User login
ACC/AHA Performance Measures Developed for Peripheral Artery Disease
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ACC/AHA Performance Measures Developed for Peripheral Artery Disease
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
In new diagnostic and treatment recommendations for peripheral artery disease, the American College of Cardiology Foundation and the American Heart Association have endeavored to eliminate a wide disparity of care in these patients who are often undiagnosed or undertreated.
In the document, the consensus of a writing committee of pertinent specialties tasked to provide performance measures for the disease, peripheral artery disease (PAD) was defined as lower extremity and abdominal aortic disease caused by atherosclerotic vascular disease. Treatment measures were developed on the basis of class I evidence and were designed to be achievable by any physician, advanced practice nurse, practice, or health care system, according to the final report to be published in the Dec. 14/21 issue of the Journal of the American College of Cardiology (J. Am. Coll. Cardiol. 2010;56:2147-81) and simultaneously in several other publications representing partners on the writing committee.
The prevalence of PAD is approximately 12% of the adult population, with men slightly more affected than women, according to the report. Above age 70 years, almost 20% of individuals have PAD. The disease often is undiagnosed because up to 50% of patients present with atypical symptoms or no symptoms at all.
For this reason, the committee was especially concerned that ankle brachial index (ABI) measurements should be performed on all patients at risk for PAD regardless of whether they have symptoms. They recognized that reimbursement for ABI in the office setting is incomplete and that performing the test would "add a burden to busy primary care physicians," according to the report, but still concluded that it was justified.
The ABI is measured with a handheld continuous wave Doppler ultrasound device and a blood pressure cuff. An ABI measurement of less than 0.90 is considered diagnostic of PAD.
"Patients with peripheral artery disease have the highest rate of heart attacks, stroke, and cardiovascular disease – higher than people with coronary artery disease – yet they remain undertreated," Dr. Jeffrey W. Olin, professor of medicine at Mount Sinai School of Medicine, New York, and chair of the writing committee, said in a published statement on the report.
As far as treatment, the committee was critical of current practice, especially among primary care physicians. "Studies have found that people with PAD are up to six times more likely to die of heart disease, compared to matched controls," but even when PAD is diagnosed, "many health care providers will often just treat the leg symptoms ... and not the heart-related risks," according to the statement.
A major goal of the guidelines is to induce practitioners to move to appropriate therapy for PAD patients once they are diagnosed, not only to improve their ability to walk further and faster without pain, but also to "lower the rate of heart attack, stroke, and death from cardiovascular disease."
Such treatment recommendations included in the measures are:
• Statin therapy to lower LDL cholesterol to less than 100 mg/dL.
• Smoking cessation intervention.
• Antiplatelet therapy with aspirin or clopidogrel for patients with a history of symptomatic PAD.
• Supervised exercise programs for patients with claudication.
• Monitoring of any existent abdominal aortic aneurysm and/or lower extremity vein bypass grafting.
The writing committee envisions that the published performance measures will be used by the Centers for Medicare and Medicaid Services and other third-party payers to assess each individual physician caring for patients with PAD.
Along with the American College of Cardiology and the American Heart Association, the Peripheral Artery Disease Performance Measures Writing Committee included representatives from the Society for Cardiac Angiography and Interventions, the American College of Radiology, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery, among others.
Dr. Olin has consulted for Genzyme, Merck, and the Sanofi/BMS partnership. Members of the writing committee had various industrial relationships but were recused from voting on recommendations for which they were deemed to have conflicts. A complete list of their disclosures is provided in each of the published versions of the report.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Below-the-Ankle Angioplasty Examined
Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.
In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.
Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.
Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).
Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.
Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.
Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years’ follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.
Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel vs. 7 months in the case of distal occlusion – a significant difference, Dr. Katsanos said.
He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.
"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).
"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.
Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.
In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.
Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.
Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).
Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.
Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.
Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years’ follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.
Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel vs. 7 months in the case of distal occlusion – a significant difference, Dr. Katsanos said.
He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.
"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).
"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.
Traditional dogma states that the primary goal of infrapopliteal revascularization is the restoration of at least one straight line of pulsatile blood flow to the distal foot to reperfuse the ischemic tissue.
In diabetic patients, obstructive lesions tend to be located in the distal tibial arteries at the malleolus level and might extend below the ankle and involve the dorsalis pedis and plantar arteries. As a result, distal bypass can be technically challenging or even impossible to perform, mainly because there is no appropriate healthy vascular segment for distal anastomosis, according to Dr. Konstantinos Katsanos.
