Article

Treat and Extend for Chorioretinal Vascular Conditions

Reducing costs and number of injections for patients.

Phase 3 registration trials for drugs that inhibit the actions of vascular endothelial growth factor (VEGF) demonstrated that regular-interval dosing of pegaptanib (6 weeks),1 ranibizumab (4 weeks),2-4 and aflibercept (4 weeks or 8 weeks)5,6 produced clinically and statistically superior visual acuity (VA) improvements over the comparator or baseline in eyes with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Patients experience clinically meaningful improvements in VA, but monthly therapy is often burdensome for physicians, patients, and caregivers, and concerns over the sustainability of these intensive treatment regimens have been voiced.7 Attempts to reduce the injection frequency to every 3 months obliterated gains in VA that had been obtained with a short course of monthly induction therapy.8-10 Investigators soon observed that frequent, regular dosing was not needed to produce satisfactory results for all patients and that individualized therapy could potentially reduce the direct and indirect costs of therapy, the number of injections, and possibly the number of visits to physicians’ offices.

HISTORY OF INDIVIDUALIZED THERAPY

The Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular AMD Treated With Intraocular Ranibizumab (PrONTO) trial11 demonstrated that pro re nata (PRN) treatment of nAMD improves best corrected visual acuity (BCVA) comparably to what was achieved in the registration trials and the Protocol I trial by the Diabetic Retinopathy Clinical Research Network12 produced similar BCVA improvements (after at least 4 monthly injections) in patients with DME. Subsequent trials, however, showed that PRN regimens for nAMD usually underperform monthly-injection regimens by approximately 2 letters without decreasing the need for monthly clinic visits and examinations.13-15 Some investigators expressed concerns that the prolonged treatment-free intervals, coupled with frequent recurrences that are inherent to PRN regimens, may increase the risk of subretinal hemorrhages.16,17

TREAT AND EXTEND FOR MACULAR DEGENERATION

The treat and extend (T&E) regimen, also referred to as inject and extend, was developed to decrease both injections and clinic visits without sacrificing the improvements in BCVA that are achieved with monthly injections. Treat and extend was formally introduced in 2007,18 but published studies did not appear for an additional 2 years.17,19-22 The early publications were predominantly retrospective analyses of nonrandomized studies. Gupta et al20 reported 92 patients treated with ranibizumab with an average follow-up of 1.6 years. Visual acuity results were impressive as 96% of patients lost fewer than 3 lines, 32% gained at least 3 lines, and the mean improvement was 2 lines. Patients received an average of 8.3 injections through 12 months. Oubraham et al22 retrospectively compared 38 patients treated according to T&E with 52 patients treated PRN. Mean improvements in VA at 1 year were +10.8 letters (T&E) and +2.3 letters (PRN) (P=.036). Patients treated according to T&E received more injections (7.8 vs 5.2).

Visual acuity results after 3 years of T&E varied among small cohorts of patients with type 3 choroidal neovascular membrane (CNVM; improved VA)17 and type 1 CNVM (stable VA).19 A large retrospective series (212 treatment-naïve eyes from 196 patients) reported the results of 12 months to 36 months (mean 1.88 years) of T&E treatment with ranibizumab or bevacizumab.23 Mean BCVA improved from 20/139 to 20/79 at 1 year, 20/69 at 2 years, and 20/64 at 3 years (P<.001 for each time point). Ninety-four percent of eyes lost fewer than 3 lines of VA and 34% gained at least 3 lines. Mean central retinal thickness (CRT) improved from 351 µm to 285 µm at 1 year, 275 µm at 2 years, and 276 µm at 3 years (P<.001 for each time point). Approximately 52% of eyes had persistent CNVM activity (presence of intraretinal or subretinal fluid) at 1 year, 2 years, and 3 years. Patients received means of 7.4, 5.7, and 5.8 injections during each of the 3 years. The average treatment interval was 11.4 weeks, 13.7 weeks, and 13.9 weeks during each of the 3 years. Only 2 patients developed submacular hemorrhage. Retrospective studies have shown that patients with type 1, 2, and 3 CNVM experience 1 to 2 lines of VA improvement when treated with aflibercept.24,25

A systematic review of PRN and T&E studies published through 2013 found that patients treated with bevacizumab and ranibizumab experienced mean BCVA improvements of 5.4 letters (PRN) and 10.4 letters (T&E) while receiving 5.6 injections and 8.1 injections through 1 year.26 The authors warned that the results from these predominantly retrospective studies should be interpreted with caution and they stressed the need for comparative, randomized, prospective trials.

