- Email: [email protected]
Endovascular brachytherapy to inhibit coronary artery restenosis: An introduction to the scripps coronary radiation to inhibit proliferation post stenting trial
EISEVIER
l
Editorial ENDOVASCULAR BRACHYTHERAPY TO INHIBIT CORONARY ARTERY RESTENOSIS: AN INTRODUCTION TO THE SCRIPPS CORONARY RADIATION TO INHIBIT PROLIFERATION POST STENTING TRIAL VINCENT MASSULLO, M.D.,* PAUL S. TEIRSTEIN, M.D.,” SHIRISH JANI, PH.D.,* ROBERT J. Russo, PH.D., M.D.,’ ERMINIA M. GUARNERI, M.D.,’ HAORAN JIN, PH.D.,* RICHARD A. SCHATZ, M.D.,+ NANCY B. MORRIS, R.N.,’ STEPHEN STEUTERMAN, M.S.,: JEFFREY J. POPMA, M.D.,§ GARY S. MINTZ, M.D.,$ MARTIN B. LEON, M.D.$ AND PRABHAKAR TRIPURANENI, M.D.* Divisions
of *Radiation Oncology, ‘Cardiology, and *Radiation Safety, Scripps Clinic and Research Foundation. 92037-7908: “Division of Cardiology, Washington Hospital Center, Washington, DC
La Jolla. CA
This year is the 100th anniversary of the use of ionizing radiation to treat disease. Since the turn of the century, many benign and malignant diseases have been treated with radiation therapy (RT). Through the decades, however, the application of RT in the treatment of benign diseases has largely disappeared-supplanted by other medical or surgical therapies. RT has most recently been committed to the treatment of malignancies to such a degree that the specialty was renamed radiation oncology. However, a continued. though very limited, role for RT has persisted in the treatment of certain benign hyperplastic disorders. RT significantly inhibits excessive fibroblast activity. Judicious clinical use of low-dose RT is highly effective in inhibiting such benign conditions as conjunctival pterygia. keloid scars. and aggressive fibromatosis. Excessive bone formation by the osteoblast, a derivative of the fibroblast. is successfully inhibited by low-dose RT and thereby inhibits heterotopic ossification. Although such benign hyperplasia disorders are significant clinical entities, the main thrust of RT continues to be the treatment of malignancies. With the coming millennium, a new therapeutic application of RT in benign disease promises to open new vistas previously unimagined. Studies have just begun in using RT to prevent vascular restenosis. RT may provide a powerful tool to solve what has become a vexing problem in vascular disease. In this review, we shall discuss early preclinical evidence that endovascular brachytherapy may inhibit coronary artery restenosis. We shall also introduce and describe the Scripps Clinic’s ongoing trial of endovascular RT in the prevention of coronary artery restenosis. The Scripps Coronary Radiation to Inhibit Proliferation Post
Stenting trial (SCRIPPS) is the first attempt to use catheter-based intracoronary ionizing radiation in a prospective double-blinded randomized study. The study’s objective is to determine the initial safety and efficacy in reversing and preventing coronary artery restenosis by adding lowdose RT to today’s optima1 conventional cardiovascular therapy. This review will hopefully also provide a basis to understand the rationale and some of the potential benefits of applying radiation in the treatment of coronary artery restenosis.
Ischemic heart disease due to coronary artery stenosis is a significant cause of morbidity and mortality. Reversal and control of such coronary artery disease was made possible by the development of surgical coronary artery bypass grafting in the 1960s and 1970s. and coronary artery angioplasty in the 1970s and 1980s. Unfortunately, despite such therapies, restensosis is a persistent problem. Over 400.000 angioplasties/year are performed in the United States alone. Studies show that 30%--40% of these angioplasties will restenose. Ongoing therapy to redilate these restenotic patients fortunately carries a low mortality rate. However, significant costs in morbidity and dedication of resources must be paid for ongoing therapy in this large subgroup of patients. For over 20 years, myriad adjunct medical and technical treatments were unsuccessful in signilicantly reducing restenosis until 1995, when endovascular stenting was shown to diminish de ~zovorestenosis significantly after PTCA. Unfortunately. rcstensosis
Reprint requests to: Vincent Massullo, M.D., Division of Radiation Oncology. Scripps Clinic and Research Foundation. 1Of566
North Tomey Pines Road. MSBl, La Jolla, CA 92037-7908. Accepted for publication 28 August 1996.