Because patency outcomes after angioplasty of the femoral artery are negatively affected by compromised and/or poor tibial runoff, infrapopliteal and distal outflow lesions must be treated accordingly. Published data regarding angioplasty or stenting of the arteries below the ankle are scarce, noted Dr. Katsanos at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
He reported on the feasibility of percutaneous angioplasty and optional bail-out stenting of distal below-the-ankle arterial occlusive disease in patients with critical limb ischemia.
Dr. Katsanos, a lecturer of radiology at the department of radiology, Patras University Hospital, Rio, Greece, and his colleagues evaluated the long-term angiographic and clinical results of such interventions based on a retrospective analysis of 17 patients who underwent infrapopliteal endovascular procedures, including angioplasty and optional bailout stenting of the dorsalis pedis and/or the plantar arteries (20 lesions in 19 limbs).
Most patients (82%) were diabetic, and most had ischemic ulcers and tissue loss. About 75% of the lesions were calcified, and 40% were initial total occlusions.
Ultralow-profile 2.0- to 2.5-mm wide and 0.014-inch over-the-wire compatible long balloon platforms were applied. In 55% of the lesions, adjunctive bail-out stenting with balloon-expandable drug-eluting stents was also performed.
Results were encouraging: a cumulative limb salvage rate of 88% at up to 4 years’ follow-up and just two major amputations. Repeat angioplasty was needed in five cases (29%) because of recurrent symptoms.
Dr. Katsanos and his colleagues also evaluated stent integrity with x-ray imaging during regular follow-up and found four deformed and/or collapsed stents and one severe stent fracture. Primary patency of the distal below-the-ankle outflow lesion was significantly, positively correlated with sustained patency of the proximal infrapopliteal lesion. Median infrapopliteal primary patency was 14 months in the case of a patent runoff vessel vs. 7 months in the case of distal occlusion – a significant difference, Dr. Katsanos said.
He discussed the safety and feasibility of below-the-ankle angioplasty for limb salvage and the improved outflow runoff, which was associated with better patency rates of the proximally treated lesions.
"According to our findings, below-the-ankle placement of balloon-expandable stents should only be reserved for bailout in exceptional cases of suboptimal postangioplasty results because of the superficial anatomical location [which renders] them highly susceptible to external compression and occlusion (almost half of the stented cases in our series).
"Previous studies from our center have also shown increased stent deformity of balloon-expandable stents placed in the distal third of the anterior tibial artery. Therefore, if it is deemed necessary, we would generally recommend using self-expanding stents at the malleolar and inframalleolar level of the tibial vasculature," Dr. Katsanos said in an interview.
FROM THE VEITH SYMPOSIUM ON VASCULAR MEDICINE
Pedal Bypass Sometimes Trumps Endovascular Therapy
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
FROM THE VEITH SYMPOSIUM ON VASCULAR MEDICINE
Pedal Bypass Sometimes Trumps Endovascular Therapy
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
Endovascular therapy has increasingly become an initial option for the treatment of critical lower limb ischemia, but there are still indications for bypass surgery in some patients, according to Dr. Werner Lang.
Despite data in favor of endovascular treatment, bypass surgery still offers the best therapy with respect to long-term patency. Even in patients for whom healing time may be short, pedal vein grafts may still be the treatment of choice, said Dr. Lang at the Veith symposium on vascular medicine sponsored by the Cleveland Clinic.
Diabetic patients in particular may benefit from the bypass surgery approach. There are no prospective randomized trials with diabetic patients that have shown, with sufficient evidence, an advantage in outcomes after endovascular therapy. However, outcomes for subgroups in some studies suggest that endovascular procedures are preferable in diabetic patients who have multifocal tibial artery stenosis or occlusions.
In addition, there are trends indicating that limb salvage rates are similar for endovascular therapy and bypass surgery. This is possible because – even though its long-term patency rates are lower – endovascular therapy is actually sufficient for many patients: Their ischemic lesions will heal within the patency period of the endovascular therapy, and thus long-term patency is not needed in all cases.
Dr. Lang, professor of surgery at the Friedrich-Alexander University Erlangen-Nuremberg (Germany) and chief of the vascular surgery department at University Hospital Erlangen, presented evidence showing that the selection of patients for either endovascular therapy or bypass surgery should depend on the ability to restore blood flow to the pedal arch with respect to the angiosomes of the ischemic lesion. Endovascular therapy must be considered inferior for any patients in whom this goal is not attainable, which can be the case for diabetic patients in particular.
