WHEN TO TREAT? WHEN TO STOP?
Sengul OZDEK *, Mehmet Cuneyt OZMEN* *
*Gazi University, School of Medicine, Department of Ophthalmology, Ankara
** Yenisehir State Hospital, Department of Ophthalmology, Kahramanmaras
MARINA and ANCHOR were the first studies showing level 1 evidence for the effect of ranibizumab for the treatment of neovascular ARMD (Brown et al., 2009; Rosenfeld et al., 2006a; Rosenfeld et al., 2006b). These studies have shown that 33-
2. How to Decrease the Number of Injections without Compromising Visual Acuity?
PIER study was the first study investigating the results of less frequent dosing regimens with ranibizumab (3-
2.1. What is “PRN” treatment regimen and what are the most reliable criteria for treatment decision?
PRN treatment regimen is a treatment schedule which allows treatment only if the lesion is active. The aim of the PRN treatment is to avoid monthly injections and to decrease the number of injections as much as possible while preserving the increase in vision during the loading period (first three months).
The key point in PRN treatment is assessment of the activity of the lesion to decide for additional treatments. It is obvious that a totally fibrotic yellow scarring lesion without any hemorrhage around, only late staining of the scar tissue in fluorescein angiography (FA), and no subretinal or intraretinal fluid in optical coherence tomography (OCT) with stable vision for a long time does not need any treatment. On the other side of the spectrum, a lesion with subretinal hemorrhages all around, significant late leakage in FA and a considerable subretinal or intraretinal fluid in OCT and deteriorating vision recently needs treatment with no doubt. However most of the lesions are in between these two ends of the spectrum especially during the course of anti-
Until recently, the presence or absence of fluorescein leakage and the angiographic appearance of the lesion were the main criteria for the decision to treat neovascular ARMD and re-
2.2. Treatment Regimens Other than PRN
Although PRN treatment regimen may reduce the number of intravitreal injections and allow the treatment plan to be individualized, it may still require monthly visits to specialized centers. In contrast to mandated monthly injections, patients treated with PRN
strategies may develop multiple recurrences of CNV activity over time. Recurrent intra-
2.2.1 Treat & Extend Dosing Regimen
In an attempt to minimize the number of intravitreal injections, office visits, and ancillary testing, a “treat and extend” regimen (TER) was first put forth by Bailey Freund, (unpublished data, February 2006) and then adopted by others (Gupta et al., 2010; Oubraham et al., 2011). A typical TER starts with monthly injections until the signs of exudation have resolved with confirmation by OCT. The treatment interval is then sequentially lengthened by 1 to 2 weeks as long as there are no signs of recurrent exudation. When recurrent exudation is detected on a follow-
In a study by Gupta et al., eyes with neovascular AMD experienced significant visual improvement when managed with intravitreal ranibizumab using a TER. This treatment approach also was associated with significantly fewer patient visits, injections, and direct annual medical cost compared with monthly injections such as in the phase III clinical trials (Gupta et al., 2010). The interval was individualized for each patient in an attempt to maintain an exudation-
2.2.2 Individualized Injection Intervals
Another individualized treatment strategy that aims to avoid recurrent CNV activity in addition to reducing the number of injections and visits may be to perform the injection immediately prior to the next recurrence. This would require the ability to determine or predict the recurrence interval for an individual patient. A treatment schedule can be obtained for some of the cases after a couple of years of experience with PRN regimen (Hörster et al., 2011). Knowledge of individual recurrence interval times may allow for the development of an individualized treatment plan (Figure 1).
Figure 1. A, Baseline, VA: 44 letters, 1st injection. B, 1st month, 53 letters, 2nd injection. C, 2nd month, 54 letters, 3rd injection. D, 51 letters, no treatment. E, 4th month, 46 letters, 4th injection. F, 5th month, 47 letters, no treatment. G, 6th month, 46 letters, 5th injection. H, 7th month, 42 letters, 6th injection. I, 8th month, 50 letters, no treatment. J, 8th month, 44 letters, 7th injection. K, 9th month, 48 letters, no treatment. L, 10th month, 38 letters, 8th injection. According to the data, this patient has a recurrence pattern of 8 weeks, thus needs re-
A retrospective study in University of Cologne analyzed the recurrence intervals of patients undergoing anti-
In conclusion, re-
2.3. The Need for an Activity Scoring for Re-
All treatment regimens mentioned above aims to reduce injection numbers without compromising the patients visual acuity. Yet there is not a consensus about the objective criteria of an active neovascular CNV lesion.
