe toxicity than chemotherapy (14 vs. 65 grade 3/4 events), except for skin rash, which was mostly mild or moderate in severity, Dr. Zhou reported.

Gefitinib is approved as first-line therapy in Europe and Asia for patients with EGFR-mutation-positive advanced NSCLC, but available only to selected patients in the United States under the Iressa Access Plan. Erlotinib is approved in the U.S. only as second- and third-line therapy for advanced NSCLC.

Roche Pharmaceutical Company China Ltd., sponsored the study. Dr. Zhou has received research grants and honoraria from F. Hoffman-La Roche Ltd., and Eli Lilly. Two co-investigators have received honoraria and served on the advisory boards of Roche and five other pharmaceutical companies.

MILAN – First-line erlotinib nearly tripled progression-free survival when compared with platinum-based chemotherapy in patients with advanced lung cancer carrying mutations activating the epidermal growth factor receptor.

Median progression-free survival in the randomized, phase III OPTIMAL trial from China reached 13.1 months in patients given erlotinib (Tarceva), compared with 4.6 months in those given gemcitabine (Gemzar) plus carboplatin chemotherapy (hazard ratio 0.16, P less than .0001).

After a median follow-up of 15.6 months, 31 patients on erlotinib are still on the study, compared with only one on chemotherapy, lead author Dr. Caicun Zhou reported in a late-breaking abstract at the 35th Congress of the European Society for Medical Oncology. There was also much less toxicity with erlotinib.

OPTIMAL is the first phase III prospective study demonstrating that erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is superior to standard platinum-based chemotherapy in Asian patients with EGFR mutation-positive non–small cell lung cancer (NSCLC).

Treatment with erlotinib more than doubled the objective response rate from 36% with chemotherapy to 83% (P less than .0001). The disease control rate also was superior at 96% vs. 82% (P = .002). Overall survival data were not available.

Subgroup analysis showed a consistent benefit with erlotinib regardless of histology, smoking history, age, sex, and disease stage, said Dr. Zhou, director of medical oncology at the Shanghai Pulmonary Hospital and of the Cancer Institute at Tongji University, Shanghai.

“A greater benefit was observed in patients with good performance status, indicating that Tarceva should be used as early as possible in this disease setting,” he told reporters at a press briefing.

Invited discussant Dr. Federico Cappuzzo said the 13-month progression-free survival is consistent with what has been observed in previous phase II erlotinib trials and seems better than results observed with gefitinib (Iressa), another EGFR inhibitor used first-line in this setting in some countries.

“Although these data could potentially suggest that erlotinib is superior to gefitinib, we don’t have a demonstration of that because we don’t have any trial directly comparing gefitinib with erlotinib and [that] therefore would allow us to conclude that one drug is superior to another,” he said.

At least four trials including the Iressa Pan-Asia Study (IPASS) have shown superior progression-free survival and response rates for gefitinib, compared with chemotherapy in Asian patients with EGFR-mutation–positive NSCLC. The problem for clinicians is the lack information on its efficacy, and that of erlotinib, in Caucasians, said Dr. Cappuzzo, director of medical oncology, Ospedale Civile-Livorno, Italy. EGFR mutations occur in about 40% of NSCLC patients from Asia, compared with about 10% of those in Western countries.

Two ongoing trials may address this knowledge gap: a single-arm study of gefitinib in Caucasians and the prospective phase III EURTAC trial evaluating the efficacy of erlotinib, compared with chemotherapy in patients in Spain, Italy, and France. The final results of EURTAC are expected next year, he said.

The first biomarker analysis from OPTIMAL also was presented at the meeting, and did not identify any additional markers (including c-MET amplification status) that predicted greater benefit with erlotinib. There was, however, a trend in the erlotinib arm for longer progression-free survival in patients with EGFR exon 19 deletions, compared with those with EGFR L858R mutations (15.3 months vs. 12.5 months, respectively, HR 0.58), reported Dr. Yi-long Wu from Guangdong General Hospital and Guangdong Academy of Medical Sciences in China.

“Exon 19 is probably the best predictor that we can use in our clinical practice,” Dr. Cappuzzo said.

OPTIMAL, also known as CTONG 0802, randomized 83 patients to receive erlotinib 150 mg per day until disease progression or unacceptable toxicity and 82 to receive gemcitabine/carboplatin administered in standard fashion for up to four cycles.

Erlotinib had less severe toxicity than chemotherapy (14 vs. 65 grade 3/4 events), except for skin rash, which was mostly mild or moderate in severity, Dr. Zhou reported.

Gefitinib is approved as first-line therapy in Europe and Asia for patients with EGFR-mutation-positive advanced NSCLC, but available only to selected patients in the United States under the Iressa Access Plan. Erlotinib is approved in the U.S. only as second- and third-line therapy for advanced NSCLC.

Roche Pharmaceutical Company China Ltd., sponsored the study. Dr. Zhou has received research grants and honoraria from F. Hoffman-La Roche Ltd., and Eli Lilly. Two co-investigators have received honoraria and served on the advisory boards of Roche and five other pharmaceutical companies.

MILAN – First-line erlotinib nearly tripled progression-free survival when compared with platinum-based chemotherapy in patients with advanced lung cancer carrying mutations activating the epidermal growth factor receptor.