The first prospective T&E study included 42 patients treated with ranibizumab for 1 year.27 Mean improvements in BCVA were 1.3 lines and patients were extended to an average of 9.1 weeks. A single-arm, 2-year, prospective study produced VA gains similar to those from the pivotal monthly ranibizumab trials.28

The most influential T&E trial was the Norwegian multicenter, randomized, double-blind Lucentis Compared to Avastin Study (LUCAS) trial that compared bevacizumab with ranibizumab.29 Patients received monthly injections (no minimum number) until signs of disease activity were absent. At 1 year, BCVA for patients receiving bevacizumab and ranibizumab were +7.9 letters and +8.2 letters, with mean decreases in CRT of 112 µm and 120 µm, after the administration of 8.9 injections and 8.0 injections, respectively. Similar results were seen at 2 years, with mean BCVA improvements of 7.4 letters and 6.6 letters, decreases in CRT of 113 μm and 122 μm, and total injections of 18.2 and 16.0 (P<.001).30

The Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration (TREX-AMD) trial has been the only randomized, prospective trial to compare T&E with monthly injections.31 Mean improvements in BCVA at 1 year were 10.5 letters and 9.2 letters (P=.60) after 10.1 injections and 13.0 injections (P<.0001), respectively. Eighteen percent of patients were maximally extended (12 weeks) and 45% were extended to 8 weeks or more.

TREAT AND EXTEND FOR DIABETIC MACULAR EDEMA

A prospective, randomized, single-blind, 24-month trial compared T&E with or without laser photocoagulation with PRN ranibizumab in 370 patients with DME.32 Both T&E regimens produced BCVA improvements comparable to PRN (+8.3, +6.5, +8.1 letters). Patients treated according to T&E received more injections than those treated PRN (12.4, 12.8, 10.7) but required 46% fewer clinical visits. Table 1 lists many of the published studies that included patients treated according to T&E protocols for nAMD and DME.

