SLT: A New Treatment for Glaucoma Becomes Available
An edited version of this column was published in OCULAR SURGERY NEWS on May 15, 2001
Technology Update
Irving J. Arons
Managing Director
Spectrum Consulting
Introduction
The FDA has recently cleared SLT (selective laser trabeculoplasty) for the treatment of primary open-angle glaucoma (OAG). Coherent Medical (Santa Clara, CA), soon to be combined with ESC Medical Systems(Yokneam, Israel) in a new company to be called Lumenis, will roll out their new Selecta 7000 laser for performing this potentially first-line therapy for primary OAG at the Spring ASCRS meeting in San Diego. The new safer alternative to ALT (argon laser trabeculoplasty), and for non-compliant patients on medical therapy, was cleared by the FDA late in March, 2001. Its key features are its minimal damage to surrounding tissue, long-lasting non-thermal effect in lowering IOP, and repeatability!
Unlike the sometime short-lived thermal effects of ALT in lowering IOP, selective laser trabeculoplasty uses a Q-switched doubled YAG laser to selectively target melanin pigmentation in trabecular meshwork cells, in a process known as selective photothermolysis, thereby delivering no damage to non-targeted adjacent tissue. Because SLT is non-thermal, it is repeatable, a distinct advantage over ALT. For this reason alone, not withstanding its clinically-proven long-term effect in lowering IOP (up to 80% success in obtaining a mean 23% reduction in IOP lasting for at least 24 months in international trials for patients on maximally tolerated medical therapy, and still uncontrolled), it could have a significant impact on glaucoma therapy, possibly becoming the first approach to treatment.
Underlying Principles and History
Dr. Mark Latina, the inventor or SLT, first became interested in selectively targeting trabecular meshwork cells while a fellow at the Boston-based Mass Eye & Ear Hospital in 1985, and later, working under an NIH grant, transferred his work to the Wellman Laboratories of Photomedicine at Mass General Hospital in 1987. Work was underway at the Wellman at that time on discovering the benefits of selective photothermolysis, discovered by Drs. Rox Anderson and John Parrish in the early 1980s. Selective photothermolysis, now used extensively in the laser treatment of several skin diseases and in laser-based hair removal, is based on three principles. First, absorption of intracellular targets must be greater than that of surrounding tissues (such as melanin as a chromophore in the trabecular meshwork). Second, a short pulse of laser energy is required to generate and confine heat to the pigmented targets, with the wavelength matching the absorption wavelength of the target. (Again, melanin proved a worthy target.) Finally, the pulse duration must be less than or equal to the thermal relaxation time of the target. When all of these conditions are met, target specificity becomes independent of focus.
Based on some published observations of Jorge Alvarado, MD, pertaining to the decreased cellularity in the trabecular meshwork, Dr. Latina and his colleagues at Wellman attempted to separate the coagulative effects from the purely biological effects, as well as the physiological effects on the TM of laser trabeculoplasty, and to see if the cells could be selectively targeted. At that time (in 1985/1986), two types of lasers were in use in ophthalmology, continuous wave argon, for thermal coagulation, and the Q-switched, pulsed Nd:YAG, just coming into use for photodisruption (optical breakdown) of secondary capsules, and for iridotomy. The conventional argon laser trabeculoplasty (ALT) used a pulse generation of 100 ms to transfer heat to the focal spot in the trabecular meshwork, causing a coagulative burn and creating a scar, which helped to improve fluid outflow through the shrunken tissue surrounding the scar. With the work underway at Wellman on confining thermal damage to selected pigmented targets, Latina and his colleagues thought that if the appropriate laser parameters were chosen, a specific type of laser tissue interaction could be achieved. And thus, after experimentation with various short-pulsed lasers, and using the melanin pigment in the TM cells as a target in cell viability cytotoxicity assays, it was discovered that a single pulse of a Q-switched 532 nm doubled YAG laser could effect only the pigmented TM cells aimed at, while not effecting pigmented cells or other structures outside of the irradiation zone, and most importantly, there was no gross disruption of the TM cells being targeted.