Median progression-free survival in the randomized, phase III OPTIMAL trial from China reached 13.1 months in patients given erlotinib (Tarceva), compared with 4.6 months in those given gemcitabine (Gemzar) plus carboplatin chemotherapy (hazard ratio 0.16, P less than .0001).

After a median follow-up of 15.6 months, 31 patients on erlotinib are still on the study, compared with only one on chemotherapy, lead author Dr. Caicun Zhou reported in a late-breaking abstract at the 35th Congress of the European Society for Medical Oncology. There was also much less toxicity with erlotinib.

OPTIMAL is the first phase III prospective study demonstrating that erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is superior to standard platinum-based chemotherapy in Asian patients with EGFR mutation-positive non–small cell lung cancer (NSCLC).

Treatment with erlotinib more than doubled the objective response rate from 36% with chemotherapy to 83% (P less than .0001). The disease control rate also was superior at 96% vs. 82% (P = .002). Overall survival data were not available.

Subgroup analysis showed a consistent benefit with erlotinib regardless of histology, smoking history, age, sex, and disease stage, said Dr. Zhou, director of medical oncology at the Shanghai Pulmonary Hospital and of the Cancer Institute at Tongji University, Shanghai.

“A greater benefit was observed in patients with good performance status, indicating that Tarceva should be used as early as possible in this disease setting,” he told reporters at a press briefing.

Invited discussant Dr. Federico Cappuzzo said the 13-month progression-free survival is consistent with what has been observed in previous phase II erlotinib trials and seems better than results observed with gefitinib (Iressa), another EGFR inhibitor used first-line in this setting in some countries.

“Although these data could potentially suggest that erlotinib is superior to gefitinib, we don’t have a demonstration of that because we don’t have any trial directly comparing gefitinib with erlotinib and [that] therefore would allow us to conclude that one drug is superior to another,” he said.

At least four trials including the Iressa Pan-Asia Study (IPASS) have shown superior progression-free survival and response rates for gefitinib, compared with chemotherapy in Asian patients with EGFR-mutation–positive NSCLC. The problem for clinicians is the lack information on its efficacy, and that of erlotinib, in Caucasians, said Dr. Cappuzzo, director of medical oncology, Ospedale Civile-Livorno, Italy. EGFR mutations occur in about 40% of NSCLC patients from Asia, compared with about 10% of those in Western countries.

Two ongoing trials may address this knowledge gap: a single-arm study of gefitinib in Caucasians and the prospective phase III EURTAC trial evaluating the efficacy of erlotinib, compared with chemotherapy in patients in Spain, Italy, and France. The final results of EURTAC are expected next year, he said.

The first biomarker analysis from OPTIMAL also was presented at the meeting, and did not identify any additional markers (including c-MET amplification status) that predicted greater benefit with erlotinib. There was, however, a trend in the erlotinib arm for longer progression-free survival in patients with EGFR exon 19 deletions, compared with those with EGFR L858R mutations (15.3 months vs. 12.5 months, respectively, HR 0.58), reported Dr. Yi-long Wu from Guangdong General Hospital and Guangdong Academy of Medical Sciences in China.

“Exon 19 is probably the best predictor that we can use in our clinical practice,” Dr. Cappuzzo said.

OPTIMAL, also known as CTONG 0802, randomized 83 patients to receive erlotinib 150 mg per day until disease progression or unacceptable toxicity and 82 to receive gemcitabine/carboplatin administered in standard fashion for up to four cycles.

Erlotinib had less severe toxicity than chemotherapy (14 vs. 65 grade 3/4 events), except for skin rash, which was mostly mild or moderate in severity, Dr. Zhou reported.

Gefitinib is approved as first-line therapy in Europe and Asia for patients with EGFR-mutation-positive advanced NSCLC, but available only to selected patients in the United States under the Iressa Access Plan. Erlotinib is approved in the U.S. only as second- and third-line therapy for advanced NSCLC.

Roche Pharmaceutical Company China Ltd., sponsored the study. Dr. Zhou has received research grants and honoraria from F. Hoffman-La Roche Ltd., and Eli Lilly. Two co-investigators have received honoraria and served on the advisory boards of Roche and five other pharmaceutical companies.

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

When a handful of oncologists from competing institutions gathered their expertise and egos together in a joint effort to define appropriate care of patients with cancer, it wasn’t entirely clear the endeavor would work. Shared concerns about HMOs had brought them together in the mid 1990s, but they also vied for the same grants, philanthropic gifts, and patients.

Under the deft leadership of the late Dr. Roger J. Winn, the National Comprehensive Cancer Network (NCCN) has parlayed that first guideline, published in 1995, into the most widely used clinical practice guidelines in oncology. By the NCCN’s own account, the guidelines cover 97% of all patients with cancer. Last year alone, nearly 3.3 million PDF copies were downloaded, with select editions now available in 10 languages including Mandarin and Turkish.

The NCCN, which has seen its original budget increase from $2 million to a little more than $30 million, also successfully flexed its political muscle in recent months over the issue of risk evaluation and mitigation strategies (or REMs), and expanded its global reach through conferences in Beijing, Brazil, and Abu Dhabi.

