MyVisionTest News Archive
Sep 19, 2009
More frequent Lucentis injection results in better outcomes
The visual outcome of patients undergoing Lucentis (ranibizumab) therapy for exudative age-related macular degeneration (AMD) under an as-needed dosing schedule is related to the number of injections received but not to the resolution of fluid by optical coherence tomography (OCT), according to a new research study.
The ANCHOR and MARINA clinical trials of Lucentis therapy for neovascular AMD did not incorporate a treatment end point - all patients recieved monthly Lucentis injections irrespective of clinical course. To minimize treatment burden some clinicians now support the adoption of a variable VEGF inhibitor dosing strategy guided by optical coherence tomography (OCT).
The PrONTO study was a prospective trial of 40 eyes that demonstrated 3 lines or more VA gain in 35% of patients and avoidance of 3 lines VA loss in 95% of eyes receiving 3 monthly Lucentis injections followed by as-needed treatment based on clinical examination and serial OCT monitoring. This as-needed dosing scheme based on OCT has largely been adopted without any clinical trial evidence. Ongoing studies are currently evaluating the effectiveness of as-needed dosing regimens compared with monthly dosing, different monitoring strategies, and combination therapies to determine the optimal niche for anti-VEGF drugs in AMD management.
Methods and Results
A total of 131 eyes with treatment-naïve, exudative AMD underwent intravitreal Lucentis monotherapy administered on an as-needed basis guided by clinical examination and OCT. The OCT scans were evaluated by the treating physicians for the presence of intraretinal fluid, subretinal fluid, intraretinal cysts, or increasing pigment epithelial detachment size. Clinical data including visual acuity (VA), choroidal neovascularization lesion morphology, and treatment course were collected retrospectively for analysis.
The mean age was 81.3 years, mean follow-up was 12 ± 4.3 months (minimum 6 months), and mean number of injections was 5.2 ± 2.8. Mean baseline Snellen VA for the entire population was 20/110 and significantly improved at 6 months (20/80) and at last follow-up (20/90). At 6 months, 31% of eyes had gained at least 3 lines of VA and 90.5% had avoided loss of 3 lines.
On average, it took 3.0 injections and 3.5 months to achieve a "dry" or "flat" macula on OCT after initiating treatment. Resolution of intra- and subretinal fluid on OCT did not correlate with the degree of vision improvement.
Eyes receiving more frequent injections (defined as <2 months mean inter-injection interval) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months). At 6 months, 3.1% of those in the more frequent injection group lost >3 lines of vision compared with 15.9% in the >2 months interval group.
Discussion and Conclusions
On the basis of the MARINA and ANCHOR trial data, the best reported efficacy of anti-VEGF therapy, in terms of VA preservation and gain, is seen with mandated monthly dosing. However, such a regimen raises concerns for overtreatment. Although reported risks of injection-related adverse events such as retinal detachment or endophthalmitis are low, they are not zero, and the results can be devastating. Minimizing the number of injections would decrease this risk. Finally, overuse of such treatments is certain to present an unnecessarily heavy financial burden on society given the cost of Lucentis. Thus, for multiple reasons, it is desirable to find a dosing regimen that is maximally effective at preserving or improving VA while at the same time is intended to avoid treatment when it is not needed.
The PrONTO study featured serial OCT monitoring as a tool to guide repeat injections on a variable as-needed basis after 3 monthly doses. The visual results at 12 months were comparable to what has been reported with monthly injections, but these results were achieved with an average of 5.6 injections over 12 months. Similar results were recently reported in an interim analysis of data from the SUSTAIN study.
The present study retrospectively examined VA change in 131 eyes with treatment-naïve CNV due to exudative AMD treated with Lucentis monotherapy once at baseline and then on an as-needed basis with OCT guidance at a single center with an average of 12 months follow-up. After a mean of 5.2 injections, there was a significant improvement in vision at last follow-up (~1 line gain), and the percentage of eyes with at least 3 lines gained (29.8%) was similar to data in the MARINA trial.
The study population was subdivided on the basis of anatomic response to treatment to distinguish those lesions that had active leakage resolved (as determined by OCT and clinical examination), and who received no further injections during follow-up, from those lesions that had recurrent fluid on follow-up and those in which intraretinal or SRF never resolved throughout the follow-up period. The group without recurrences (also by definition the group receiving the fewest injections; FIGURE 1) exhibited least VA improvement compared with the other 2 groups. This suggests that anatomic outcomes and functional outcomes may not coincide, and what some may consider anatomic "failures" (e.g., refractory or recurrent fluid) may actually be associated with favorable visual outcomes if continued to be treated appropriately.
One variable that may affect visual outcomes among the anatomic response groups is the number of injections given, as mandated by the as-needed treatment strategy. In this study, we are not able to directly compare monthly dosing with a less frequent variable regimen; however, as an approximation of such a comparison, we distinguished those eyes given injections at an average spacing of 2 months or less over the follow-up period from the rest of the study population. Comparison of these groups revealed a greater mean VA improvement (>2 lines difference) and a lower proportion with moderate VA loss in the group receiving injections at an average interval of 2 months or less (FIGURE 3 and FIGURE 4).