With the argon laser, there was no region where selective killing could be achieved, even with short pulse durations. However, with the 532 nm Q-switched laser, selective targeting was achieved using threshold fluences of only 50 mJ/cm2. This was a much lower fluence that the 107 mJ/cm2 then in use with the conventional Nd:YAG 1064 nm photodisruptive laser. A 400 um spot size is used with the 532 nm laser for SLT, which is quite large compared to the typical 10 um spot used with the Nd:YAG (or 50 um spot used with the argon laser in ALT). Thus pumping 1 mJ of energy into the 10 um spot results in extremely high irradiances, while the same 1 mJ pumped into the 400 um spot of the SLT laser results in very low energy per unit area. This discovery was patented by Dr. Latina in U.S. Patent 5,549,596.
Beginning about 1993, as part of a support program for work underway at the Wellman Laboratories, Coherent Medical became aware of Dr. Latina's work and began supporting it directly, including building a clinical laser for him. The company modified one of its ophthalmic Nd:YAG lasers, adding the doubling crystals to bring the wavelength down to 532 nm, and added the optics necessary to create the 400 um spot. This ultimately became the Selecta 7000, used in both the U.S. and international clinical trials, and now approved by the FDA for treating primarily open angle glaucoma with SLT. Coherent obtained an exclusive license to the SLT patent from Mass General Hospital upon its issue in 1996.
The major advantages of SLT over ALT are: 1) selectivity, only the melanin pigment in TM cells is targeted; 2) no thermal damage or gross disruption of the TM cell architecture (and thus excellent safety); and 3) the potential for repeatability of the process. Unlike ALT that creates scars in the trabecular meshwork, SLT does not do damage to other than the targeted cells, and thus the treatment can be repeated if further reduction in IOP is needed. With the FDA approval of SLT in late March 2001, HCFA has approved reimbursement equivalent to ALT, or on average of about $385 per procedure. The Selecta 7000, which has the CE mark and has been available for sale in the European Union since 1998, and is approved by the Ministry of Health for sale in Japan, will be commercially launched in the U.S. at the Spring ASCRS meeting, priced at $55,000.
Technique and Clinical Trial Data
The procedure for use is similar to a conventional ALT. Preoperatively, careful gonioscopy is done to visualize the trabecular meshwork and plan the treatment area. A drop of each of Iopidine or Alphagan and topical anesthesia are applied, and a Goldman three-mirror goniolens is placed on the eye with methylcellulose. The aiming beam is focused onto the pigmented trabecular meshwork and the treatment is done by placing 50±5 contiguous but not overlapping 400 um single laser spots along an 180° treatment arc. Unlike argon laser trabeculoplasty, there are no visible coagulation burns to the trabecular meshwork. If bubble formation occurs, it means the pulse energy is too high. Bubble formation is monitored with each pulse. After laser treatment, prednisolone acetate 1% is administered and continued in the treated eye four times daily for four to seven days.
Selective trabeculoplasty is not associated with coagulation damage, but significantly lowers IOP. This indicates that coagulation of the TM structure is not important to the mechanism of IOP-lowering. It is believed that SLT works on the cellular level, either through migration and phagocytosis of TM debris by the macrophages, or by stimulation of formation of healthy trabecular tissue which may enhance the outflow properties of the TM.
Beginning in 1998, a prospective, U.S. multicenter pilot study was conducted at three sites for evaluating the IOP-lowering effect of SLT. Fifty-three eyes of 53 patients whose IOP was not controlled with maximum medical therapy, the OAG group; and a second group of 67 patients with uncontrolled OAG who had previously failed argon laser trabeculoplasty, the post-ALT group, were included. Most patients had primary OAG, a few had pseudoexfoliative glaucoma, and a further few had other types of the disease. All anti-glaucoma medications were maintained during the treatment and follow-up periods. Of the 120 patients treated with SLT, 101 (84%) were evaluated in terms of efficacy analysis for the FDA. Fifteen patients discontinued the study early for various reasons. The remaining patients were followed for 26 weeks postoperativelyy.
The results showed that 72% of both SLT treatment groups of patients were responders. The average preoperative baseline IOP was 25.4 mm Hg, and showed a mean IOP reduction of 5.9 mm Hg (23%) at 26 weeks. In the OAG group, the mean baseline was 25.1 mm Hg. These patients showed an IOP reduction of 6.0 mm Hg, or a 23.9% drop. The post-ALT group was slightly closer in both the responder rate as well as IOP reduction overall, with 71.4% responding with an IOP reduction of 5.8 mm Hg. The untreated eyes had an average preoperative IOP of 21.2 mm Hg and had a reduction of 2.8 mm Hg (13.2%). SLT was equally effective in IOP reduction as ALT in both the OAG and post-ALT groups. There was no persistent IOP elevation following the SLT treatment in the post-ALT group, which is prevalent following ALT treatment.