Definition of an active lesion should not be done only with the OCT based criteria. We believe that, other parameters like visual acuity, presence of hemorrhage associated with the lesion, lesion size and FA staining pattern (when needed) are all also important for assessment of neovascular AMD activity. The PrONTO study put some of these parameters together and created their criteria for retreatment. Retreatment with ranibizumab was performed only if one of the following occurred in PrONTO study (Fung et al., 2007):
1. An increase in central OCT thickness of at least 100 mm,
2. A loss of five letters in conjunction with recurrent fluid by OCT,
4. New macular hemorrhage.
SUSTAIN study used only VA and OCT criteria for retreatment decision. We believe that these are very well prepared criteria, however, some of the items could be changed and some new criteria could be added to make it more reliable.
3. A Clinical Activity Scoring for Re-
In this chapter a new clinical activity scoring (AS) is proposed to assess activity of lesions, to quantify the activity for statistical purposes in clinical studies and to standardize the re-
The proposed AS is based on the well known and widely used signs and findings of active neovascular AMD (Table 1):
1) Presence of subretinal or intraretinal fluid in OCT,
2) Presence of hemorrhage associated with the lesion,
3) Change in vision;
a) Objective measured visual acuity (VA)
b) Subjective vision (what patient feels about his vision)
4) Change in size of the lesion,
5) FA staining pattern (when needed).
Amount of hemorrhage associated with the lesion No hemorrhage 0
Same amount 2
Subretinal fluid / retinal thickening / PED None 0
Any amount at beginning / Stable 2
No change 1
No change 1
Staining pattern No staining/window defect 0
Staining of scar tissue/PED 1
Late leakage 2
Size of the lesion
Lesion area in FA
Beginning size / Stable 1
Table 1: Clinical Activity Scoring for neovascular AMD lesions
Apart from FA staining pattern, all of the other assessments are based on the changes (same-
We have used this scoring in a group of neovascular AMD patients all of which have been involved in a prospective study for intravitreal bevacizumab (IVB) in our clinic (Şekeryapan et al., 2011). All of them received IVB monotherapy. The reports of the patients were reviewed retrospectively and demographic features as well as lesion characteristics of the patients were noted. AS of all of the lesions were calculated according to the following criteria:
1. OCT: OCT was performed using the Humphrey model 3000 (Zeiss-
2. Amount of hemorrhage: The amount of hemorrhage associated with the lesion (in ophthalmoscopy, colored fundus photography or FA) was noted and if there is any hemorrhage at the beginning it was scored as 2. If there is no hemorrhage it was scored as 0, if it was decreased it was scored as 1, if it was the same, scored as 2, and if it was increased scored as 3.
3. Visual assessment:
a. Objective VA is measured with ETDRS and noted as a baseline and scored as 1. If there is a decrease in vision (any line or ≥5 letters loss) it was scored as 2 and if there is any increase in vision (any line or ≥5 letters gain) it was scored as 0.
b. Subjective vision (what patient feels about his vision): Patient’s feeling about any change in his vision was also asked and noted as subjective vision which was scored as 0 if he feels better, 2 if he feels worse and 1 if he did not feel any change (baseline).
4. FA staining pattern: No staining or window defect (0), staining of scar tissue or PED (1) and late leakage (2) were noted.
5. The area of the lesion (mm2): It was measured in FA and the baseline area (or no change) was scored as 1, at least 10% (of the original area) increase was scored as 2 and at least 10% decrease was scored as 0.
Records of the patients at the 1st month visit after the treatment were also noted and all of the above parameters were again noted, so that an AS is calculated both before and after the treatment. AS could range between 0 and 14. Change in AS after the treatment was analyzed by using Wilcoxon signed rank test.