Membership in the not-for-profit alliance was capped 2 years ago at 21 cancer centers in the United States. These member institutions fund the guidelines through dues and millions of dollars worth of free time, said Dr. David S. Ettinger, the Alex Grass professor of oncology at Johns Hopkins University, Baltimore, and chair of the NCCN’s non–small cell lung cancer and occult primary clinical practice panels.

“Fifteen years later, although there may still be some differences, the guidelines are as specific as you can get,” he said.

They also hold tremendous sway with public and private insurers, raising concerns over how they are being used and whether strict adherence can lead to “cookbook” medicine.

Insurers Base Coverage on Guidelines

The NCCN tracks and monitors guideline compliance for breast, colorectal, non-Hodgkin’s lymphoma, non–small cell lung cancer and, most recently, ovarian cancer, with compliance at about 90%-92% for recommendations with level 1 evidence and 85% overall, said NCCN chief executive officer William T. McGivney, Ph.D. For the remaining 15%, patient characteristics, patient preference, and physician disagreement with the guidelines will direct care. The transparency of the guidelines allows physicians to review the references, the category of evidence, and level of consensus, and decide on their own to use them or not, he said. Still, Dr. Ettinger acknowledges that treatment “decisions are made not wanting to fight insurance companies.”

The NCCN noticed early on that its guidelines were being used as the basis for setting coverage policy, prompting the creation in 2004 of the first NCCN Drugs and Biologics Compendium, Dr. McGivney said. The compendium is now used by such key stakeholders as the Centers for Medicare and Medicaid Services and UnitedHealthcare Inc., one of the nation’s largest private insurers.

“On the private side, you see payers basically saying “If it’s in the NCCN Compendium, it’s covered,’ which is critically important for clinicians and patients,” he said. “We have tremendous influence and collaborative influence I think, with payers.”

If a physician uses a drug covered by the compendium to treat any of the 20,000 patients UnitedHealthcare (UHC) has on active chemotherapy in any given year, the drug is automatically covered, said Dr. Lee N. Newcomer, senior vice president, oncology, for the Minnesota-based insurer. Cases involving drugs not covered by the compendium are reviewed by a medical director who looks at state laws and regulations and the employer’s specific requirements. If an employer requires that any chemotherapy recommended by a physician is covered, then the drug would be covered by UHC, even if it’s not in the compendium, he said.

Prior to UHC’s adopting the compendium, 15% of treatments given by its oncologists didn’t match NCCN recommendations. “I would argue that this was both waste and exposing patients to toxicity and drugs that wouldn’t help them,” said Dr. Newcomer, adding that noncompliance is now less than 1%.

Oncologists Rated on Quality of Care

Earlier this year, UHC unveiled the Oncology Care Analysis program that uses clinical and claims data from about 2,600 oncologists and 14,000 patients from across the country with breast, colon and lung cancer to gauge quality of care based on adherence to NCCN guidelines. Oncologists receive a report showing their individual results along with aggregate national results.

Dr. Newcomer dismisses concerns that the program could pressure oncologists into making treatment decisions based on their standing with UHC rather than the best choice for patients who don’t fit the guidelines because such patients are excluded from the analysis. Moreover, there are no financial incentives or penalties associated with the program. “UHC has always emphasized that the information is for quality improvement,” he said. “We let physicians decide how to act on the information.”

The first pass at the data shows that compliance with the NCCN guidelines is stronger in the treatment of breast than colon or lung cancer, but also that about one-third of breast cancer patients prescribed tamoxifen or an aromatase inhibitor aren’t renewing their prescriptions. “We can bring that information back to the physician, and they can have a discussion with their patient about why they aren’t taking that medicine,” he said.

Feedback from physicians has also identified coding problems for carcinoid tumors of the colon and disagreement over whether bevacizumab (Avastin) is truly contraindicated in patients with lung cancer and brain metastases. UHC shares these concerns, along with the national aggregate data, with the NCCN.

Dr. Eric P. Winer, director of the Breast Oncology Center at the Dana-Farber Cancer Institute in Boston and chief scientific adviser for Susan G. Komen for the Cure, said that of all the guidelines to use, the NCCN guidelines make the most sense, but that oncologists would hear and listen more closely to the message that their practice is out of line if it were delivered by a state or national accreditation program.

“The practicing physician is less likely to trust that the insurer has a clear understanding of what the optimal practice would be,” he said. “It’s just not a credible source in the way that a committee of one’s peers might be.”

Dr. Newcomer said he’d love to see other groups take on the task but has not seen similar published quality data coming out of medical groups. “We are filling a void that’s there,” he said.

Is the Fast Lane Too Broad?

Dr. Ira Klein, clinical head of oncology condition analysis for Aetna Inc., said it doesn’t rely exclusively on the NCCN for the development of guidelines and payment. Aetna has covered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater but looks to a variety of sources including top-tier journals and outside opinions when creating guidelines and their clinical practice policy bulletins.

“Relying solely on the NCCN would be like using the Cliff Notes,” he said.

Dr. Klein went on to say that the strength of the NCCN guidelines is that they are evidence based and very good at bringing experts together for consensus-based care when the evidence isn’t particularly strong. Their weakness is that they “could be likened to a 50-lane highway” in cases where multiple treatment options would be appropriate for one disease at one stage, Dr. Klein said.