CORONARY ARTERY RESTENUSIS: MAGNITUDE OF PROBLEM
973
974
I. J. Radiation Oncology 0 Biology 0 Physics
rates of 20% are still seen after optimal PTCA with stenting, and a significant number of patients are relegated to undergo multiple procedures in an attempt to control such restenosis.
POTENTIAL
MECHANISMS
OF RESTENOSIS
Preclinical research in the animal coronary artery model has elucidated the basic mechanisms involved in restenosis after artery damage (such as CABG or PTCA). Two mechanisms are thought to cause restenosis-initial mechanical recoil followed later by myointimal cellular hyperplasia, which eventually causes vessel remodeling. The mechanical recoil phenomenon was recently addressed by development of endovascular stent appliances. The stent has succeeded in diminishing the restenosis rate to 20% when used in de novo lesions after initial PTCA. The endovascular stent is thought to provide a mechanical buttress to restenosis, by physically separating the vessel walls by a cylindrical meshwork of struts. However, the stent itself can also act as a strong stimulant of cellular proliferation. By damaging the intimal wall or myointimal junction, a stent stimulates myointimal proliferation as a repair mechanism. When this repair mechanism is overly exuberant, the cellular component can bridge the stent’s struts and proliferate to invade and obstruct the arterial lumen. A better understanding of the hyperplasia component of restenosis was needed. Work by Drs. Robinson, Wilcox, and Scott at Emory University using a balloon overstretch technique in the porcine coronary artery has shown results which mimic the finding of restenosis in human coronary arteries. After overstretch injury using an angioplasty balloon, direct histologic, as well as antibody-labeling immunohistochemical were performed. Initial trauma findings of denuding of the intimal cell layer with rupture of the internal elastic lamina (IEL) and fissuring into the tunica media with frequent dehiscence of the media from the adventitia were seen. Over the ensuing 24-72 h, hemorrhage, perivascular hematoma, and mural thrombus were seen on areas of exposed external elastic lamina (EEL). Along with the hemorrhagic reaction, an inflammatory response of primarily neutrophils was seen in these areas of exposed EEL. At 72 h, cellular proliferation and differentiation is seen involving initially the adventitia overlying the traumatized areas as well as the rupture-dissected ends of the mediaadventitia interface. Immunohistochemical labeling with 5bromo-2-deoxyuridine (BrDU) reveals that incorporation and active cell division first occurs in the adventitia. Timed-incorporation studies of BrDU show that a significant number of these proliferating cells migrate and are incorporated into the newly formed neointima. Additional immunohistochemical staining studies with ant&-actin antibodies have shown that initially the ad-
Volume 36, Number 4, 1996
ventitial cells and later, the neointimal cells, develop stainable a-actin smooth muscle: At 5 days the neointima begins to form and continues to lay down new cells until approximately 2 weeks following trauma. The adventitial a-actin staining disappears at 2 weeks, whereas the neointima staining persists for some time. This entire process commences immediately following arterial trauma. The vast majority of clinically relevant coronary artery restenosis occurs within 6 months of arterial injury. These studies help to explain both the hyperplasia and remodeling elements of restenosis. Initial healing of the traumatized intima/myointima is accomplished by in-migration of the adventitial cells, and later, by proliferation of myointimal cells. Excessive neointimal hyperplasia then causes luminal loss. Eventual cY-actin smooth-muscle differentiation in the surrounding adventitial myofibroblasts may also cause vessel wall constriction and remodeling with late luminal loss. It is postulated that trauma may cause release of a second-messenger which initiates the proliferation of adventitial cells and synthesis of growth factors causing neointimal hyperplasia. The exact mechanism of this cascade of events is unknown. The location of the tissues or cells that might be involved in elaborating this second messenger is unknown as well. However, it is thought that the controls for the restenosis process exist locally, based on these immunohistochemical studies as well as the successful inhibition of restenosis in animals using locally delivered radiation. Several theories have evolved to explain how radiation inhibits the restenosis process. Direct and indirect DNA damage might inhibit cellular proliferation or differentiation. In so doing, the hyperplastic response might be inhibited at the level of cellular reproduction. RT might also inhibit elaboration or amplification of the stimulatory secondary messenger. A local collateral effect of RT might be arterial medial fibrosis causing a diffusion barrier to the secondary messenger and chemotactic response. This fibrotic barrier might also inhibit actual adventitial cell inward migration. SCRIPPS TRIAL
