CONTROVERSIES IN CARE

“Treat and Extend” Dosing for Wet AMD: Optimal or Daring?

Edited by Michael Colucciello, MD

The treatment of choroidal neovascularization in neovascular (“wet”) age-related macular degeneration, the leading cause of vision loss in our ever-expanding mature population, has undergone a paradigm shift over the last decade from laser and photodynamic therapy to pharmacologic approaches with intravitreal injections of anti–vascular endothelial growth factor agents. But what is the best dosing schedule for these patients using the currently available agents?

The ANCHOR (treatment of predominantly classic CNV)¹ and MARINA (treatment of minimally classic/occult CNV)² studies demonstrated that monthly intravitreal 0.5 mg ranibizumab treatments for 24 months were associated with 95% of the participants losing fewer than 15 letters of visual acuity compared to about 60% of the control cohort. In addition, 30% to 40% of participants demonstrated improvements in vision of at least 15 letters (three lines).

Monthly injections, however, may be expensive and practically difficult in this mature patient population.

Nevertheless, monthly intravitreal injections of antiangiogenic agents have been shown more effective than less frequently administered injections for the treatment of wet AMD.

Less frequent anti-VEGF dosing, as undertaken in the PIER study³ (in which patients received quarterly injections after an initial series of three monthly injections), provided results inferior to those obtained in trials using monthly dosing.

Using a different approach, the PrONTO (prospective OCT imaging of patients with neovascular AMD treated with intraocular ranibizumab) study⁴ attempted to tailor the dosing to the individual needs of the patient based on visual acuity, macular examination, or OCT evidence of exudation. Although this approach was associated with good visual results after a 24-month period, it does require monthly visits, clinical examinations, and OCT testing with patients to determine if or when patients will need retreatment.

The “treat and extend” (TAE) dosing regimen⁵ is an attempt to benefit from the PrONTO experience while gradually becoming more liberal with dosing regimens, in the hopes that the CNV will gradually become less active and become fibrotic over time. TAE consists of an initial induction (“loading”) sequence of at least three monthly injections, with a gradually increased interval between injections provided that dry anatomy is obtained upon evaluation at the time of the next scheduled injection. If evidence of increased exudation exists at the next scheduled injection, the interval to the next scheduled injection is decreased to four weeks. If dry anatomy is maintained, the treatment and evaluation interval is gradually extended, to a maximum of 10 weeks.

Unfortunately, some patients managed with this strategy will return with irreversible vision loss if they have developed macular hemorrhages in the injection-free interval.

So, in clinical practice, how do we optimize current anti-VEGF treatment for our patients? Is TAE optimal — or daring — at this time? In this month's column, Drs. Carl Regillo and John Thompson discuss the benefits, drawbacks and alternatives of treat-and-extend dosing.

REFERENCES

1. Brown DM, Kaiser PK, Michels, M. et al. for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
2. Rosenfeld PJ, Brown DM, Heier JS, et al. for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
3. Regillo CD, Brown DM, Abraham P, et al. on behalf of the PIER Study Group. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol. 2008;145:2392-2348.
4. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148:43-58.
5. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina. 2009;29:1424-1431.

The “Treat and Extend” Regimen Using Intravitreal Anti-VEGF Agents to Manage Neovascular AMD

Carl D. Regillo, MD, FACS

The “treat and extend” (TAE) regimen of anti-VEGF therapy for neovascular AMD was first proposed by K. Bailey Freund, MD, in New York City several years ago as an alternative to the traditional as needed (PRN) or “treat and observe” (TAO) style of therapy.^1-3 With the TAE approach, there is a treatment rendered at every visit. At first, visits and treatments are frequent, approximately every month or so. Once the macula is dry, the encounters are gradually spread apart by approximately one to two weeks until there is a recurrence. Some clinicians extend out to two months if tolerated, others three months. Few physicians spread the treatment interval out more than that. If there is evidence for recurrent neovascular activity on a given follow-up examination (eg, edema or subretinal fluid on OCT, leakage on angiography, new hemorrhage on ophthalmoscopy, etc.), then the treatment interval is shortened. Ideally, the clinician attempts to find the optimal treatment interval for a given patient in an attempt to keep the macula dry and minimize recurrent neovascular growth or leakage. Theoretically, this should allow for the best possible visual outcome with the fewest number of treatments, examinations, and tests.