Adverse effects consisted of peripheral anterior synechiae in 8 patients (6.7%) of treated eyes, one in the OAG group and seven in the post-ALT group. (Seven patients also were reported to have peripheral anterior synechiae in the untreated eyes.) Anterior chamber inflammation with observable cells and flare was noted in approximately 80% of eyes in the early postoperative period. The inflammation was treated with topical steroids and dissipated within 24-72 hours. Fifteen percent of patients complained of minimal pain, discomfort, and redness during treatment or at follow-up.
A prospective, randomized Canadian clinical study by Dr. Karim Damji compared SLT with ALT in 36 eyes. Baseline IOP was 22.8 mm Hg and the SLT group had 22.5 mm Hg. For the ALT group, IOP reductions were 4.8 mm Hg at 6 months, while the SLT group had an average reduction of 5.0 mm Hg.
The largest group of patients treated to date were in Germany, where Drs. Weimer, and Kaulen investigated 460 eyes with 2 years of follow-up. The SLT-treated group had a mean decrease in IOP of 23%, with a two-year success rate of 80%. The complication rate was roughly 4.5%, much lower than the complication rate for ALT, which can reach 34%. The most common complications were elevation of IOP (2.4%), and significant inflammatory reaction in the anterior chamber without an IOP spike (1.5%). All complications were easily treated.
Conclusion
SLT is as effective as ALT in the treatment of primary OAG patients. SLT appears to be repeatable, because of the lack of coagulation damage and the demonstrated efficacy in patients with previously failed ALT treatments. With this lack of tissue damage, SLT should be considered, and has the potential to evolve as an ideal primary treatment option in open angle glaucoma patients who cannot tolerate or are non-compliant with medications, without interfering with the success of future surgery.
Technology Update
Irving J. Arons
Managing Director
Spectrum Consulting
Introduction
The FDA has recently cleared SLT (selective laser trabeculoplasty) for the treatment of primary open-angle glaucoma (OAG). Coherent Medical (Santa Clara, CA), soon to be combined with ESC Medical Systems(Yokneam, Israel) in a new company to be called Lumenis, will roll out their new Selecta 7000 laser for performing this potentially first-line therapy for primary OAG at the Spring ASCRS meeting in San Diego. The new safer alternative to ALT (argon laser trabeculoplasty), and for non-compliant patients on medical therapy, was cleared by the FDA late in March, 2001. Its key features are its minimal damage to surrounding tissue, long-lasting non-thermal effect in lowering IOP, and repeatability!
Unlike the sometime short-lived thermal effects of ALT in lowering IOP, selective laser trabeculoplasty uses a Q-switched doubled YAG laser to selectively target melanin pigmentation in trabecular meshwork cells, in a process known as selective photothermolysis, thereby delivering no damage to non-targeted adjacent tissue. Because SLT is non-thermal, it is repeatable, a distinct advantage over ALT. For this reason alone, not withstanding its clinically-proven long-term effect in lowering IOP (up to 80% success in obtaining a mean 23% reduction in IOP lasting for at least 24 months in international trials for patients on maximally tolerated medical therapy, and still uncontrolled), it could have a significant impact on glaucoma therapy, possibly becoming the first approach to treatment.
Underlying Principles and History
Dr. Mark Latina, the inventor or SLT, first became interested in selectively targeting trabecular meshwork cells while a fellow at the Boston-based Mass Eye & Ear Hospital in 1985, and later, working under an NIH grant, transferred his work to the Wellman Laboratories of Photomedicine at Mass General Hospital in 1987. Work was underway at the Wellman at that time on discovering the benefits of selective photothermolysis, discovered by Drs. Rox Anderson and John Parrish in the early 1980s. Selective photothermolysis, now used extensively in the laser treatment of several skin diseases and in laser-based hair removal, is based on three principles. First, absorption of intracellular targets must be greater than that of surrounding tissues (such as melanin as a chromophore in the trabecular meshwork). Second, a short pulse of laser energy is required to generate and confine heat to the pigmented targets, with the wavelength matching the absorption wavelength of the target. (Again, melanin proved a worthy target.) Finally, the pulse duration must be less than or equal to the thermal relaxation time of the target. When all of these conditions are met, target specificity becomes independent of focus.