Table 1. Published Treat and Extend Studies
AUTHOR, JOURNAL, YEAR IMPORTANT CHARACTERISTICS IMPORTANT FINDINGS
Retrospective Studies
Engelbert et al17
Retina 2009
11 eyes
Type 3 CNVM
BCVA 20/80 to 20/40 at 36 months (P<.04)
Decrease in center point thickness (320 µm to 180-230 µm; P<.02)
Number of injections: 7 in year 1, 6 in year 2, 7 in year 3
Engelbert et al19
Retina 2010
18 eyes
Type 1 CNVM
Change in BCVA from LogMAR 0.53 to LogMAR 0.52 at 36 months
Mean of 20 injections
No vision-threatening hemorrhages
Gupta et al20
Ophthalmology 2010
92 patients
Ranibizumab
With mean follow-up of 1.6 years:
  • 96% of patients lost <3 lines
  • 32% gained >3 lines
  • Mean BCVA improvement of 2 lines
Oubraham et al22
Retina 2011
38 with T&E vs 52 with PRN
Ranibizumab
Mean BCVA improvements at 1 year:
  • +10.8 letters with T&E
  • +2.3 letters with PRN (P=.36)
Patients treated with T&E received more injections (7.8 vs 5.2)
Shienbaum et al21
Am J Ophthal 2012
74 eyes
Bevacizumab
Mean BCVA improvements at 1 year (20/230 to 20/109; P<.001)
Mean CRT improvement at 1 year (316 µm to 239 µm; P<.001)
Mean of 7.9 injections
Rayess et al23
Am J Ophthal 2015
212 eyes
Ranibizumab
Bevacizumab
Mean BCVA improvements at 3 years (20/139 to 20/64; P<.001)
Mean CRT improvement at 1 year (351 µm to 276 µm; P<.001)
Houston et al33
Retina 2015
204 eyes
153 without VMA
51 eyes with VMA
Mean BCVA improvements at 2 years:
  • 20/133 to 20/64 (non-VMA)
  • 20/145 to 20/85 (VMA)
Mean numbers of injections for non-VMA and VMA in year 1 (7.4 vs 8.4; P=.001) and in year 2 (5.5 vs. 6.7; P=.005)
Rahimy et al34
Retina 2016
42 Eyes with VA
>20/40
Ranibizumab
Bevacizumab
Mean BCVA changes at 2 years (LogMAR 0.226 vs LogMAR 0.267)
Mean CRT improvement at 2 years (306 µm to 266 µm; P=.015)
BCVA of ≥20/40 maintained in 75% of eyes
Castro-Navarro et al24
Ophthalmologica 2016
30 eyes
Aflibercept
Mean BCVA improvements at 1 year (LogMAR 0.61 vs LogMAR 0.38)
No difference among CNV subtypes
Ohnaka et al25
Graefes Arch Clin Exp Oph 2016
36 eyes
Aflibercept
Mean BCVA improvements at 1 year (LogMAR 0.48 vs LogMAR 0.40)
Interval of ≥8 weeks in 64.7%
Systematic Review
Chin-Yee et al26
Br J Oph 2015
Systematic Review
8 included manuscripts
Mean BCVA improvements:
  • +10.4 letters with T&E
  • +5.4 letters with PRN (P=.36)
Mean numbers of injections (8.1 vs 5.6)
Prospective Studies
Toalster et al27
Retina 2013
Ranibizumab BCVA improved by mean of 1.3 lines (P=.008)
Three-line gainers: 26%; 3-line losers: 5%
Abedi et al28
Retina 2014
120 eyes
Ranibizumab
Bevacizumab
Mean improvements in BCVA of +9.5 letters (1 year) and +8.0 letters (2 years)
Mean numbers of injections: 8.6 (1st year) and 5.6 (2nd year)
LUCAS (Berg et al)29,30
Ophthalmology 2015, 2016
441 patients
Ranibizumab vs bevacizumab
Mean BCVA improvements at 1 year and 2 years:
  • +8.2 letters and +6.6 letters with ranibizumab
  • +7.9 letters and +7.4 letters with bevacizumab
Mean injections at 1 year and through 2 years:
  • 8.0 and 16.0 with ranibizumab
  • 8.9 and 18.2 with bevacizumab
TREX-AMD (Wykoff et al)31
Ophthalmology 2015
T&E vs. monthly
ranibizumab
Mean BCVA improvements at month 12:
  • +10.5 letters with T&E
  • +9.2 letters with PRN (P=.60)
Mean numbers of injections: 10.1 and 13
Prünte et al32
Br J Ophthal 2016
Diabetic macular edema
Ranibizumab
T&E + laser, T&E, or PRN
372 eyes
Mean BCVA improvements at month 24:
  • +8.3 letters with T&E + laser
  • +6.5 letters with T&E
  • +8.1 letters with PRN
Mean numbers of injections: 12.4, 12.8, 10.7
BCVA, BEST CORRECTED VISUAL ACUITY; CNVM, CHOROIDAL NEOVASCULAR MEMBRANE; PRN, PRO RE NATA; T&E, TREAT AND EXTEND; VMA, VITREOMACULAR ADHESION; CRT, CENTRAL RETINAL THICKNESS.

IMPLEMENTING THE STRATEGY

The algorithm directing performance of T&E is well known to most retinal specialists, but it will be briefly discussed with emphasis on decision points where physicians can further individualize therapy (Figure 1). Eyes are injected monthly until neovascular activity has ceased or the physician believes that maximum improvement has been achieved. The interval to the next visit (which includes an injection) is then extended by 2 weeks, a practice that is continued until recurrent disease is noted. At this point, the interval is shortened by 2 weeks and treatment continues indefinitely with this visit interval. Criteria used to diagnose recurrent activity differ among studies but generally include the following: persistent or new subretinal or intraretinal fluid, new hemorrhage, macular thickening of at least 50 µm or 100 µm, decrease in vision of 5 ETDRS letters, and persistent neovascularization on fluorescein angiography. Once the longest injection interval that maintains a stable macula has been determined, the patient can be repeatedly treated for long periods of time, with reasonable assurance that disease activation or worsening will not occur between injections.

Figure 1. Clinic visits without injections (unshaded rectangles) and injection visits (shaded squares) for a patient treated with either the treat and extend or modified observe and extend (O&E) regimen. The schematic assumes that the macula becomes dry after the first injection, the extension interval is 2 weeks, and macular leakage reappears after an interval of 8 weeks. The figure shows that a patient treated by O&E requires 2 extra clinic visits early in the course in exchange for delaying injections by 2 weeks.

The longest interval to which patients can be safely extended while still benefiting from the injections has not been determined, but many physicians will not extend beyond 12 weeks. Because 20% of eyes with nAMD can be successfully treated with single injections and many eyes with DME require no additional injections after an initial period of intensive therapy, attempting to identify these eyes is a reasonable strategy. If patients can be successfully extended to 12 weeks, then many physicians will observe without additional treatments.