METHOD
AND DESIGN
Although the specifics of the restenosis mechanism are still unclear, the promising results of radiation inhibition of stenosis in the animal model are compelling. Unlike in RT of malignant disease, most benign fibroplasia disorders do not require high doses of radiation. In fact, no collateral damage to surrounding myocardium has been seen in preclinical radiation stenosis inhibition studies. In thin-walled animal vessels, a very superficial dose of radiation with a centered endovascular ,&emitter was highly effective in inhibiting stenosis after overstretch injury. While designing the SCRIPPS trial, numerous intravascular ultrasound (IVUS) studies of diseased human coro-
Endovascular
brachytherapy
to inhibit
coronary
nary arteries were reviewed. Human coronary arteries after angioplasty revealed a situation very different from the more ideal animal model. The end result in most cases after balloon angioplasty was an eccentric coronary artery lumen. The lumen would be against the intima and IEL at one wall. but two to three times as far from the contralatera1 intima or IEL. A thick layer of residual plaque deviated the new lumen significantly from a central location which would possibly have been more ideal from a radiotherapeutic dosimetry standpoint. In addition to the eccentric lumen within the artery, the catheter within that lumen was eccentrically located as well. This final displacement is caused by the normal curving of the coronary artery within which passes the less than perfectly compliant endovascular catheter. Presuming the intima and IEL to be instrumental in the stenosis control mechanism, and taking into account the wide range of depths of these tissues from the newly angioplastied lumen. a y source was selected. Such a source is needed ideally to treat a range of approximately l-3-mm radius from the lumen central axis based on our IVUS studies. In the animal model, doses of 2 14 Gy prescribed to the intimal wall were very effective in preventing overstretch injury stenosis. In other human benign hyperplasia disorders, doses of 27-8 Gy have proven effective. Based on normal tissue tolerances, as well as tissue dose-volume consideration, a maximal dose of approximately 30 Gy was selected. Fortuitously. ‘“*lr fulfilled these requirements relatively well in providing a dose range of approximately 8-30 Gy over the target volume. Additionally, “)‘Ir was readily available and approved for other human uses.
artery
restenosis
0 V.
MASS~~LL.O
rt
(II.
X.5
Inasmuch as the efficacy and safety of endovascular brachytherapy are unknown, it was decided to enroll pa-tients with proven preexisting coronary artery restenosis. Such patients are known actually to have a higher restenosis rate than de novo patients, and, it was thought, would best test the effectiveness of endovascular brachytherapy. These patients are also those who might best benefit from RT intervention, inasmuch as they are usually fated to undergo procedure after procedure in an attempt to control this stubborn disease. After initial intervention with angioplasty and intravascular stenting, all patients will be randomized to receive endovascular application of either “‘Ir or placebo. Patients will be followed-up at 1 tnonth with clinical evaluation and at 6 months with clinical evaluation, exercise stress testing. and repeat angiogram with IVUS study. Finally, to assure unbiased implementation and interpretation of the trial, a prospective randomized, doubleblinded trial design was selected. The clinical procedures and data retrieval are taking place at the Scripps Clinic and Research Foundation in a double-blinded fashion. lnterpretation of the initial and ongoing follow-up data will be performed by the Washington Hospital Center, Division of Cardiology. In so doing, an additional level of blinding will be assured. Endovascular brachytherapy may be effective in preventing coronary artery restenosis. Well-controlled clinical trials, such as the SCRIPPS trial, are needed to determine the feasibility. safety. and efficacy of endovascular brachytherapy in preventing coronary arter? restenosis.