Based on some published observations of Jorge Alvarado, MD, pertaining to the decreased cellularity in the trabecular meshwork, Dr. Latina and his colleagues at Wellman attempted to separate the coagulative effects from the purely biological effects, as well as the physiological effects on the TM of laser trabeculoplasty, and to see if the cells could be selectively targeted. At that time (in 1985/1986), two types of lasers were in use in ophthalmology, continuous wave argon, for thermal coagulation, and the Q-switched, pulsed Nd:YAG, just coming into use for photodisruption (optical breakdown) of secondary capsules, and for iridotomy. The conventional argon laser trabeculoplasty (ALT) used a pulse generation of 100 ms to transfer heat to the focal spot in the trabecular meshwork, causing a coagulative burn and creating a scar, which helped to improve fluid outflow through the shrunken tissue surrounding the scar. With the work underway at Wellman on confining thermal damage to selected pigmented targets, Latina and his colleagues thought that if the appropriate laser parameters were chosen, a specific type of laser tissue interaction could be achieved. And thus, after experimentation with various short-pulsed lasers, and using the melanin pigment in the TM cells as a target in cell viability cytotoxicity assays, it was discovered that a single pulse of a Q-switched 532 nm doubled YAG laser could effect only the pigmented TM cells aimed at, while not effecting pigmented cells or other structures outside of the irradiation zone, and most importantly, there was no gross disruption of the TM cells being targeted.
With the argon laser, there was no region where selective killing could be achieved, even with short pulse durations. However, with the 532 nm Q-switched laser, selective targeting was achieved using threshold fluences of only 50 mJ/cm2. This was a much lower fluence that the 107 mJ/cm2 then in use with the conventional Nd:YAG 1064 nm photodisruptive laser. A 400 um spot size is used with the 532 nm laser for SLT, which is quite large compared to the typical 10 um spot used with the Nd:YAG (or 50 um spot used with the argon laser in ALT). Thus pumping 1 mJ of energy into the 10 um spot results in extremely high irradiances, while the same 1 mJ pumped into the 400 um spot of the SLT laser results in very low energy per unit area. This discovery was patented by Dr. Latina in U.S. Patent 5,549,596.
Beginning about 1993, as part of a support program for work underway at the Wellman Laboratories, Coherent Medical became aware of Dr. Latina's work and began supporting it directly, including building a clinical laser for him. The company modified one of its ophthalmic Nd:YAG lasers, adding the doubling crystals to bring the wavelength down to 532 nm, and added the optics necessary to create the 400 um spot. This ultimately became the Selecta 7000, used in both the U.S. and international clinical trials, and now approved by the FDA for treating primarily open angle glaucoma with SLT. Coherent obtained an exclusive license to the SLT patent from Mass General Hospital upon its issue in 1996.
The major advantages of SLT over ALT are: 1) selectivity, only the melanin pigment in TM cells is targeted; 2) no thermal damage or gross disruption of the TM cell architecture (and thus excellent safety); and 3) the potential for repeatability of the process. Unlike ALT that creates scars in the trabecular meshwork, SLT does not do damage to other than the targeted cells, and thus the treatment can be repeated if further reduction in IOP is needed. With the FDA approval of SLT in late March 2001, HCFA has approved reimbursement equivalent to ALT, or on average of about $385 per procedure. The Selecta 7000, which has the CE mark and has been available for sale in the European Union since 1998, and is approved by the Ministry of Health for sale in Japan, will be commercially launched in the U.S. at the Spring ASCRS meeting, priced at $55,000.