PHARMACOKINETIC RATIONALE FOR TREAT AND EXTEND

The duration of clinical action attributable to an intravitreal drug injection probably depends on several factors — size of the eye, liquefaction of the vitreous, vitreomacular traction/adhesion, permeability of the retina, composition of the neovascular lesion, and contribution of other chemokines and cytokines to neovascular growth — and probably others that have yet to be determined.35 Mathematical models have been developed to predict the duration of clinical actions of the anti-VEGF drugs, but they are capable of determining only relative and not absolute durations of action. Predicting the clinical response of an eye to anti-VEGF therapy a priori is not yet possible.

Muether et al analyzed the time-dependent intraocular VEGF concentrations, macula appearances on OCT, and visual acuities in cohorts of patients with treatment-naïve nAMD35 and DME.36 Intraocular VEGF concentrations were measured before each ranibizumab injection and compared to OCT scans and VA measurements. The authors found that the duration of VEGF suppression in patients with nAMD ranged from 26 days to 49 days, OCT evidence of neovascular activity was seen at a mean of 93.7 days, and VA decreased at a mean of 114 days. Intraocular VEGF concentrations were never suppressed at the time of recurrence, and VEGF concentration at the time of recurrence resembled those at baseline. These data suggest that OCT can be used to diagnose recurrence before VA becomes affected. But more importantly for each patient, the duration of ranibizumab action after each injection remains stable over periods up to 3 years.37 Similar results, but with shorter disease-free intervals, were seen in eyes with DME.36 This suggests that the duration of drug action in each eye is quite stable, which is an important requirement for the success of T&E. This pattern of stable disease-free intervals was validated in a prospective study38 and led to the “observe and plan (O&P)” regimen. With O&P, patients are treated until dry, examined monthly (until 8 weeks) without repeat injections until disease recurrence is observed. This period (less 2 weeks) is used as the extended interval.39

ADVANTAGES AND DISADVANTAGES OF TREAT AND EXTEND

Treat and extend is implemented with the hope that each patient can be treated after the longest possible interval that still prevents reactivation of disease and that in doing so, the number of injections is minimized. Rayess et al23 found that their patients received a mean of 13.3 injections through 2 years compared to 9.9 received by patients in the PrONTO trial. During this period, patients treated with T&E received 50% fewer examinations and OCT tests. By preventing disease reactivation, it is believed that VA gains with T&E exceed those with PRN therapy and are comparable to monthly injections.

FUTURE OF TREAT AND EXTEND

Results from the LUCAS trial and other recently published studies suggest that T&E may be as effective as monthly therapy. The TREX-AMD trial provides the only direct comparison of T&E with monthly therapy, and additional studies are still needed to validate efficacy. The LUCAS trial showed that ranibizumab has a slightly longer duration of action than bevacizumab (fewer injections) but direct comparisons with aflibercept have not been done.

Most investigators begin a T&E regimen with 3 monthly injections before they consider extending by 2 weeks. LUCAS has been the only prospective T&E trial to allow extension after the first injection, similar to how the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) required only a single “loading dose” after each recurrence. Current data do not support the necessity of a 3-injection loading dose, so extension after the first anti-VEGF injection — if the disease activity has ceased — would seem to be a reasonable strategy.

Both experimental data and prospective clinical studies show that disease-free intervals after injections fluctuate little for each patient. Treat and extend eventually identifies this interval after repeated injections, observations, and extensions. The O&E strategy aims to identify the same disease-free interval, but much earlier in the course of treatment. Thus, patients treated with O&E have their office visits “front-loaded” are not treated at each of the early visits, but require nearly the same number of injections during the first year. Additional randomized, prospective studies with this strategy are needed to fully characterize its efficacy.

Treat and extend was adopted rapidly by US physicians despite the early lack of supportive clinical trial data. By 2010 it had become the first choice of 37% of American Society of Retinal Specialists members for the treatment of nAMD40 and only 3 years later was preferred by 77% of specialists as determined by its Preferences and Trends survey.41 Use of T&E appears to be less frequent in other parts of the world. In the United Kingdom, an expert panel recommended T&E (up to 12 weeks) be considered for patients with stable AMD after 1 year of bimonthly aflibercept42 and a Delphi study found that T&E is used infrequently in Spain.43 Though international patterns of regimen use depend upon many factors, including drug labeling and regulatory guidance, the burden placed on physicians by the increasing number of patients receiving anti-VEGF therapy may serve to increase the use of T&E throughout the world. RP

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