l
Editorial ENDOVASCULAR BRACHYTHERAPY TO INHIBIT CORONARY ARTERY RESTENOSIS: AN INTRODUCTION TO THE SCRIPPS CORONARY RADIATION TO INHIBIT PROLIFERATION POST STENTING TRIAL VINCENT MASSULLO, M.D.,* PAUL S. TEIRSTEIN, M.D.,” SHIRISH JANI, PH.D.,* ROBERT J. Russo, PH.D., M.D.,’ ERMINIA M. GUARNERI, M.D.,’ HAORAN JIN, PH.D.,* RICHARD A. SCHATZ, M.D.,+ NANCY B. MORRIS, R.N.,’ STEPHEN STEUTERMAN, M.S.,: JEFFREY J. POPMA, M.D.,§ GARY S. MINTZ, M.D.,$ MARTIN B. LEON, M.D.$ AND PRABHAKAR TRIPURANENI, M.D.* Divisions
of *Radiation Oncology, ‘Cardiology, and *Radiation Safety, Scripps Clinic and Research Foundation. 92037-7908: “Division of Cardiology, Washington Hospital Center, Washington, DC
La Jolla. CA
This year is the 100th anniversary of the use of ionizing radiation to treat disease. Since the turn of the century, many benign and malignant diseases have been treated with radiation therapy (RT). Through the decades, however, the application of RT in the treatment of benign diseases has largely disappeared-supplanted by other medical or surgical therapies. RT has most recently been committed to the treatment of malignancies to such a degree that the specialty was renamed radiation oncology. However, a continued. though very limited, role for RT has persisted in the treatment of certain benign hyperplastic disorders. RT significantly inhibits excessive fibroblast activity. Judicious clinical use of low-dose RT is highly effective in inhibiting such benign conditions as conjunctival pterygia. keloid scars. and aggressive fibromatosis. Excessive bone formation by the osteoblast, a derivative of the fibroblast. is successfully inhibited by low-dose RT and thereby inhibits heterotopic ossification. Although such benign hyperplasia disorders are significant clinical entities, the main thrust of RT continues to be the treatment of malignancies. With the coming millennium, a new therapeutic application of RT in benign disease promises to open new vistas previously unimagined. Studies have just begun in using RT to prevent vascular restenosis. RT may provide a powerful tool to solve what has become a vexing problem in vascular disease. In this review, we shall discuss early preclinical evidence that endovascular brachytherapy may inhibit coronary artery restenosis. We shall also introduce and describe the Scripps Clinic’s ongoing trial of endovascular RT in the prevention of coronary artery restenosis. The Scripps Coronary Radiation to Inhibit Proliferation Post
Stenting trial (SCRIPPS) is the first attempt to use catheter-based intracoronary ionizing radiation in a prospective double-blinded randomized study. The study’s objective is to determine the initial safety and efficacy in reversing and preventing coronary artery restenosis by adding lowdose RT to today’s optima1 conventional cardiovascular therapy. This review will hopefully also provide a basis to understand the rationale and some of the potential benefits of applying radiation in the treatment of coronary artery restenosis.
Ischemic heart disease due to coronary artery stenosis is a significant cause of morbidity and mortality. Reversal and control of such coronary artery disease was made possible by the development of surgical coronary artery bypass grafting in the 1960s and 1970s. and coronary artery angioplasty in the 1970s and 1980s. Unfortunately, despite such therapies, restensosis is a persistent problem. Over 400.000 angioplasties/year are performed in the United States alone. Studies show that 30%--40% of these angioplasties will restenose. Ongoing therapy to redilate these restenotic patients fortunately carries a low mortality rate. However, significant costs in morbidity and dedication of resources must be paid for ongoing therapy in this large subgroup of patients. For over 20 years, myriad adjunct medical and technical treatments were unsuccessful in signilicantly reducing restenosis until 1995, when endovascular stenting was shown to diminish de ~zovorestenosis significantly after PTCA. Unfortunately. rcstensosis
Reprint requests to: Vincent Massullo, M.D., Division of Radiation Oncology. Scripps Clinic and Research Foundation. 1Of566
North Tomey Pines Road. MSBl, La Jolla, CA 92037-7908. Accepted for publication 28 August 1996.