"Another reason for a bypass-first strategy is the ability to combine vascular surgery with plastic reconstructive surgery – [for example,] free flaps with a microvascular anastomosis. For diabetic patients, a microvascular anastomosis will not usually be possible after endovascular therapy alone, as the quality of the vessel wall of the original artery is generally poor in diabetic patients even after such therapy," Dr. Lang said in an interview.
Finally, the decision between a bypass-first strategy and an angioplasty-first strategy should depend not only on angiographic findings alone, but also on clinical characteristics and the need to achieve direct revascularization of the pedal arteries, Dr. Lang added.
FROM THE VEITH SYMPOSIUM ON VASCULAR MEDICINE
NIH at Forefront of New Clinical Trials Push, Director Says
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HUMAN GENETICS
NIH at Forefront of New Clinical Trials Push, Director Says
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
WASHINGTON – Breakthroughs in human genetics combined with funding from the Affordable Care Act have poised the National Institutes of Health to make real progress in the areas of orphan human diseases, according to NIH Director Francis S. Collins.
Speaking with enthusiasm to those he addressed as his "peeps" at the annual meeting of the American Society of Human Genetics, Dr. Collins shared his excitement at the state of human genetics in the post-genomic world, in large part driven by technology that has significantly lowered the cost of DNA sequencing, in turn speeding genetic research tremendously.
This, combined with new ACA funding, has enabled NIH to fund and pursue translational research, moving laboratory results toward and into clinical trials, something that is a new way of thinking for the agency, Dr. Collins said.
Rather than relying on pharmaceutical and biotechnology companies to take charge of the translational research, Dr. Collins encouraged academic researchers to consider partnering with NIH, at least for those orphan disease conditions in which the federal government would not be seen as being in competition with private enterprise.
"There is a serious crisis underway in the way in which this pipeline for drug discovery has been floundering. ... Pharma has been investing a larger and larger amount of money – between $40 and $50 billion dollars a year – and yet in spite of that, FDA approvals of new molecular entities, that is genuinely new drug therapeutics, not ‘me-toos,’ have been dropping steadily over the last 15 years," Dr. Collins said.
The reasons for this are complex, he said, but a big part of the problem involves coming up with appropriate targets and targeting compounds. He said this is an area in which NIH is and can be very much involved.
NIH now encourages academic researchers to take their targets to the assay stage and beyond, providing high-throughput screening (HTS) assistance from the NIH Chemical Genomics Center. Subsequent medicinal chemistry assistance is also available to help to modify HTS hits to enable compounds to become more drug-like and to match current ADME (absorption, distribution, metabolism, and excretion) criteria.
With NIH assistance, more than 150 lead compounds have reached this stage over the last 4-5 years, more than half of which are "poised to go to the next step" of preclinical trials in animals, or the "Valley of Death," according to Dr. Collins, "because this is where projects often go to die."
NIH is now able to assist in this high-risk area through the Therapeutics for Rare and Neglected Diseases (TRND) program in its Office of Rare Diseases Research. The TRND was funded at $24 million in fiscal year 2009.
NIH also is positioned to assist researchers in early phase human trials of orphan diseases through its 240-bed Clinical Center, Dr. Collins said.
"And we have 50 and soon we will have 60 Clinical and Translational Science Awards scattered all across the country which will also be set up to conduct these sorts of trials for new molecular entities," he added.
This new direction in research funding has involved unprecedented cooperation with the Food and Drug Administration, Dr. Collins said, with an NIH-FDA leadership council formed to ensure that new drug candidates are most safely and efficiently moved into the clinical trials framework in ways that would best enable FDA analysis and validation, particularly for rare diseases.
Dr. Collins was particularly excited about five instances in which NIH is using this new model of helping "de-risk" the drug development process for orphan or neglected diseases through TRND. These include four rare diseases (Niemann-Pick Disease Type C, hereditary inclusion body myopathy, sickle cell disease, and chronic lymphocytic leukemia) and one neglected disease (schistosomiasis).
If and when these compounds and those for other rare diseases become ready for marketing and production, NIH would then work with private companies to achieve licensing agreement to enable their manufacture and sale, according to Dr. Collins.
Dr. Collins reported having no financial conflicts of interest with regard to his presentation.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HUMAN GENETICS
What Is the Best Approach for High-Risk or Inoperable NSCLC?
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
What Is the Best Approach for High-Risk or Inoperable NSCLC?
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
Lobectomy is the standard of care in resectable lung cancer and appears to offer the best chance of cure in early, nonmetastasized disease. However, the presence of comorbidities can put a significant number of patients into a surgically high-risk or medically inoperable status, requiring alternative methods of treatment.