Dr. Newcomer echoed this sentiment, faulting the NCCN for not assigning a hierarchy to its decisions. He cited the array of recommended chemotherapy regimens for breast cancer, and said, “Where I’d like to see the NCCN guidelines go is to say that of these 14, these 2 are the best.”

Still, both insurers are looking to the NCCN regarding coverage of bevacizumab, following the FDA’s Oncologic Drugs Advisory Committee July vote recommending against its use for the first-line treatment of metastatic breast cancer. Dr. Newcomer said UHC will continue to cover the drug for this indication until the NCCN makes its recommendation following the FDA’s final vote. Dr. Klein said if the FDA removes breast cancer as an indication for bevacizumab, Aetna would consider dropping its existing coverage for the drug and would take the NCCN’s position into consideration in its decision.

The speed at which the NCCN can make such a revision to its guidelines is part of what makes them so unusual. “They are assiduously up to date,” Dr. McGivney said. Staff members track the literature, news of large clinical trials, and FDA filings in order to stay abreast of changes in the evidence, with some 2010 guidelines already in their third or fourth edition.

“We really are in the information age and, of all the areas of medicine, cancer care is probably the most rapidly advancing with respect to the science and research,” he said.

This point was driven home when the American Society of Clinical Oncology (ASCO) published guidelines for stage IV non–small cell lung cancer earlier this year without encompassing emerging data on the importance of epidermal growth factor receptor mutations in treatment response.

“The advantage of systematic review-based guidelines like ASCO uses is that they are more evidence-based, strictly speaking, but take longer to conduct and require methodological expertise,” said Dr. Ethan M. Basch, chair of ASCO’s clinical practice guidelines committee. “The advantage of narrative review with consensus-based guidelines such as used by NCCN is that they can be conducted more rapidly, but are less evidence-based in terms of their degree of systematic approach and hence may be more subject to the biases of panel members.”

INDIANAPOLIS – A retrospective analysis has shed some light on the prevalence of carotid artery stent fracture, but ultimately underscores how little is known about the durability of carotid stents.

No accepted standard currently exists for carotid artery stent surveillance specific to fracture identification. In addition, the etiology of these fractures is unknown, as is their clinical relevance, Dr. Anthony Nigliazzo said at the annual meeting of the Midwestern Vascular Surgical Society.

He presented a retrospective analysis of 91 patients who received 107 carotid artery stents from January 2002 through December 2009 at the Michigan Vascular Center in Flint, a group that has significant carotid artery stenting (CAS) experience, including 14 CAS trials.

Two vascular surgeons and two radiologists independently reviewed anteroposterior and lateral cervical x-rays taken at a median follow-up of 28 months to evaluate for stent fractures. Because the reviewers did not all agree, a peer review consensus conference was held to determine whether fractures had occurred, Dr. Nigliazzo explained. Information from duplex ultrasounds obtained at 30 days, 6 months, and 1 year was also used to determine flow velocities and to correlate with a fracture diagnosis.

“We found this was a very difficult thing to do, not only in diagnosing stent fractures, but we really didn’t find a good correlation between our ultrasound findings and those patients” who developed fracture, he said.

Ultimately, the experts agreed that 4 of the 107 stents (3.7%) were fractured. Only one of the fractures had any evidence of restenosis, and none had clinical sequelae or were symptomatic at the time of identification.

When the team asked outside expert Dr. Michael Dake, a pioneer in endovascular stent development from Stanford (Calif.) University Medical Center, to review the same films, however, the fracture rate reached 7.7% for the 91 patients and 107 stents.

Overall, Dr. Nigliazzo said that the prevalence of carotid artery stent fracture appears to be low, but added that “the true incidence of stent fracture remains elusive.”

Part of the difficulty in making the diagnosis is that some fractures could not be seen on certain x-ray projections, and many stents had significant deformities. One such deformity – called “fish scaling,” in which layers of an open-cell stent protrude – make it appear that a fracture is present when it is not. Although vessel angulation greater than 45 degrees and calcification have been identified as risk factors for stent fracture, this was not apparent in the analysis, said Dr. Nigliazzo, a senior resident with the department of surgery at Michigan State University in Flint.

He noted that reported prevalence rates of carotid stent fracture vary widely, from 1.9% to 29%. “We believe this magnifies the difficulty in identifying stent fractures and the different modalities that investigators are using,” he said.

The researchers, led by Dr. Robert G. Molnar, who is with the Michigan Vascular Center and is chief of vascular surgery at McLaren Regional Medical Center, also in Flint, called for further research to determine the ideal methods for long-term CAS surveillance. For the time being, they recommended obtaining anteroposterior/lateral and oblique images for poststent fracture surveillance. One attendee cautioned that this type of surveillance may be “overkill” until it’s known whether clinical sequelae are associated with stent fracture.

Dr. Nigliazzo responded that the argument can go both ways, and highlighted a recent prospective Italian study reporting that stent fracture was significantly associated with restenosis (J. Vasc. Surg. 2010;51:1397-405).

Limitations of the current study include its retrospective design, the analysis of only 33% of the 272 patients who received stents during the study period, and the fact that x-ray quality varied with patient anatomy, calcifications, and angulation.

The cohort had a mean age of 71.6 years and was mostly male (61%). Overall, 45% had received a carotid stent after carotid endarterectomy whereas 15% did so after radiation. Only 4% were classified as low risk according to entry criteria for the CREST and CARESS trials.