In previously reported subgroup analyses of the MARINA trial data, higher baseline VA, larger CNV, and increasing age were found to be associated with less vision gain and greater vision loss in Lucentis-treated groups. The current study found no such association between age and VA change. There was a weak to moderate association between lower baseline VA and VA improvement at month 3, month 6, and last follow-up. However, there was no significant difference in age, baseline CNV size, or baseline VA between the <2 months and >2 months mean injection interval subgroups.
One implication of these findings is that a strictly as-needed treatment strategy based on serial OCT scans may lead to undertreatment with anti-VEGF therapies. An important question that remains to be answered is whether continued anti-VEGF injections in eyes with apparent resolution of fluid on OCT may lead to continued VA improvement. Although some have chosen fixed monthly dosing until more definitive data on alternative regimens emerge, there is at present no consensus on optimal treatment and monitoring strategies, and many clinicians prefer a variable dosing regimen to avoid unnecessary overtreatment.
The conceptual disadvantage of an as-needed treatment strategy is its reliance on a deterioration event (e.g., recurrence of fluid, clinically apparent hemorrhage, VA loss) as the trigger for reinitiation of therapy, which would, based on known statistics on vision gain versus stabilization with this class of drugs, tend to reinitiate therapy at a less favorable "baseline" lesion status every time treatment is restarted. The "treat and extend" approach avoids this potential pitfall because this strategy assumes a predictable "fluid-free interval" for a given lesion or eye, and although this concept seems to be supported by empiric experience, it has yet to be proven.
In summary, this study finds that in eyes with treatment-naïve CNV due to exudative AMD treated with Lucentis monotherapy on an as-needed basis, resolution of intraretinal or SRF on OCT (a favorable anatomic outcome) does not correspond to the degree of VA preservation and gain (favorable functional outcomes) seen in the pivotal clinical trials. The investigators conclude that more frequent injections (on average 1 injection every 1 to 2 months) were associated with a greater mean VA improvement and a lower proportion of eyes with moderate vision loss than less frequent injections. They state that treatment with Lucentis on a strictly as-needed basis may result in undertreatment and significantly less visual gain.
WHAT IT MEANS TO YOU: It is hard to imagine why patients who appear dry on OCT (treatment responders) would have worse vision outcomes than patients who are never dry (treatment nonresponders), but that is exactly what this study found. This study suggests that the most popular dosing strategy for Lucentis and Avastin leads to undertreatment, and vision outcomes would improve if more frequent injections were administered. The researchers state that the "treat-and-extend" dosing strategy, which has never been tested in a randomized controlled trial, may result in superior outcomes to the currently popular as-needed strategy. Clearly, there is a pressing need to find the optimal dosing regimen that balances the benefits and risks of these powerful new drugs.
Read more...
Ophthalmology 2009;116:1740–1747
Tags: PrONTO, Lucentis, wet AMD, prognosis, dosing strategy
The visual outcome of patients undergoing Lucentis (ranibizumab) therapy for exudative age-related macular degeneration (AMD) under an as-needed dosing schedule is related to the number of injections received but not to the resolution of fluid by optical coherence tomography (OCT), according to a new research study. The ANCHOR and MARINA clinical trials of Lucentis therapy for neovascular AMD did not incorporate a treatment end point - all patients recieved monthly Lucentis injections irrespective of clinical course. To minimize treatment burden some clinicians now support the adoption of a variable VEGF inhibitor dosing strategy guided by optical coherence tomography (OCT).
Methods and Results
A total of 131 eyes with treatment-naïve, exudative AMD underwent intravitreal Lucentis monotherapy administered on an as-needed basis guided by clinical examination and OCT. The OCT scans were evaluated by the treating physicians for the presence of intraretinal fluid, subretinal fluid, intraretinal cysts, or increasing pigment epithelial detachment size. Clinical data including visual acuity (VA), choroidal neovascularization lesion morphology, and treatment course were collected retrospectively for analysis.
The mean age was 81.3 years, mean follow-up was 12 ± 4.3 months (minimum 6 months), and mean number of injections was 5.2 ± 2.8. Mean baseline Snellen VA for the entire population was 20/110 and significantly improved at 6 months (20/80) and at last follow-up (20/90). At 6 months, 31% of eyes had gained at least 3 lines of VA and 90.5% had avoided loss of 3 lines.
On average, it took 3.0 injections and 3.5 months to achieve a "dry" or "flat" macula on OCT after initiating treatment. Resolution of intra- and subretinal fluid on OCT did not correlate with the degree of vision improvement.
Eyes receiving more frequent injections (defined as <2 months mean inter-injection interval) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months). At 6 months, 3.1% of those in the more frequent injection group lost >3 lines of vision compared with 15.9% in the >2 months interval group.