Technique and Clinical Trial Data
The procedure for use is similar to a conventional ALT. Preoperatively, careful gonioscopy is done to visualize the trabecular meshwork and plan the treatment area. A drop of each of Iopidine or Alphagan and topical anesthesia are applied, and a Goldman three-mirror goniolens is placed on the eye with methylcellulose. The aiming beam is focused onto the pigmented trabecular meshwork and the treatment is done by placing 50±5 contiguous but not overlapping 400 um single laser spots along an 180° treatment arc. Unlike argon laser trabeculoplasty, there are no visible coagulation burns to the trabecular meshwork. If bubble formation occurs, it means the pulse energy is too high. Bubble formation is monitored with each pulse. After laser treatment, prednisolone acetate 1% is administered and continued in the treated eye four times daily for four to seven days.
Selective trabeculoplasty is not associated with coagulation damage, but significantly lowers IOP. This indicates that coagulation of the TM structure is not important to the mechanism of IOP-lowering. It is believed that SLT works on the cellular level, either through migration and phagocytosis of TM debris by the macrophages, or by stimulation of formation of healthy trabecular tissue which may enhance the outflow properties of the TM.
Beginning in 1998, a prospective, U.S. multicenter pilot study was conducted at three sites for evaluating the IOP-lowering effect of SLT. Fifty-three eyes of 53 patients whose IOP was not controlled with maximum medical therapy, the OAG group; and a second group of 67 patients with uncontrolled OAG who had previously failed argon laser trabeculoplasty, the post-ALT group, were included. Most patients had primary OAG, a few had pseudoexfoliative glaucoma, and a further few had other types of the disease. All anti-glaucoma medications were maintained during the treatment and follow-up periods. Of the 120 patients treated with SLT, 101 (84%) were evaluated in terms of efficacy analysis for the FDA. Fifteen patients discontinued the study early for various reasons. The remaining patients were followed for 26 weeks postoperativelyy.
The results showed that 72% of both SLT treatment groups of patients were responders. The average preoperative baseline IOP was 25.4 mm Hg, and showed a mean IOP reduction of 5.9 mm Hg (23%) at 26 weeks. In the OAG group, the mean baseline was 25.1 mm Hg. These patients showed an IOP reduction of 6.0 mm Hg, or a 23.9% drop. The post-ALT group was slightly closer in both the responder rate as well as IOP reduction overall, with 71.4% responding with an IOP reduction of 5.8 mm Hg. The untreated eyes had an average preoperative IOP of 21.2 mm Hg and had a reduction of 2.8 mm Hg (13.2%). SLT was equally effective in IOP reduction as ALT in both the OAG and post-ALT groups. There was no persistent IOP elevation following the SLT treatment in the post-ALT group, which is prevalent following ALT treatment.
Adverse effects consisted of peripheral anterior synechiae in 8 patients (6.7%) of treated eyes, one in the OAG group and seven in the post-ALT group. (Seven patients also were reported to have peripheral anterior synechiae in the untreated eyes.) Anterior chamber inflammation with observable cells and flare was noted in approximately 80% of eyes in the early postoperative period. The inflammation was treated with topical steroids and dissipated within 24-72 hours. Fifteen percent of patients complained of minimal pain, discomfort, and redness during treatment or at follow-up.
A prospective, randomized Canadian clinical study by Dr. Karim Damji compared SLT with ALT in 36 eyes. Baseline IOP was 22.8 mm Hg and the SLT group had 22.5 mm Hg. For the ALT group, IOP reductions were 4.8 mm Hg at 6 months, while the SLT group had an average reduction of 5.0 mm Hg.
The largest group of patients treated to date were in Germany, where Drs. Weimer, and Kaulen investigated 460 eyes with 2 years of follow-up. The SLT-treated group had a mean decrease in IOP of 23%, with a two-year success rate of 80%. The complication rate was roughly 4.5%, much lower than the complication rate for ALT, which can reach 34%. The most common complications were elevation of IOP (2.4%), and significant inflammatory reaction in the anterior chamber without an IOP spike (1.5%). All complications were easily treated.
Conclusion
SLT is as effective as ALT in the treatment of primary OAG patients. SLT appears to be repeatable, because of the lack of coagulation damage and the demonstrated efficacy in patients with previously failed ALT treatments. With this lack of tissue damage, SLT should be considered, and has the potential to evolve as an ideal primary treatment option in open angle glaucoma patients who cannot tolerate or are non-compliant with medications, without interfering with the success of future surgery.
posted by Irv Arons @ 3:32 PM
5 comments
5 Comments:
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David
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With the best regards!
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