For surgically high-risk patients, sublobar (segmental or wedge) resection instead of lobectomy has become standard, with recent studies reporting 2- and 5-year survival rates of 90% and 83%, respectively. For medically inoperable patients, conventional radiotherapy has been used as an alternative, but has led to disappointing 5-year survival rates ranging from 10% to 30% (J. Thorac. Cardiovasc. Surg. 2007;134:857-67).
More recently, stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) have been offered as alternatives for medically inoperable and even for high-risk surgical patients, based on early, encouraging results.
Dr. Arjun Pennathur of the University of Pittsburgh and his colleagues are among a growing group of researchers who are demonstrating the benefits of RFA and SBRT as either a curative approach for early-stage non–small cell lung cancer (NSCLC) or as a palliative approach to more advanced lung neoplasms. Dr. Pennathur’s group reported SBRT survival rates at 1 and 5 years of 81% and 60%, respectively. Other researchers reported SBRT 1-year survival rates of 90%-95%, with 2-year survival of 60%-75%, and 5-year survival of 20%-65%.
For RFA treatment, Dr. Pennathur reported 1-year survival of stage I NSCLC patients at 95% and 2-year survival at 68%, as noted in an article by Dr. Hiran C. Fernando and colleagues from Boston University (Ann. Thorac. Surg. 2010;89:S2123-7).
Recently reported results by Dr. Lijun Huang and colleagues for patients treated with RFA have shown 1-, 2-, 5-year survival rates of 80.1%, 45.8%, and 24.3% for patients with NSCLC and 50.6%, 30.1%, and 17.3%, respectively, for patients with a pulmonary metastasis tumor (Eur. J. Cardio-Thorac. Surg. 2010 July 20 [doi:10.1016/j.ejcts.2010.06.004]).
Dr. Huang of the Fourth Military Medical University in Xi’an, China, found that progression-free survival was directly related to tumor size. Local progression occurred in 27% of patients with tumors measuring less than 3 cm and in 27.5% of patients with tumors of 3-4 cm, a nonsignificant difference. However, 42% of patients with tumors larger than 4 cm had a local recurrence, which was a significant difference. Based upon their findings, they recommended that RFA not be used in patients with tumors larger than 4 cm.
Tumor size was also seen as a significant factor in prognosis by Dr. Pennathur’s group (Ann. Thorac. Surg. 2009;87:1030-9).
With nonoperative techniques, it is always a question as to whether recurrence was truly recurrence. “It must be acknowledged that local tumor progression seen in this series most likely represents incomplete tumor treatment,” stated Dr. Huang and colleagues.
This is a good example of how nonoperative techniques, despite their benefits, have the inherent risk of not treating the complete tumor and can miss occult nodal disease (which has been determined to have around a 7% incidence even with peripheral tumors of 1 cm or smaller). This leads to undertreatment, according to Dr. Hiran C. Fernando and colleagues from the University of Pittsburgh, who object to current trends to recommend SBRT for high-risk (but not surgically inoperable) patients and even for patients considered eligible for lobectomy (Ann. Thorac. Surg. 2010;89:S2123-7). “Nonoperative therapies such as RFA and SBRT should be reserved for medically inoperable patients,” they stated.
Compared with surgical approaches, there are other considerations with both SBRT and RFA. Both approaches leave a scar that can interfere with future imaging assessment, making serial imaging and long-term follow-up a requisite to differentiate scar from recurring tumor. For SBRT, “the optimal method of delivery has not been determined with respect to the system used, the dose, and the fractionation schedule,” according to Dr. Fernando and his colleagues, thereby making comparisons and determination of optimal treatment difficult.
There are other differences between an operative and nonoperative approach that may be even more important in the future, as tailored cancer therapies become more available. Sublobar resection, compared with SBRT or RFA, provides adequate tissue for molecular profiling and for chemoresistance and sensitivity testing of tumors, all of which may be helpful in directing adjuvant chemotherapy if indicated, Dr. Fernando said.
In addition, the results of sublobar resection can be greatly improved by close attention to the surgical margin and lymph node assessment, taking advantage of the benefits of adjuvant brachytherapy to improve the surgical margins. “With these approaches, local recurrence can be reduced from the 17.2% reported in [an earlier] lung cancer group study to 5% or less,” according to Dr. Fernando.
However, despite all this, there is still no clear-cut solution to making the decision in patients for whom sublobar resection is possible.
For the high-risk patient, in whom lobectomy is not appropriate, “RFA or SBRT may be clinically equivalent to resection because they may be associated with a lower complication profile and quicker return to normal function and quality of life. Randomized studies are needed to determine whether this is true, but these studies must be limited to high-risk patients rather than lobectomy candidates until further data are available,” concluded Dr. Fernando.