A fluorescein angiogram of a four disc-area occult choroidal neovascular membrane in a patient with neovascular age-related macular degeneration, with superimposed corresponding spectral-domain optical coherence tomography image (inferior) and macular cube section (superior). The OCT images demonstrate choroidal neovascularization, retinal pigment epithelial detachment, subretinal fluid (serous retinal detachment) and macular edema with associated disruption of the foveal photoreceptor layer and external limiting membrane.

The main potential advantages of TAE over continuous monthly injections such as what was performed in the pivotal phase 3 ranibizumab studies (MARINA and ANCHOR) are greater safety (ocular and systemic), convenience, and cost-effectiveness. The potential advantages of TAE over TAO, if the latter is practiced with monthly follow-up, are greater convenience and less frequent testing. Depending on which drug is used (ranibizumab or bevacizumab) and the mean number of treatments, the overall cost may be more or less with TAE compared with TAO. The potential drawback to any individualized approach or any regimen with less than monthly, continuous dosing whether it is TAE, TAO, every six weeks, or every eight weeks, etc., is lower efficacy.

To date, there are more published studies utilizing TAO types of individualized regimens compared to TAE. With the former, the efficacy results have been variable. Some studies show one-year results that appear comparable to the MARINA and ANCHOR ranibizumab studies, but most do not.^4-9 Those TAO studies in which there is a mean number of ranibizumab or bevacizumab injections of between 5.6 and 7.0 treatments in the first year have the best results. Those with a lower mean number of treatments have suboptimal visual outcomes.

With TAE, the visual results have been more consistently good.^10-12 Our group on the Retina Service at Wills Eye Institute published results of a retrospective study using ranibizumab to treat neovascular AMD in a TAE fashion that were on par with the phase 3 studies. In that study, there was a mean of eight treatments in the first year and seven in the second year.¹¹ We have also had similarly good results with bevacizumab (unpublished data, Shienbaum et al., ARVO abstract 2010). A more recent study out of Paris retrospectively compared TAO- to TAE-treated groups. The TAE group was found to have significantly better visual outcomes with a mean visual acuity change at one year of 10.8 letters compared to 2.3 letters gained from baseline. The mean number of ranibizumab treatments in the two groups was 7.8 and 5.2, respectively.¹²

In summary, recently published studies using the TAE style of individualized anti-VEGF therapy by intravitreal injection with either ranibizumab or bevacizumab have shown very favorable visual results. Although there are no prospective comparative trials comparing a continuous, monthly dosing regimen to a TAE regimen at this time, the approach appears to be a reasonable alternative. TAO approaches may also yield good results, but very close monthly follow-up and a relatively high mean number of treatments are needed to yield good visual outcomes.

Although the TAO approach is being put to the test against monthly dosing in several large, prospective, randomized controlled trials, such as the CATT trial, there are no studies under way to date that are comparing the TAE regimen to monthly dosing, and so how the TAE approach stacks up to the gold standard for either ranibizumab or bevacizumab will not be known any time in the near future.

REFERENCES

1. Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007;143:679-680.
2. Brown DM, Regillo CR. Anti-VEGF agents in the treatment of neovascular age-related macular degeneration: applying clinical trial results to the treatment of everyday patients. Am J Ophthalmol. 2007;144:627-637.
3. Spaide R. The as-needed treatment strategy for choroidal neovascularization: a feedback-based treatment system. Am J Ophthalmol. 2009; 148:1-3.
4. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.
5. Boyer DS, Heier JS, Brown DM, et al. A Phase IIIb Study to Evaluate the Safety of Ranibizumab in Subjects with Neovascular Age-related Macular Degeneration. Ophthalmology. 2009;116:1731-1739.
6. Rothenbuehler SP, Waeber D. Brinkmann CK, et al. Effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration. Am J Ophthalmol. 2009;147:831-837.
7. Dadgostar H, Ventura AA, Chung JY, Sharma S, Kaiser PK. Evaluation of injection frequency and visual acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration. Ophthalmology. 2009;116:1740-1747.
8. Cohen SY, Dubois L, Tadayoni R, et al. Results of one-year's treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol. 2009;148:409-413.
9. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010;340:2459.
10. Engelbert M, Zweifel SA, Freund KB. Treat and extend dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina. 2009;29:1424-1431.
11. Gupta OP, Shienbaum G, Patel AH, et al. A Treat and extend regimen using ranibizumab for neovascular age-related macular degeneration: clinical and economic impact. Ophthalmology. 2010;117;2134-2140.
12. Oubraham H, Cohen SY, Samimi S, et al. Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration. Retina. 2011;31:26-30.

