Download High-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation

Eur J Ophthalmol 2013; 23 ( 6 ): 850-856
DOI: 10.5301/ejo.5000333
Original Article
High-dose (2.0 mg) intravitreal ranibizumab for
recalcitrant radiation retinopathy
Paul T. Finger, Kimberly J. Chin
The New York Eye Cancer Center, New York, New York - USA
Purpose: To evaluate the safety and tolerability and treatment efficacy of high-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy.
Methods: A phase I to II open-label, nonrandomized prospective clinical trial was performed on
10 eyes of 10 patients with recalcitrant radiation retinopathy who were failing standard dose anti–
vascular endothelial growth factor (VEGF) therapy. External beam or plaque brachytherapy–associated
retinopathy was characterized by persistent macular edema or leakage on optical coherence tomography or fluorescein angiography. Intravitreal 2.0 mg ranibizumab was given monthly up to 12 months
and monitored for tolerability and change in best-corrected visual acuity (BCVA), central foveal thickness, and clinical signs of radiation retinopathy.
Results: Seven patients completed the 1-year study and received all 12 injections; 3 withdrew from
the study due to worsening retinopathy (1 after external beam, 2 following plaque). Treatment was
well-tolerated with no severe adverse reactions. A total of 70% had stable (n = 3) or improved (n = 4)
BCVA. Mean change in BCVA was +3.3 letters at 6 months and +0.7 letters at 1 year. Mean improvement in central foveal thickness (CFT) was −19.3% (range −57 to +15%) at 1 year. Initial mean CFT was
428 µm (range 192-776); final mean CFT was 333 µm (range 190-532). A total of 80% demonstrated a
statistically significant (p<0.05) reduction in CFT.
Conclusions: Regardless of radiation source, intravitreal injections of 2.0 ranibizumab induced significant reductions in macular edema and maintained or improved BCVA in most patients who were
failing standard dose anti-VEGF therapy.
Keywords: Intravitreal, Macular edema, Melanoma, Radiation, Ranibizumab, Recalcitrant, Retinopathy
Accepted: June 1, 2013
INTRODUCTION
Radiation therapy is an effective tool in the fight against
eye cancer. However, successful radiotherapy for uveal
melanoma or orbital tumors can be marred by radiationrelated vision loss. Radiation retinopathy is a progressive disease, first characterized by exudation of vascular
components, followed by vascular occlusions, hypoxia,
neovascularization, and finally scarification. This natural
course results in vision loss.
Prior to the advent of anti–vascular endothelial growth factor (VEGF) therapy, all patients with radiation maculopa850
thy were expected to lose vision. In 2007, we reported the
first case series in which intravitreal anti-VEGF injections
were found to successfully decrease vascular transudation associated with radiation maculopathy (RM) (1). Now
there are many worldwide reports that radiation-induced
macular retinal vessel transudation can be controlled with
periodic intravitreal anti-VEGF medication (2-10).
However, over the last 6 years our clinical experience has
uncovered a subset of patients who do not respond to
standard anti-VEGF therapy. In these cases of recalcitrant
disease, anti-VEGF therapy induces an initial improvement in retinal edema but the macula does not regain a
© 2013 Wichtig Editore - ISSN 1120-6721
Finger and Chin
normal contour, and/or the signs of RM (hemorrhages,
cotton-wool spots, microangiopathy) worsen despite
monthly dosing.
This investigator-sponsored trial sought to determine
whether an increased dose (2.0 mg) of ranibizumab (Lucentis, Genentech, Inc., South San Francisco, California,
USA) could benefit patients with recalcitrant retinopathy.
In this study, we examined the safety and tolerability
of high-dose ranibizumab as well as treatment effectivity based on outcomes of visual acuity and central
foveal thickness (CFT) on optical coherence tomography
(OCT).
MATERIALS AND METHODS
Federal Drug Administration (FDA), Investigational New
Drug, and New York Eye Cancer Center Institutional
Review Board approvals were prospectively obtained.
This clinical trial was Health Insurance Portability and
Accountability Act–compliant, and was registered with
www.clinicaltrials.gov. After informed consent was obtained, 10 patients from a single clinical practice were
enrolled in this phase I/II, open-label, prospective,
clinical trial. As this drug is not commercially available,
the drug was supplied at no charge to the patients by
Genentech, Inc.
Study entry criteria
Patients eligible for this study were required to have
1) a clinical diagnosis of RM; 2) prior treatment with intravitreal anti-VEGF therapy with incomplete response;
3) been irradiated more than 6 months and no more than
10 years prior to enrollment; 4) an initial visual acuity
of 20/400 or better in the study eye; and 5) age >21 years.
Exclusion criteria included pregnancy, aphakia, uncontrolled glaucoma in the study eye, or history of glaucoma
filtering surgery.