None of the authors of the referenced articles reported relevant conflicts. A portion of Dr. Pennathur’s research was funded by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh.
Choice of Surgical Treatment for Mesothelioma Remains Complex
Surgery for malignant pleural mesothelioma remains a complicated and controversial issue. Thus far, the benefits of surgery vs. nonsurgical treatment have yet to be demonstrated.
Complete resection with surgery alone (R0) appears theoretically unattainable since it is impossible to eradicate residual microscopic disease, regardless of the surgical method used. Hence, most surgical treatment today is coupled to various adjuvant treatments, primarily a trimodality mode with radiotherapy and chemotherapy, according to Dr. Raja M. Flores, professor and chief of thoracic surgery, Mount Sinai School of Medicine, New York.
A “curative” surgical procedure remains an elusive goal, and thus the focus of lung surgery for malignant pleural mesothelioma (MPM) has shifted to R1 surgical resection for cytoreduction in the hope of prolonging life, relieving symptoms, and enhancing the effectiveness of adjuvant therapies. This approach has often meant a shift from the more radical extrapleural pneumonectomy (EPP), when possible, to the more lung-sparing pleurectomy/decortication (PD) procedure, according to Dr. Flores (Sem. Thorac. Cardiovasc. Surg.2009;21:149-53).
EPP involves a radical en bloc resection of the lung, pleura, diaphragm, and pericardium. PD involves resection of the parietal and visceral pleurae, pericardium, and – when necessary – the diaphragm, but it spares the entire lung. Both operations are technically complex and require extensive surgical expertise.
The operative mortality rate of EPP in the literature ranges from 4% to 15%, vs. and 1% to 5% for PD. In addition, PD has lower morbidity than does EPP. But the two techniques are not interchangeable, according to Dr. Flores. The choice of surgical technique depends on multiple factors, and the decision is often made at the time of surgery because the preoperative imaging may have underestimated the amount of disease present.
Staging is critical in determining the appropriate procedure, and the merits of each surgical approach have been debated in several recent clinical and registry trials examining individual mortality and morbidity of these procedures at different stages, coupled with the use of a variety of adjuvant therapies. However, many decisions are based on surgical conjecture and bias rather than scientific data.
Evidence indicates that PD provides a survival advantage for patients with stage I MPM, which may be accounted for by “lower mortality, lower postoperative adverse events, and greater lung capacity when relapse occurs,” according to Dr. Flores. However, he explained, most patients with mesothelioma will present at a stage that requires EPP to eradicate all gross disease. PD can provide an R1 resection in early-stage disease, but as the tumor enlarges and invades the lung, fissures, and costophrenic sulcus, a PD is suboptimal regardless of resection of the pericardium and diaphragm.
There is, however, a critical balance between optimal cytoreduction and morbidity that varies across stages for these two procedures. For stage II disease, there is a “trend toward improved survival for EPP, despite an inherently higher tumor stage than PD,” Dr. Flores said.
Stage III disease proved more complex, with similar survival data seen for both EPP and PD. Ultimately, “one should focus on obtaining a complete macroscopic resection based on the extent of tumor” for this stage of disease, choosing the best procedure accordingly, he advised.
For more advanced (stage IV) disease characterized by diffuse chest wall invasion and extensions through the diaphragm to the underlying peritoneum, the situation is much different.
“The tumor may be amenable to EPP, but there will be gross residual tumor left behind in the hemithorax. Because one of the most likely sites of recurrence is the contralateral pleura, the patient is better served by preserving lung function,” Dr. Flores explained.
In stage IV disease, PD trended toward better survival, presumably because “when disease spreads to the contralateral lung, PD or debulked patients will be less symptomatic and better functionally able to tolerate systemic therapy because of their greater pulmonary reserve,” he said.
“The goal is to remove all gross tumor while preserving as much of the lung as possible. Every patient and clinical situation is unique; therefore, treatment is difficult to generalize. Find an experienced mesothelioma surgeon you trust and leave it in their hands,” Dr. Flores said in an interview.
Ultimately, the situation remains complex. Dr. Heyman Luckraz of the New Cross Hospital, Wolverhampton, United Kingdom, and his colleagues recently reported results with 139 patients. EPP was chosen for clinically fit patients with stage I disease, while patients with advanced disease or who were unfit for EPP underwent PD. “EPP may only have a limited role in diffuse MPM, particularly as neither operative procedure is curative. Ultimately, the place of EPP will only be determined by randomized trial in comparison to PD in stage I disease with both groups receiving adjuvant therapy,” the investigators concluded (Eur. J. Cardio-Thorac. Surg. 2010;37:552-6).