We hypothesized that, the more active the lesion the more it may respond to the anti-
Eyes with favorable treatment response (two or more units of decrease in AS) and unfavorable treatment response (one unit or no decrease in AS) were separated and the mean pre and posttreatment AS were calculated for both groups. The mean AS of these two groups were compared by using Mann-
A total of 52 eyes with neovascular AMD were involved in the study. Mean age of the patients was 72.7 (52-
Pretreatment mean AS of eyes was 7.4 (ranged between 3 and 10) which decreased significantly to 4.2 after treatment (p<0.001, Wilcoxon). There was a significant positive correlation between the pretreatment AS of eyes and the posttreatment decrease in AS (Pearson correlation coefficient: 0.534, p<0.001, Figure 2).
Figure 2. Correlation between the pretreatment AS of eyes and the post-
To define a cut-
Figure 3. The pretreatment AS was statistically significantly higher in favorable treatment response group than unfavorable treatment response group (Mann Whitney U test p=0.003).
The sensitivity, specificity, negative and positive predictive values of the AS with different cut off points were calculated (table 2) and an AS of 7 was found to be most suitable as a cut-
Pretreatment AS≥ 6 Pretreatment AS≥ 7 Pretreatment AS≥ 8
Positive predictive value 85,10% 90,20% 100,00%
Negative predictive value 40,00% 45,50% 25,70%
Sensitivity 93,00% 86,00% 39,50%
Specificity 22,20% 55,60% 100,00%
Table 2. Predictive values, sensitivity and specificity of AS for detecting favorable treatment response (2 or more decrease in AS)
Eyes with an AS of 7 or more (group 1, highly active group, n=41) were separated from those less than 7 (group 2, less active group, n=11) and a subgroup analysis was done. The mean AS in group 1 was 7.8 (7-
Figure 4. Pretreatment and posttreatment mean AS of eyes in group 1 (with an AS of 7 or more, highly active group) and in group 2 (with an AS of less than 7, less active group).
Figure 5. Pre and post treatment difference in AS of highly active group and less active group. Decrease in AS was significantly more in highly active group (pretreatment AS≥7) (p=0.003).
Sensitivity of AS (ratio of eyes with a favorable response and an AS of 7 or more to the total number of eyes with favorable response) was 86% and, specificity of AS (ratio of eyes with an unfavorable response and an AS of less than 7 to the total number of eyes with unfavorable response) was 56% with a cut-
Favorable Response Unfavorable Response Total
AS ≥7 37 4 41
AS <7 6 5 11
Total 43 9 52
Positive predictive value, 37 of 41 = 90%; negative predictive value, 5 of 11 = 45%, sensitivity, 37 of 43 = 86%, specificity, 5 of 9 = 56%.
Table 3. Accuracy of activity score (AS) in predicting therapeutic outcome of treatment in neovascular AMD.
Neovascular AMD activity is an important factor to determine if it should be treated or not. It is important not to over-
Although most of the studies used OCT findings and VA changes to determine the need for additional therapy (Holz et al., 2011), we believe that, some other parameters like, subjective feeling of patients about their vision, presence of hemorrhage associated with the lesion, lesion size, FA staining pattern and are also important for assessment of neovascular AMD activity especially in those undetermined cases. AS is defined to standardize the understanding of findings and definition of active lesion. We are studying on this system since 2002 and have used it in our practice as well as in some of our studies (Ozdek et al.,2005; Ozdek et al.,2007).
It is obvious that ophthalmoscopic appearance of a lesion is very important during interpretation of OCT and FA findings. This is to see new subretinal hemorrhages, exudates and fibrotic scar tissues so that FA and OCT findings can correctly be interpreted. OCT is a very important indicator of neovascular AMD activity and may be assumed as the main determinant for deciding the need for re-
Although we used FA as a parameter in AS, we do not mean to say that we have to perform FA at every visit. Actually, we need to score the lesion only if it is not so clear that the lesion is active or not what we call as “undetermined cases”(Figure 5) . In other words, if we are not sure that a patient should be retreated or not, we can apply to the AS just to bring all the parameters together. If we still do not want to perform a FA, we can add only 1 point for FA which is neutral for activity scoring for FA.