The study was funded by the McLaren Foundation and the Michigan Vascular Center. The authors reported no conflicts of interest.

INDIANAPOLIS – A retrospective analysis has shed some light on the prevalence of carotid artery stent fracture, but ultimately underscores how little is known about the durability of carotid stents.

No accepted standard currently exists for carotid artery stent surveillance specific to fracture identification. In addition, the etiology of these fractures is unknown, as is their clinical relevance, Dr. Anthony Nigliazzo said at the annual meeting of the Midwestern Vascular Surgical Society.

He presented a retrospective analysis of 91 patients who received 107 carotid artery stents from January 2002 through December 2009 at the Michigan Vascular Center in Flint, a group that has significant carotid artery stenting (CAS) experience, including 14 CAS trials.

Two vascular surgeons and two radiologists independently reviewed anteroposterior and lateral cervical x-rays taken at a median follow-up of 28 months to evaluate for stent fractures. Because the reviewers did not all agree, a peer review consensus conference was held to determine whether fractures had occurred, Dr. Nigliazzo explained. Information from duplex ultrasounds obtained at 30 days, 6 months, and 1 year was also used to determine flow velocities and to correlate with a fracture diagnosis.

“We found this was a very difficult thing to do, not only in diagnosing stent fractures, but we really didn’t find a good correlation between our ultrasound findings and those patients” who developed fracture, he said.

Ultimately, the experts agreed that 4 of the 107 stents (3.7%) were fractured. Only one of the fractures had any evidence of restenosis, and none had clinical sequelae or were symptomatic at the time of identification.

When the team asked outside expert Dr. Michael Dake, a pioneer in endovascular stent development from Stanford (Calif.) University Medical Center, to review the same films, however, the fracture rate reached 7.7% for the 91 patients and 107 stents.

Overall, Dr. Nigliazzo said that the prevalence of carotid artery stent fracture appears to be low, but added that “the true incidence of stent fracture remains elusive.”

Part of the difficulty in making the diagnosis is that some fractures could not be seen on certain x-ray projections, and many stents had significant deformities. One such deformity – called “fish scaling,” in which layers of an open-cell stent protrude – make it appear that a fracture is present when it is not. Although vessel angulation greater than 45 degrees and calcification have been identified as risk factors for stent fracture, this was not apparent in the analysis, said Dr. Nigliazzo, a senior resident with the department of surgery at Michigan State University in Flint.

He noted that reported prevalence rates of carotid stent fracture vary widely, from 1.9% to 29%. “We believe this magnifies the difficulty in identifying stent fractures and the different modalities that investigators are using,” he said.

The researchers, led by Dr. Robert G. Molnar, who is with the Michigan Vascular Center and is chief of vascular surgery at McLaren Regional Medical Center, also in Flint, called for further research to determine the ideal methods for long-term CAS surveillance. For the time being, they recommended obtaining anteroposterior/lateral and oblique images for poststent fracture surveillance. One attendee cautioned that this type of surveillance may be “overkill” until it’s known whether clinical sequelae are associated with stent fracture.

Dr. Nigliazzo responded that the argument can go both ways, and highlighted a recent prospective Italian study reporting that stent fracture was significantly associated with restenosis (J. Vasc. Surg. 2010;51:1397-405).

Limitations of the current study include its retrospective design, the analysis of only 33% of the 272 patients who received stents during the study period, and the fact that x-ray quality varied with patient anatomy, calcifications, and angulation.

The cohort had a mean age of 71.6 years and was mostly male (61%). Overall, 45% had received a carotid stent after carotid endarterectomy whereas 15% did so after radiation. Only 4% were classified as low risk according to entry criteria for the CREST and CARESS trials.

The study was funded by the McLaren Foundation and the Michigan Vascular Center. The authors reported no conflicts of interest.

INDIANAPOLIS – A retrospective analysis has shed some light on the prevalence of carotid artery stent fracture, but ultimately underscores how little is known about the durability of carotid stents.

No accepted standard currently exists for carotid artery stent surveillance specific to fracture identification. In addition, the etiology of these fractures is unknown, as is their clinical relevance, Dr. Anthony Nigliazzo said at the annual meeting of the Midwestern Vascular Surgical Society.

He presented a retrospective analysis of 91 patients who received 107 carotid artery stents from January 2002 through December 2009 at the Michigan Vascular Center in Flint, a group that has significant carotid artery stenting (CAS) experience, including 14 CAS trials.

Two vascular surgeons and two radiologists independently reviewed anteroposterior and lateral cervical x-rays taken at a median follow-up of 28 months to evaluate for stent fractures. Because the reviewers did not all agree, a peer review consensus conference was held to determine whether fractures had occurred, Dr. Nigliazzo explained. Information from duplex ultrasounds obtained at 30 days, 6 months, and 1 year was also used to determine flow velocities and to correlate with a fracture diagnosis.

“We found this was a very difficult thing to do, not only in diagnosing stent fractures, but we really didn’t find a good correlation between our ultrasound findings and those patients” who developed fracture, he said.

Ultimately, the experts agreed that 4 of the 107 stents (3.7%) were fractured. Only one of the fractures had any evidence of restenosis, and none had clinical sequelae or were symptomatic at the time of identification.