CORONARY ARTERY RESTENUSIS: MAGNITUDE OF PROBLEM
973
974
I. J. Radiation Oncology 0 Biology 0 Physics
rates of 20% are still seen after optimal PTCA with stenting, and a significant number of patients are relegated to undergo multiple procedures in an attempt to control such restenosis.
POTENTIAL
MECHANISMS
OF RESTENOSIS
Preclinical research in the animal coronary artery model has elucidated the basic mechanisms involved in restenosis after artery damage (such as CABG or PTCA). Two mechanisms are thought to cause restenosis-initial mechanical recoil followed later by myointimal cellular hyperplasia, which eventually causes vessel remodeling. The mechanical recoil phenomenon was recently addressed by development of endovascular stent appliances. The stent has succeeded in diminishing the restenosis rate to 20% when used in de novo lesions after initial PTCA. The endovascular stent is thought to provide a mechanical buttress to restenosis, by physically separating the vessel walls by a cylindrical meshwork of struts. However, the stent itself can also act as a strong stimulant of cellular proliferation. By damaging the intimal wall or myointimal junction, a stent stimulates myointimal proliferation as a repair mechanism. When this repair mechanism is overly exuberant, the cellular component can bridge the stent’s struts and proliferate to invade and obstruct the arterial lumen. A better understanding of the hyperplasia component of restenosis was needed. Work by Drs. Robinson, Wilcox, and Scott at Emory University using a balloon overstretch technique in the porcine coronary artery has shown results which mimic the finding of restenosis in human coronary arteries. After overstretch injury using an angioplasty balloon, direct histologic, as well as antibody-labeling immunohistochemical were performed. Initial trauma findings of denuding of the intimal cell layer with rupture of the internal elastic lamina (IEL) and fissuring into the tunica media with frequent dehiscence of the media from the adventitia were seen. Over the ensuing 24-72 h, hemorrhage, perivascular hematoma, and mural thrombus were seen on areas of exposed external elastic lamina (EEL). Along with the hemorrhagic reaction, an inflammatory response of primarily neutrophils was seen in these areas of exposed EEL. At 72 h, cellular proliferation and differentiation is seen involving initially the adventitia overlying the traumatized areas as well as the rupture-dissected ends of the mediaadventitia interface. Immunohistochemical labeling with 5bromo-2-deoxyuridine (BrDU) reveals that incorporation and active cell division first occurs in the adventitia. Timed-incorporation studies of BrDU show that a significant number of these proliferating cells migrate and are incorporated into the newly formed neointima. Additional immunohistochemical staining studies with ant&-actin antibodies have shown that initially the ad-
Volume 36, Number 4, 1996
ventitial cells and later, the neointimal cells, develop stainable a-actin smooth muscle: At 5 days the neointima begins to form and continues to lay down new cells until approximately 2 weeks following trauma. The adventitial a-actin staining disappears at 2 weeks, whereas the neointima staining persists for some time. This entire process commences immediately following arterial trauma. The vast majority of clinically relevant coronary artery restenosis occurs within 6 months of arterial injury. These studies help to explain both the hyperplasia and remodeling elements of restenosis. Initial healing of the traumatized intima/myointima is accomplished by in-migration of the adventitial cells, and later, by proliferation of myointimal cells. Excessive neointimal hyperplasia then causes luminal loss. Eventual cY-actin smooth-muscle differentiation in the surrounding adventitial myofibroblasts may also cause vessel wall constriction and remodeling with late luminal loss. It is postulated that trauma may cause release of a second-messenger which initiates the proliferation of adventitial cells and synthesis of growth factors causing neointimal hyperplasia. The exact mechanism of this cascade of events is unknown. The location of the tissues or cells that might be involved in elaborating this second messenger is unknown as well. However, it is thought that the controls for the restenosis process exist locally, based on these immunohistochemical studies as well as the successful inhibition of restenosis in animals using locally delivered radiation. Several theories have evolved to explain how radiation inhibits the restenosis process. Direct and indirect DNA damage might inhibit cellular proliferation or differentiation. In so doing, the hyperplastic response might be inhibited at the level of cellular reproduction. RT might also inhibit elaboration or amplification of the stimulatory secondary messenger. A local collateral effect of RT might be arterial medial fibrosis causing a diffusion barrier to the secondary messenger and chemotactic response. This fibrotic barrier might also inhibit actual adventitial cell inward migration. SCRIPPS TRIAL