Discussion and Conclusions
On the basis of the MARINA and ANCHOR trial data, the best reported efficacy of anti-VEGF therapy, in terms of VA preservation and gain, is seen with mandated monthly dosing. However, such a regimen raises concerns for overtreatment. Although reported risks of injection-related adverse events such as retinal detachment or endophthalmitis are low, they are not zero, and the results can be devastating. Minimizing the number of injections would decrease this risk. Finally, overuse of such treatments is certain to present an unnecessarily heavy financial burden on society given the cost of Lucentis. Thus, for multiple reasons, it is desirable to find a dosing regimen that is maximally effective at preserving or improving VA while at the same time is intended to avoid treatment when it is not needed. The PrONTO study featured serial OCT monitoring as a tool to guide repeat injections on a variable as-needed basis after 3 monthly doses. The visual results at 12 months were comparable to what has been reported with monthly injections, but these results were achieved with an average of 5.6 injections over 12 months. Similar results were recently reported in an interim analysis of data from the SUSTAIN study.
The present study retrospectively examined VA change in 131 eyes with treatment-naïve CNV due to exudative AMD treated with Lucentis monotherapy once at baseline and then on an as-needed basis with OCT guidance at a single center with an average of 12 months follow-up. After a mean of 5.2 injections, there was a significant improvement in vision at last follow-up (~1 line gain), and the percentage of eyes with at least 3 lines gained (29.8%) was similar to data in the MARINA trial.
The study population was subdivided on the basis of anatomic response to treatment to distinguish those lesions that had active leakage resolved (as determined by OCT and clinical examination), and who received no further injections during follow-up, from those lesions that had recurrent fluid on follow-up and those in which intraretinal or SRF never resolved throughout the follow-up period. The group without recurrences (also by definition the group receiving the fewest injections; FIGURE 1) exhibited least VA improvement compared with the other 2 groups. This suggests that anatomic outcomes and functional outcomes may not coincide, and what some may consider anatomic "failures" (e.g., refractory or recurrent fluid) may actually be associated with favorable visual outcomes if continued to be treated appropriately.One variable that may affect visual outcomes among the anatomic response groups is the number of injections given, as mandated by the as-needed treatment strategy. In this study, we are not able to directly compare monthly dosing with a less frequent variable regimen; however, as an approximation of such a comparison, we distinguished those eyes given injections at an average spacing of 2 months or less over the follow-up period from the rest of the study population. Comparison of these groups revealed a greater mean VA improvement (>2 lines difference) and a lower proportion with moderate VA loss in the group receiving injections at an average interval of 2 months or less (FIGURE 3 and FIGURE 4).
In previously reported subgroup analyses of the MARINA trial data, higher baseline VA, larger CNV, and increasing age were found to be associated with less vision gain and greater vision loss in Lucentis-treated groups. The current study found no such association between age and VA change. There was a weak to moderate association between lower baseline VA and VA improvement at month 3, month 6, and last follow-up. However, there was no significant difference in age, baseline CNV size, or baseline VA between the <2 months and >2 months mean injection interval subgroups.
One implication of these findings is that a strictly as-needed treatment strategy based on serial OCT scans may lead to undertreatment with anti-VEGF therapies. An important question that remains to be answered is whether continued anti-VEGF injections in eyes with apparent resolution of fluid on OCT may lead to continued VA improvement. Although some have chosen fixed monthly dosing until more definitive data on alternative regimens emerge, there is at present no consensus on optimal treatment and monitoring strategies, and many clinicians prefer a variable dosing regimen to avoid unnecessary overtreatment. The conceptual disadvantage of an as-needed treatment strategy is its reliance on a deterioration event (e.g., recurrence of fluid, clinically apparent hemorrhage, VA loss) as the trigger for reinitiation of therapy, which would, based on known statistics on vision gain versus stabilization with this class of drugs, tend to reinitiate therapy at a less favorable "baseline" lesion status every time treatment is restarted. The "treat and extend" approach avoids this potential pitfall because this strategy assumes a predictable "fluid-free interval" for a given lesion or eye, and although this concept seems to be supported by empiric experience, it has yet to be proven.
In summary, this study finds that in eyes with treatment-naïve CNV due to exudative AMD treated with Lucentis monotherapy on an as-needed basis, resolution of intraretinal or SRF on OCT (a favorable anatomic outcome) does not correspond to the degree of VA preservation and gain (favorable functional outcomes) seen in the pivotal clinical trials. The investigators conclude that more frequent injections (on average 1 injection every 1 to 2 months) were associated with a greater mean VA improvement and a lower proportion of eyes with moderate vision loss than less frequent injections. They state that treatment with Lucentis on a strictly as-needed basis may result in undertreatment and significantly less visual gain.
WHAT IT MEANS TO YOU: It is hard to imagine why patients who appear dry on OCT (treatment responders) would have worse vision outcomes than patients who are never dry (treatment nonresponders), but that is exactly what this study found. This study suggests that the most popular dosing strategy for Lucentis and Avastin leads to undertreatment, and vision outcomes would improve if more frequent injections were administered. The researchers state that the "treat-and-extend" dosing strategy, which has never been tested in a randomized controlled trial, may result in superior outcomes to the currently popular as-needed strategy. Clearly, there is a pressing need to find the optimal dosing regimen that balances the benefits and risks of these powerful new drugs.
Read more...
Ophthalmology 2009;116:1740–1747