When the team asked outside expert Dr. Michael Dake, a pioneer in endovascular stent development from Stanford (Calif.) University Medical Center, to review the same films, however, the fracture rate reached 7.7% for the 91 patients and 107 stents.

Overall, Dr. Nigliazzo said that the prevalence of carotid artery stent fracture appears to be low, but added that “the true incidence of stent fracture remains elusive.”

Part of the difficulty in making the diagnosis is that some fractures could not be seen on certain x-ray projections, and many stents had significant deformities. One such deformity – called “fish scaling,” in which layers of an open-cell stent protrude – make it appear that a fracture is present when it is not. Although vessel angulation greater than 45 degrees and calcification have been identified as risk factors for stent fracture, this was not apparent in the analysis, said Dr. Nigliazzo, a senior resident with the department of surgery at Michigan State University in Flint.

He noted that reported prevalence rates of carotid stent fracture vary widely, from 1.9% to 29%. “We believe this magnifies the difficulty in identifying stent fractures and the different modalities that investigators are using,” he said.

The researchers, led by Dr. Robert G. Molnar, who is with the Michigan Vascular Center and is chief of vascular surgery at McLaren Regional Medical Center, also in Flint, called for further research to determine the ideal methods for long-term CAS surveillance. For the time being, they recommended obtaining anteroposterior/lateral and oblique images for poststent fracture surveillance. One attendee cautioned that this type of surveillance may be “overkill” until it’s known whether clinical sequelae are associated with stent fracture.

Dr. Nigliazzo responded that the argument can go both ways, and highlighted a recent prospective Italian study reporting that stent fracture was significantly associated with restenosis (J. Vasc. Surg. 2010;51:1397-405).

Limitations of the current study include its retrospective design, the analysis of only 33% of the 272 patients who received stents during the study period, and the fact that x-ray quality varied with patient anatomy, calcifications, and angulation.

The cohort had a mean age of 71.6 years and was mostly male (61%). Overall, 45% had received a carotid stent after carotid endarterectomy whereas 15% did so after radiation. Only 4% were classified as low risk according to entry criteria for the CREST and CARESS trials.

The study was funded by the McLaren Foundation and the Michigan Vascular Center. The authors reported no conflicts of interest.

INDIANAPOLIS – Analyzing myofibers obtained from muscle biopsies of patients with peripheral arterial disease may provide objective criteria to diagnose disease and determine its severity, a study has shown.

Researchers collected needle biopsies of the gastrocnemius muscle from 20 patients with peripheral arterial disease (PAD) with claudication, 19 patients with PAD and critical limb ischemia, and 20 controls. Individual myofibers in the samples were partitioned using image-processing algorithms.

Morphologic deterioration of myofibers in the ischemic muscle is closely linked to limb dysfunction in PAD, Dr. Dimitrios Miserlis explained at the meeting. Previous studies have used morphologic analyses of PAD muscle, but they have been largely qualitative and included very limited quantitative information.

A team of vascular surgeons, biologic imaging specialists, and biologic systems engineers from the University of Nebraska in Omaha and in Lincoln are developing a highly quantitative morphologic analysis of PAD myofibers. Using data from 31 patients, they tested 96 morphometric parameters and identified 8 that objectively define the myopathic changes in PAD muscle.

Combinations of these parameters in a two-stage mathematical model were able to discriminate healthy controls from PAD patients, and claudicating patients from patients with critical limb ischemia, said Dr. Miserlis of the department of surgery at the University of Nebraska Medical Center in Omaha.

“Our findings are correlated with the clinical picture,” he said.

Based on the first 31 patients, the 5 morphometric parameters used in the first stage of the model were variation in major axis [length], variation in solidity, variation in roundness, solidity, and fiber density.

Then in the remaining 28 participants, the model was able to identify all 19 controls and claudicating patients (100% accuracy) and 8 of 9 patients with critical limb ischemia (89% accuracy), for an overall accuracy of 96.4%, he said.

The second stage of the model used the morphometric parameters of variation in eccentricity, variation in minor axis (width), variation in solidity, variation in roundness, and average roundness. Among the same 28 participants, the model was able to identify 7 of 10 controls (70% accuracy), 8 of 9 claudicating patients (89% accuracy), and 8 of 9 critical limb ischemia patients (89% accuracy), for an overall accuracy of 82%.

The study proves that morphometrics can be developed into mathematical equations that categorize PAD patients according to degree of damage in their ischemic limb, Dr. Miserlis said. Each of these categories of damage can be targeted for biochemical analysis, providing precisely determined biochemical signatures of PAD initiation and disease progression.

This is important because “biochemical signatures may be used to direct and assess stage-specific therapeutic interventions,” he said.

The investigators, who continue to refine the model, believe that most fibers exhibiting these abnormal morphologic characteristics may be reparable with appropriate therapy, and they plan to evaluate this possibility in the near future. The study was led by coprincipal investigators George Casale, Ph.D.; Jeyamkondan Subbiah, Ph.D.; and Dr. Iraklis Pipinos.

Dr. Miserlis is supported by a scholarship from the Propondis Foundation. His colleagues received awards from the National Heart, Lung, and Blood Institute; the American Vascular Association; and the University of Nebraska.