Figure 5. 85 year old woman with a neovascular AMD on the left eye received four doses of intravitreal bevacizumab. On the last visit she had lost 5 letters with a subjective visual impairment. A, early phase of the angiogram. B, late phase of the angiogram. C, fundus photograph. D, OCT image of fovea. This would be an undetermined case without FA. Although the OCT has no sign of active lesion, there are late leakage in FA and objective and subjective visual loss. According to table 1 the patient has an activity score of 8 and assessed as an active lesion.
Change in VA is another very important determinant factor in assessment of treatment effect on neovascular AMD. Usually worsening of VA is a sign of bad response to the treatment and, a stable or increased VA is supposed as a favorable treatment response. It is possible to see patients with a dry OCT and silent ophthalmoscopy without any hemorrhage having a decreased VA both objectively and subjectively. Those patients may have a late leakage in FA indicating activity and treatment need or that VA decrease may be a sign of progression of dry component of AMD.
Vision is not only the central VA and it has many other components like scotomas in visual field, contrast sensitivity, color vision etc. So snellen or ETDRS visual acuity measurement may not be enough to assess vision especially in macular diseases. The simplest measure may be to ask the patient his feelings about his vision; if it is the same, decreased or increased. The subjective change in vision may also give important clues about the effect of treatment. However, it is highly dependent on the patients’ personality and on the eye (in the better eye or in the worse eye). Patient may feel always worse if he is pessimistic and depressive or vice versa. Patient may feel the changes more precisely if the problem is in the better eye, on the other hand, may not feel the significant changes if the disease is in the worse eye. To overcome such shortcomings of subjective assessment of vision, more objective measures for the assessment of the other components of the central vision may be used. VFQ25 may be an option but takes a long time for these cases and is not so practical. Unver et al have developed a new tool for the automated assessment of functional central vision called central field acuity perimetry to solve such problems (Unver et al., 2009). However there is no clinical study with central field acuity perimetry for this purpose up till now. Microperimetry and functional magnetic resonance imaging are other new tools to measure objective measure of topographic visual function (Baseler et al., 2011; Uppal et al., 2011). On the other hand, deterioration of vision is not always an indication of lesion activity itself. Progression of the dry component of the disease (atrophic changes), fibrosis and cicatrisation of the lesion during healing period following treatment may also cause deterioration of vision. Vision cannot be a sole criterion (just like other parameters) but may add to other factors indicating lesion activity.
Change in lesion area is another important determinant of the activity of the lesion. It is not seldom to see a central inactive lesion without any fluid in OCT or any change in objective measured VA may enlarge with a pseudo-
The major problem that we faced during the assessment of the reliability of this scoring system was the absence of a gold standard to define an active lesion which can be used for comparison. Rosenfeld et al were the first to define some criteria to identify an active lesion which needs retreatment with anti-
We would like to emphasize on the unequal distribution of points between different parameters of the AS. We have purposefully given higher scores for hemorrhage (3 points), OCT (3 points) and VA (2+2 points) which are more powerful indicators of the lesion activity than the FA and lesion size.
When we take all of these parameters into account and score it, we observed that pretreatment mean AS was 7.4 which decreased significantly to 4.2 after treatment. Which means that AS really indicates the activity of the lesion. We also observed that a lesion with a higher AS is more likely to give more dramatic response to the anti-
Transferring these data to the clinical applications, it seems logical to treat lesions with an AS of 7 or more with anti-
In addition to routine clinical practice, AS may be used as a standard way of assessment of lesion activity especially in clinical studies for the statistical comparison of the results. AS may be a valuable tool to see the picture (both the lesion and the response to the treatment) as a whole.
In conclusion, assessment of the lesion activity is important for PRN treatment approaches and AS seems to be a standardized measure to assess the activity of the lesion at the beginning as well as the treatment effect after anti-
Individualized approaches, on the other side, may be a good option in suitable cases. Re-
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