Treat and Extend, or Treat, Extend and Regret?

John T. Thompson, MD

One of the most important questions facing retina specialists concerning treatment of choroidal neovascularization with anti-VEGF drugs is defining the most appropriate treatment regimen. It is of interest that the treatment recommendations from the MARINA¹ and ANCHOR² trials were ignored almost as soon as they were published. It is important to realize that anti-VEGF drugs merely suppress CNV and associated vascular permeability. These drugs rarely cure choroidal neovascularization. It is not surprising that treatment would be needed long-term to continue to suppress the deleterious effects of CNV. The same biologic factors that precipitated choroidal neovascularization continue to exist in the eye after the anti-VEGF drug concentration decreases to subtherapeutic levels.

I have used a modified treat-and-extend protocol with ranibizumab and bevacizumab in my practice and have analyzed the results of constant dosing vs extended dosing. This protocol was developed as a result of observations about my patients in the SAILOR study that used a schedule of three monthly doses followed by PRN dosing and a second phase of the SAILOR study that required only a single dose followed by PRN dosing. I saw recurrences and visual acuity loss in a number of these patients and immediately questioned the wisdom of extended dosing and office visits.

As a result, my treatment paradigm from 2005 to 2009 was the following: Patients treated with ranibizumab received monthly injections for one year followed by office visits/injections every two months from months 12 to 18, office visits/injections every three months from months 18-24 followed by PRN dosing after 24 months.

My treatment regimen for bevacizumab was similar, but dosing was given every six weeks for the first year, followed by every three months from months 12-18, and PRN dosing after 18 months since it was my impression that eyes treated with bevacizumab every six weeks fared similarly to eyes treated with ranibizumab every four weeks. Most patients followed this regimen of regular dosing during the first year with extended dosing during the second year. If patients missed visits or refused to continue regular dosing before one year, they were categorized as having extended dosing during that interval.

I analyzed the slope of the visual acuity using multiple linear regression analysis of visual acuity in 165 consecutive eyes. The dosing schedules were defined as follows: The induction phase was the first three doses followed by a regular dosing phase (approximately q4wk for ranibizumab and q6wk for bevacizumab) for the remainder of the first year. During the second year, eyes were treated with extended dosing and office visits (less than every six weeks) as described above. If a recurrence developed, then regular dosing was repeated three times and repeat extended dosing was attempted when the eye was stable.

Linear regression analysis of visual acuity showed a rapid improvement in visual acuity during the induction phase (+22 letters/year), relatively stable visual acuities during the regular dosing phase (−2 letters/year) and more rapid decline in visual acuities during extended dosing (−4 letters/year). The decline in visual acuity during extended dosing was significantly greater than regular dosing (P<.001). Repeat regular dosing stabilized the visual acuity again (−1 letter/year) and repeat extended dosing was associated with more rapid visual acuity loss (−7 letters/year).

These data raise the question of how retina specialists can avoid continuing monthly dosing of anti-VEGF agents on all patients with choroidal neovascularization indefinitely. Analysis of individual eyes in the data set confirmed what all retina specialists know: Some eyes remain stable on extended and even PRN dosing of anti-VEGF agents, but recurrences can cause visual acuity loss at any time. It was impossible to predict when choroidal neovascularization would again become active, even using spectral-domain OCT in most of the eyes on extended dosing. When recurrence develops, the baseline visual acuity may not be regained with regular dosing.

Visual acuity is an important factor in the decision about whether to chance extended dosing. Eyes with good visual acuities (20/100 or better) are at greatest risk of visually significant (to the patient) vision loss when CNV recurs. These eyes should be followed frequently (no less often than every two months if there is no remaining subretinal or intraretinal fluid) and regular dosing every one to two months is prudent. Eyes with visual acuities ≤20/200 (especially when the fellow eye has better vision) may be treated (and possibly followed) less often as the risk of visually significant vision loss is lower. Eyes with ≤20/200 in the treated eye and even worse visual acuity in the fellow eye may wish to be treated more aggressively.

The risks of extended dosing in anti-VEGF therapy should be discussed with the patient so that they can participate in the decision and assume the risks if they wish to consider extended dosing and visits. Only by factoring all of these considerations can patients be treated optimally for choroidal neovascularization. RP

REFERENCES

1. Rosenfeld PJ, Brown DM, Heier JS, et al. for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
2. Brown DM, Kaiser PK, Michels M, et al. for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.