INDIANAPOLIS – Analyzing myofibers obtained from muscle biopsies of patients with peripheral arterial disease may provide objective criteria to diagnose disease and determine its severity, a study has shown.

Researchers collected needle biopsies of the gastrocnemius muscle from 20 patients with peripheral arterial disease (PAD) with claudication, 19 patients with PAD and critical limb ischemia, and 20 controls. Individual myofibers in the samples were partitioned using image-processing algorithms.

Morphologic deterioration of myofibers in the ischemic muscle is closely linked to limb dysfunction in PAD, Dr. Dimitrios Miserlis explained at the meeting. Previous studies have used morphologic analyses of PAD muscle, but they have been largely qualitative and included very limited quantitative information.

A team of vascular surgeons, biologic imaging specialists, and biologic systems engineers from the University of Nebraska in Omaha and in Lincoln are developing a highly quantitative morphologic analysis of PAD myofibers. Using data from 31 patients, they tested 96 morphometric parameters and identified 8 that objectively define the myopathic changes in PAD muscle.

Combinations of these parameters in a two-stage mathematical model were able to discriminate healthy controls from PAD patients, and claudicating patients from patients with critical limb ischemia, said Dr. Miserlis of the department of surgery at the University of Nebraska Medical Center in Omaha.

“Our findings are correlated with the clinical picture,” he said.

Based on the first 31 patients, the 5 morphometric parameters used in the first stage of the model were variation in major axis [length], variation in solidity, variation in roundness, solidity, and fiber density.

Then in the remaining 28 participants, the model was able to identify all 19 controls and claudicating patients (100% accuracy) and 8 of 9 patients with critical limb ischemia (89% accuracy), for an overall accuracy of 96.4%, he said.

The second stage of the model used the morphometric parameters of variation in eccentricity, variation in minor axis (width), variation in solidity, variation in roundness, and average roundness. Among the same 28 participants, the model was able to identify 7 of 10 controls (70% accuracy), 8 of 9 claudicating patients (89% accuracy), and 8 of 9 critical limb ischemia patients (89% accuracy), for an overall accuracy of 82%.

The study proves that morphometrics can be developed into mathematical equations that categorize PAD patients according to degree of damage in their ischemic limb, Dr. Miserlis said. Each of these categories of damage can be targeted for biochemical analysis, providing precisely determined biochemical signatures of PAD initiation and disease progression.

This is important because “biochemical signatures may be used to direct and assess stage-specific therapeutic interventions,” he said.

The investigators, who continue to refine the model, believe that most fibers exhibiting these abnormal morphologic characteristics may be reparable with appropriate therapy, and they plan to evaluate this possibility in the near future. The study was led by coprincipal investigators George Casale, Ph.D.; Jeyamkondan Subbiah, Ph.D.; and Dr. Iraklis Pipinos.

Dr. Miserlis is supported by a scholarship from the Propondis Foundation. His colleagues received awards from the National Heart, Lung, and Blood Institute; the American Vascular Association; and the University of Nebraska.

INDIANAPOLIS – Analyzing myofibers obtained from muscle biopsies of patients with peripheral arterial disease may provide objective criteria to diagnose disease and determine its severity, a study has shown.

Researchers collected needle biopsies of the gastrocnemius muscle from 20 patients with peripheral arterial disease (PAD) with claudication, 19 patients with PAD and critical limb ischemia, and 20 controls. Individual myofibers in the samples were partitioned using image-processing algorithms.

Morphologic deterioration of myofibers in the ischemic muscle is closely linked to limb dysfunction in PAD, Dr. Dimitrios Miserlis explained at the meeting. Previous studies have used morphologic analyses of PAD muscle, but they have been largely qualitative and included very limited quantitative information.

A team of vascular surgeons, biologic imaging specialists, and biologic systems engineers from the University of Nebraska in Omaha and in Lincoln are developing a highly quantitative morphologic analysis of PAD myofibers. Using data from 31 patients, they tested 96 morphometric parameters and identified 8 that objectively define the myopathic changes in PAD muscle.

Combinations of these parameters in a two-stage mathematical model were able to discriminate healthy controls from PAD patients, and claudicating patients from patients with critical limb ischemia, said Dr. Miserlis of the department of surgery at the University of Nebraska Medical Center in Omaha.

“Our findings are correlated with the clinical picture,” he said.

Based on the first 31 patients, the 5 morphometric parameters used in the first stage of the model were variation in major axis [length], variation in solidity, variation in roundness, solidity, and fiber density.

Then in the remaining 28 participants, the model was able to identify all 19 controls and claudicating patients (100% accuracy) and 8 of 9 patients with critical limb ischemia (89% accuracy), for an overall accuracy of 96.4%, he said.

The second stage of the model used the morphometric parameters of variation in eccentricity, variation in minor axis (width), variation in solidity, variation in roundness, and average roundness. Among the same 28 participants, the model was able to identify 7 of 10 controls (70% accuracy), 8 of 9 claudicating patients (89% accuracy), and 8 of 9 critical limb ischemia patients (89% accuracy), for an overall accuracy of 82%.

The study proves that morphometrics can be developed into mathematical equations that categorize PAD patients according to degree of damage in their ischemic limb, Dr. Miserlis said. Each of these categories of damage can be targeted for biochemical analysis, providing precisely determined biochemical signatures of PAD initiation and disease progression.