Whether such trials will ever be performed is an open question. Despite the recent Mesothelioma and Radical Surgery (MARS) trial, which demonstrated the possibility of randomizing patients to surgical vs. nonsurgical treatment, there will likely never be a randomized clinical trial powered enough to completely solve the puzzle, according to Dr. Tom Treasure of the University College of London (Eur. J. Cardio-Thorac. Surg. 2010;37:509-10).
Efforts continue to develop surgical alternatives with less mortality and morbidity than those of the standard EPP and PD procedures. For example, Dr. M.D. Kluger and colleagues at Columbia University, New York, reported the phase I and II results of a recent clinical trial on a two-stage operative cytoreduction procedure coupled with intraperitoneal chemotherapy (Eur. J. Surg. Oncol. 2010; doi:10.1016/j.ejso.2010.07.001). They found that their protocol offered median survival comparable to that of one-stage protocols; rates of morbidity, mortality, visceral resections were relatively low and length of stay was relatively short despite the need for two operations.
Ultimately, surgery might be totally immaterial in some cases. In two recent papers, the type of surgery was not found to be predictive of survival. The poor prognosis of sarcomatoid MPM was independent of the extent of surgery, unlike other cell types (Ann. Thorac. Surg. 2010;89:907-11), and the combination of several immunohistochemical markers was found to be the only valid prognostic indicator of survival, including type of surgery (Eur. J. Cardio-Thorac. Surg. 2010;38:245-53).
None of the authors mentioned in this article had disclosures deemed relevant to their reported research.
Surgery for malignant pleural mesothelioma remains a complicated and controversial issue. Thus far, the benefits of surgery vs. nonsurgical treatment have yet to be demonstrated.
Complete resection with surgery alone (R0) appears theoretically unattainable since it is impossible to eradicate residual microscopic disease, regardless of the surgical method used. Hence, most surgical treatment today is coupled to various adjuvant treatments, primarily a trimodality mode with radiotherapy and chemotherapy, according to Dr. Raja M. Flores, professor and chief of thoracic surgery, Mount Sinai School of Medicine, New York.
A “curative” surgical procedure remains an elusive goal, and thus the focus of lung surgery for malignant pleural mesothelioma (MPM) has shifted to R1 surgical resection for cytoreduction in the hope of prolonging life, relieving symptoms, and enhancing the effectiveness of adjuvant therapies. This approach has often meant a shift from the more radical extrapleural pneumonectomy (EPP), when possible, to the more lung-sparing pleurectomy/decortication (PD) procedure, according to Dr. Flores (Sem. Thorac. Cardiovasc. Surg.2009;21:149-53).
EPP involves a radical en bloc resection of the lung, pleura, diaphragm, and pericardium. PD involves resection of the parietal and visceral pleurae, pericardium, and – when necessary – the diaphragm, but it spares the entire lung. Both operations are technically complex and require extensive surgical expertise.
The operative mortality rate of EPP in the literature ranges from 4% to 15%, vs. and 1% to 5% for PD. In addition, PD has lower morbidity than does EPP. But the two techniques are not interchangeable, according to Dr. Flores. The choice of surgical technique depends on multiple factors, and the decision is often made at the time of surgery because the preoperative imaging may have underestimated the amount of disease present.
Staging is critical in determining the appropriate procedure, and the merits of each surgical approach have been debated in several recent clinical and registry trials examining individual mortality and morbidity of these procedures at different stages, coupled with the use of a variety of adjuvant therapies. However, many decisions are based on surgical conjecture and bias rather than scientific data.
Evidence indicates that PD provides a survival advantage for patients with stage I MPM, which may be accounted for by “lower mortality, lower postoperative adverse events, and greater lung capacity when relapse occurs,” according to Dr. Flores. However, he explained, most patients with mesothelioma will present at a stage that requires EPP to eradicate all gross disease. PD can provide an R1 resection in early-stage disease, but as the tumor enlarges and invades the lung, fissures, and costophrenic sulcus, a PD is suboptimal regardless of resection of the pericardium and diaphragm.
There is, however, a critical balance between optimal cytoreduction and morbidity that varies across stages for these two procedures. For stage II disease, there is a “trend toward improved survival for EPP, despite an inherently higher tumor stage than PD,” Dr. Flores said.