METHOD
AND DESIGN
Although the specifics of the restenosis mechanism are still unclear, the promising results of radiation inhibition of stenosis in the animal model are compelling. Unlike in RT of malignant disease, most benign fibroplasia disorders do not require high doses of radiation. In fact, no collateral damage to surrounding myocardium has been seen in preclinical radiation stenosis inhibition studies. In thin-walled animal vessels, a very superficial dose of radiation with a centered endovascular ,&emitter was highly effective in inhibiting stenosis after overstretch injury. While designing the SCRIPPS trial, numerous intravascular ultrasound (IVUS) studies of diseased human coro-
Endovascular
brachytherapy
to inhibit
coronary
nary arteries were reviewed. Human coronary arteries after angioplasty revealed a situation very different from the more ideal animal model. The end result in most cases after balloon angioplasty was an eccentric coronary artery lumen. The lumen would be against the intima and IEL at one wall. but two to three times as far from the contralatera1 intima or IEL. A thick layer of residual plaque deviated the new lumen significantly from a central location which would possibly have been more ideal from a radiotherapeutic dosimetry standpoint. In addition to the eccentric lumen within the artery, the catheter within that lumen was eccentrically located as well. This final displacement is caused by the normal curving of the coronary artery within which passes the less than perfectly compliant endovascular catheter. Presuming the intima and IEL to be instrumental in the stenosis control mechanism, and taking into account the wide range of depths of these tissues from the newly angioplastied lumen. a y source was selected. Such a source is needed ideally to treat a range of approximately l-3-mm radius from the lumen central axis based on our IVUS studies. In the animal model, doses of 2 14 Gy prescribed to the intimal wall were very effective in preventing overstretch injury stenosis. In other human benign hyperplasia disorders, doses of 27-8 Gy have proven effective. Based on normal tissue tolerances, as well as tissue dose-volume consideration, a maximal dose of approximately 30 Gy was selected. Fortuitously. ‘“*lr fulfilled these requirements relatively well in providing a dose range of approximately 8-30 Gy over the target volume. Additionally, “)‘Ir was readily available and approved for other human uses.
artery
restenosis
0 V.
MASS~~LL.O
rt
(II.
X.5
Inasmuch as the efficacy and safety of endovascular brachytherapy are unknown, it was decided to enroll pa-tients with proven preexisting coronary artery restenosis. Such patients are known actually to have a higher restenosis rate than de novo patients, and, it was thought, would best test the effectiveness of endovascular brachytherapy. These patients are also those who might best benefit from RT intervention, inasmuch as they are usually fated to undergo procedure after procedure in an attempt to control this stubborn disease. After initial intervention with angioplasty and intravascular stenting, all patients will be randomized to receive endovascular application of either “‘Ir or placebo. Patients will be followed-up at 1 tnonth with clinical evaluation and at 6 months with clinical evaluation, exercise stress testing. and repeat angiogram with IVUS study. Finally, to assure unbiased implementation and interpretation of the trial, a prospective randomized, doubleblinded trial design was selected. The clinical procedures and data retrieval are taking place at the Scripps Clinic and Research Foundation in a double-blinded fashion. lnterpretation of the initial and ongoing follow-up data will be performed by the Washington Hospital Center, Division of Cardiology. In so doing, an additional level of blinding will be assured. Endovascular brachytherapy may be effective in preventing coronary artery restenosis. Well-controlled clinical trials, such as the SCRIPPS trial, are needed to determine the feasibility. safety. and efficacy of endovascular brachytherapy in preventing coronary arter? restenosis.