This is important because “biochemical signatures may be used to direct and assess stage-specific therapeutic interventions,” he said.

The investigators, who continue to refine the model, believe that most fibers exhibiting these abnormal morphologic characteristics may be reparable with appropriate therapy, and they plan to evaluate this possibility in the near future. The study was led by coprincipal investigators George Casale, Ph.D.; Jeyamkondan Subbiah, Ph.D.; and Dr. Iraklis Pipinos.

Dr. Miserlis is supported by a scholarship from the Propondis Foundation. His colleagues received awards from the National Heart, Lung, and Blood Institute; the American Vascular Association; and the University of Nebraska.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.

Major Finding: INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

Data Source: A retrospective analysis of children in the International Neuroblastoma Risk Group database.

Disclosures: The study was supported by the Little Heroes Pediatric Cancer Research Foundation, the Forbeck Foundation, and a grant from the National Institutes of Health. Dr. London and her associates reported no conflicts of interest.

CHICAGO — Time to relapse is highly predictive of overall survival post relapse in children with neuroblastoma, according to an analysis of 2,266 children in the International Neuroblastoma Risk Group database.

The analysis identified other factors prognostic of overall survival post relapse as well as a small proportion of relapsed patients who are salvageable, Wendy B. London, Ph.D., reported at the meeting.

Currently, clinicians do not know how to identify which patients are more likely to respond to postrelapse therapy and have difficulty in interpreting time to relapse because neuroblastoma is a heterogeneous disease, she said.

The median time to relapse among the 2,266 children was 13.2 months, with a wide range from 1 day to 11.4 years.

All told, 73% of children who relapsed were aged 18 months or older, 72% were International Neuroblastoma Staging System (INSS) stage 4, and 33% had amplified MYCN oncogene expression.

Overall survival at 5 years was 20%.

It was not possible to categorize time to relapse using a simple 1-year cutoff, said Dr. London, director of biostatistics at Children's Hospital Boston.

The risk of death was about the same for children who relapsed within the first 6 months as it was for those who relapsed at 18-24 months. The risk of death was highest in those who relapsed between 6 and 18 months.

All three groups had a significantly higher risk of death, compared with patients who relapsed after 36 months (P less than .001).

The association between time to relapse and overall survival appears to be driven by stage 3, 4, and MYCN-amplified patients, Dr. London said.

In a survival tree regression analysis that adjusted for time to relapse, disease stage was identified as the most highly significant variable for survival post relapse. INSS stage 4 patients had a 5-year survival of 8%, compared with 52% for those who were stage 1, 2, 3, or 4S.

“Aggressive disease that advances unhindered by treatment has a highly predictable time course and ultimate death; we already knew this, but now we're able to describe it quantitatively,” she said.

Upon further analysis, three cohorts emerged as salvageable after relapse:

▸ Patients who are stage 4, with nonamplified MYCN, and less than 18 months of age.

▸ Patients who are stage 1, 2, 3, or 4S with MYCN amplification.

▸ Patients who are stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4%, compared with 12% for stage 4 patients with nonamplified MYCN.

Time to first relapse as a predictor of survival is important for two reasons, said Dr. Andrew Pearson, chair of pediatric oncology at the Institute of Cancer Research and the Royal Marsden Hospital in London, who was invited to discuss the findings. It can be used to stratify and/or describe patients in early clinical trials and to identify a salvageable population post relapse.

“In the past, I'm sure that some agents have had a negative response in early clinical studies because a group of very poor prognosis patients were included,” he said.

The study findings will also be utilized by the International Neuroblastoma Risk Group, which is nearing completion of standardized international criteria for eligibility and response for phase II studies in neuroblastoma, he said.

In multivariable analysis, factors at diagnosis that were independently predictive of overall survival post relapse were stage 4 (hazard ratio, 6.9); stage 3 (HR, 4.3); stage 4S (HR, 3.5); MYCN amplification (HR, 2.4); age less than 18 months (HR, 1.6); and time to relapse less than 12 months (HR, 2.0) – all with a P value less than 0.0001, Dr. London said.

Time to relapse was predictive of survival post relapse in patients with stage 1, stage 2, or no MYCN amplification, but it was not independently predictive, she said.

My Take

Time to Relapse Useful for Determining Trial Eligibility

The observation that time to relapse predicts survival in neuroblastoma is made possible by the analysis of a large international collaborative database. Given the unique biology of neuroblastoma and the extreme clinical heterogeneity that impacts its natural history despite therapy and initial response to therapy, this finding will be important as new agents become available for investigation in this disease and especially when nontraditional end points such as time to progression and progression-free survival are considered.

In addition, refining and enriching patient populations for some degree of biological homogeneity is important, not only for the purpose of accurately defining activity of a specific investigational agent in this specific disease, but also for potentially identifying a group of patients with relapsed disease who may be candidates for more conventional or standard salvage therapy approaches. This will also aid in defining eligibility criteria and estimating accrual requirements for investigational approaches.

Vitals

GREGORY H. REAMAN, M.D., is chair of the United States–based Children's Oncology Group. He is also a professor of pediatrics at George Washington University School of Medicine and Health and member of the Division of Hematology-Oncology at the Children's National Medical Center, both in Washington.