Stage III disease proved more complex, with similar survival data seen for both EPP and PD. Ultimately, “one should focus on obtaining a complete macroscopic resection based on the extent of tumor” for this stage of disease, choosing the best procedure accordingly, he advised.
For more advanced (stage IV) disease characterized by diffuse chest wall invasion and extensions through the diaphragm to the underlying peritoneum, the situation is much different.
“The tumor may be amenable to EPP, but there will be gross residual tumor left behind in the hemithorax. Because one of the most likely sites of recurrence is the contralateral pleura, the patient is better served by preserving lung function,” Dr. Flores explained.
In stage IV disease, PD trended toward better survival, presumably because “when disease spreads to the contralateral lung, PD or debulked patients will be less symptomatic and better functionally able to tolerate systemic therapy because of their greater pulmonary reserve,” he said.
“The goal is to remove all gross tumor while preserving as much of the lung as possible. Every patient and clinical situation is unique; therefore, treatment is difficult to generalize. Find an experienced mesothelioma surgeon you trust and leave it in their hands,” Dr. Flores said in an interview.
Ultimately, the situation remains complex. Dr. Heyman Luckraz of the New Cross Hospital, Wolverhampton, United Kingdom, and his colleagues recently reported results with 139 patients. EPP was chosen for clinically fit patients with stage I disease, while patients with advanced disease or who were unfit for EPP underwent PD. “EPP may only have a limited role in diffuse MPM, particularly as neither operative procedure is curative. Ultimately, the place of EPP will only be determined by randomized trial in comparison to PD in stage I disease with both groups receiving adjuvant therapy,” the investigators concluded (Eur. J. Cardio-Thorac. Surg. 2010;37:552-6).
Whether such trials will ever be performed is an open question. Despite the recent Mesothelioma and Radical Surgery (MARS) trial, which demonstrated the possibility of randomizing patients to surgical vs. nonsurgical treatment, there will likely never be a randomized clinical trial powered enough to completely solve the puzzle, according to Dr. Tom Treasure of the University College of London (Eur. J. Cardio-Thorac. Surg. 2010;37:509-10).
Efforts continue to develop surgical alternatives with less mortality and morbidity than those of the standard EPP and PD procedures. For example, Dr. M.D. Kluger and colleagues at Columbia University, New York, reported the phase I and II results of a recent clinical trial on a two-stage operative cytoreduction procedure coupled with intraperitoneal chemotherapy (Eur. J. Surg. Oncol. 2010; doi:10.1016/j.ejso.2010.07.001). They found that their protocol offered median survival comparable to that of one-stage protocols; rates of morbidity, mortality, visceral resections were relatively low and length of stay was relatively short despite the need for two operations.
Ultimately, surgery might be totally immaterial in some cases. In two recent papers, the type of surgery was not found to be predictive of survival. The poor prognosis of sarcomatoid MPM was independent of the extent of surgery, unlike other cell types (Ann. Thorac. Surg. 2010;89:907-11), and the combination of several immunohistochemical markers was found to be the only valid prognostic indicator of survival, including type of surgery (Eur. J. Cardio-Thorac. Surg. 2010;38:245-53).
None of the authors mentioned in this article had disclosures deemed relevant to their reported research.
Surgery for malignant pleural mesothelioma remains a complicated and controversial issue. Thus far, the benefits of surgery vs. nonsurgical treatment have yet to be demonstrated.
Complete resection with surgery alone (R0) appears theoretically unattainable since it is impossible to eradicate residual microscopic disease, regardless of the surgical method used. Hence, most surgical treatment today is coupled to various adjuvant treatments, primarily a trimodality mode with radiotherapy and chemotherapy, according to Dr. Raja M. Flores, professor and chief of thoracic surgery, Mount Sinai School of Medicine, New York.
A “curative” surgical procedure remains an elusive goal, and thus the focus of lung surgery for malignant pleural mesothelioma (MPM) has shifted to R1 surgical resection for cytoreduction in the hope of prolonging life, relieving symptoms, and enhancing the effectiveness of adjuvant therapies. This approach has often meant a shift from the more radical extrapleural pneumonectomy (EPP), when possible, to the more lung-sparing pleurectomy/decortication (PD) procedure, according to Dr. Flores (Sem. Thorac. Cardiovasc. Surg.2009;21:149-53).
EPP involves a radical en bloc resection of the lung, pleura, diaphragm, and pericardium. PD involves resection of the parietal and visceral pleurae, pericardium, and – when necessary – the diaphragm, but it spares the entire lung. Both operations are technically complex and require extensive surgical expertise.
The operative mortality rate of EPP in the literature ranges from 4% to 15%, vs. and 1% to 5% for PD. In addition, PD has lower morbidity than does EPP. But the two techniques are not interchangeable, according to Dr. Flores. The choice of surgical technique depends on multiple factors, and the decision is often made at the time of surgery because the preoperative imaging may have underestimated the amount of disease present.
Staging is critical in determining the appropriate procedure, and the merits of each surgical approach have been debated in several recent clinical and registry trials examining individual mortality and morbidity of these procedures at different stages, coupled with the use of a variety of adjuvant therapies. However, many decisions are based on surgical conjecture and bias rather than scientific data.
Evidence indicates that PD provides a survival advantage for patients with stage I MPM, which may be accounted for by “lower mortality, lower postoperative adverse events, and greater lung capacity when relapse occurs,” according to Dr. Flores. However, he explained, most patients with mesothelioma will present at a stage that requires EPP to eradicate all gross disease. PD can provide an R1 resection in early-stage disease, but as the tumor enlarges and invades the lung, fissures, and costophrenic sulcus, a PD is suboptimal regardless of resection of the pericardium and diaphragm.
There is, however, a critical balance between optimal cytoreduction and morbidity that varies across stages for these two procedures. For stage II disease, there is a “trend toward improved survival for EPP, despite an inherently higher tumor stage than PD,” Dr. Flores said.
Stage III disease proved more complex, with similar survival data seen for both EPP and PD. Ultimately, “one should focus on obtaining a complete macroscopic resection based on the extent of tumor” for this stage of disease, choosing the best procedure accordingly, he advised.
For more advanced (stage IV) disease characterized by diffuse chest wall invasion and extensions through the diaphragm to the underlying peritoneum, the situation is much different.
“The tumor may be amenable to EPP, but there will be gross residual tumor left behind in the hemithorax. Because one of the most likely sites of recurrence is the contralateral pleura, the patient is better served by preserving lung function,” Dr. Flores explained.
In stage IV disease, PD trended toward better survival, presumably because “when disease spreads to the contralateral lung, PD or debulked patients will be less symptomatic and better functionally able to tolerate systemic therapy because of their greater pulmonary reserve,” he said.
“The goal is to remove all gross tumor while preserving as much of the lung as possible. Every patient and clinical situation is unique; therefore, treatment is difficult to generalize. Find an experienced mesothelioma surgeon you trust and leave it in their hands,” Dr. Flores said in an interview.
Ultimately, the situation remains complex. Dr. Heyman Luckraz of the New Cross Hospital, Wolverhampton, United Kingdom, and his colleagues recently reported results with 139 patients. EPP was chosen for clinically fit patients with stage I disease, while patients with advanced disease or who were unfit for EPP underwent PD. “EPP may only have a limited role in diffuse MPM, particularly as neither operative procedure is curative. Ultimately, the place of EPP will only be determined by randomized trial in comparison to PD in stage I disease with both groups receiving adjuvant therapy,” the investigators concluded (Eur. J. Cardio-Thorac. Surg. 2010;37:552-6).
Whether such trials will ever be performed is an open question. Despite the recent Mesothelioma and Radical Surgery (MARS) trial, which demonstrated the possibility of randomizing patients to surgical vs. nonsurgical treatment, there will likely never be a randomized clinical trial powered enough to completely solve the puzzle, according to Dr. Tom Treasure of the University College of London (Eur. J. Cardio-Thorac. Surg. 2010;37:509-10).
Efforts continue to develop surgical alternatives with less mortality and morbidity than those of the standard EPP and PD procedures. For example, Dr. M.D. Kluger and colleagues at Columbia University, New York, reported the phase I and II results of a recent clinical trial on a two-stage operative cytoreduction procedure coupled with intraperitoneal chemotherapy (Eur. J. Surg. Oncol. 2010; doi:10.1016/j.ejso.2010.07.001). They found that their protocol offered median survival comparable to that of one-stage protocols; rates of morbidity, mortality, visceral resections were relatively low and length of stay was relatively short despite the need for two operations.
Ultimately, surgery might be totally immaterial in some cases. In two recent papers, the type of surgery was not found to be predictive of survival. The poor prognosis of sarcomatoid MPM was independent of the extent of surgery, unlike other cell types (Ann. Thorac. Surg. 2010;89:907-11), and the combination of several immunohistochemical markers was found to be the only valid prognostic indicator of survival, including type of surgery (Eur. J. Cardio-Thorac. Surg. 2010;38:245-53).
None of the authors mentioned in this article had disclosures deemed relevant to their reported research.