Radiation maculopathy was defined by new-onset intraretinal hemorrhage, intraretinal microangiopathy, neovascularization, cotton-wool spots, vascular sheathing, or macular
edema. Incomplete response was defined as persistent or
worsening leakage on OCT or fluorescein angiography and/
or persistent clinical signs of retinopathy (exudate, hemorrhage, cotton-wool spots, microangiopathy) despite monthly
anti-VEGF therapy.
Intravitreal injections
Intravitreal injections of 2.0 mg ranibizumab (recombinant
humanized anti-VEGF monoclonal antibody fragment, rhuFab V2 [Genentech, Inc., South San Francisco, California,
USA]) were given. This drug provides 4 times the strength
of standard ranibizumab (0.5 mg).
In this series, eyes were prepared with topical proparacaine,
then betadine. Then a subconjunctival injection of xylocaine for focal anesthesia was performed. The injecting surgeon wore a surgical mask over his nose and mouth. While
the anesthetic took effect, ranibizumab was drawn from
the bottle into a 1-cc syringe; then, a 30-gauge needle was
placed for injection. After a second application of antibiotic
drops, an eyelid speculum was placed, followed by transscleral injection through the pars plana. Optic nerve perfusion
was checked by indirect ophthalmoscopy. After 30 minutes
(±10 minutes), intraocular pressures were checked by Goldmann tonometry. Patients were prescribed antibiotic steroid
drops to be taken 4 times a day for 7 days. Patients returned
for a safety visit to check for any adverse side effects 7 days
(±3 days) after the first injection.
Treatments were continued if clinical examination revealed
improved or persistent RM and OCT showed improved or
stable macular and retinal edema. Treatments were discontinued and patients withdrawn from the study per the
principal investigator’s discretion (P.T.F.) if it was determined that the retinopathy was worsening despite monthly
dosing and the patient could seek alternative treatments.
Main outcome measures
Outcome measures recorded at baseline and then monthly
were best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts in Collaborative
Ocular Melanoma Study–certified examination rooms. Fundus photography and CFT on spectral-domain OCT were
performed at each visit. Fluorescein angiography and ultrasound imaging (for uveal melanoma patients) were examined
at baseline and at months 3, 6, 9, and 12. Blood pressure
and any adverse events were recorded at each visit.
Study design
As per FDA protocol, subjects were assigned to one of
two groups in an alternating manner. Group 1 (n = 5)
subjects received injections every 30 days (±7 days)
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High-dose ranibizumab for radiation retinopathy
TABLE I - TUMOR CHARACTERISTICS AND RADIATION DATA FOR STUDY PATIENTS
Patient
number
Radiation
type
Tumor
location
Initial tumor
thickness, mm
Initial tumor
LBD, mm
Dose to
fovea, Gy
Dose to
apex, Gy
Time from
radiation to
RR, mo
Time from
RR to study
enrollment, mo
1
Proton beam
Lacrimal gland
NA
NA
NA
NA
22
43
2
Pd-103
6EP
9
11.9
76.4
71
3
17
3
IMRT
Sinus
NA
NA
NA
NA
48
26
4
Pd-103
7PE
2.8
13.3
52.8
85
17
35
5
Pd-103
6PE
6.3
13.7
30.6
82.6
69
11
6
Pd-103
2P
2.4
8.7
111.9
80.4
56
16
7
Pd-103
9P
5.2
13.3
83.4
89.4
20
50
8
Pd-103
12PE
2.8
8
121.8
87.4
49
42
9
Pd-103
9EA
11.3
17
33.5
58.8
9
33
10
Pd-103
9P
2
7.7
137.6
84.6
49
21
5.2
11.7
81
80
34.2
29.4
Mean
EA = equator anterior; IMRT = intensity modulated radiation therapy; NA = not applicable; P = tumor centered posterior; Pd-103 = palladium-103; PE = tumor centered at equator anterior location; RR = radiation retinopathy; LBD = largest basal dimension.
through 12 months (maximum 12) and group 2 (n = 5)
subjects received injections every 30 days (±7 days) for
the first 4 months and every month thereafter until month
12 (maximum of 12 injections) if the subjects had signs of
intraretinal hemorrhage or macular edema as determined
by ophthalmoscopic examination, fluorescein angiography, color fundus photography, and/or OCT when compared to their last visit.
Statistical analysis
We calculated the rates of change of CFT between initial
treatment month and follow-up treatment months for every
patient. The nonparametric Wilcoxon signed rank test was
then used to test if the patient’s CFT significantly changed
with time. In the test, the median change of foveal thickness was assumed to be zero (no change). Actual median
change of foveal thickness was considered to be significantly different from hypothetical zero median changes if
p value was smaller than 0.05. We also used the KaplanMeier method to estimate the cumulative change rates of
foveal thickness over time. To better present the status of
change, we defined 3 outcomes of foveal thickness decreasing at least 10%, 15%, and 20% during the follow-up
time, and then drew the corresponding curves.
852
RESULTS
Patient demographics
There were 7 women and 3 men, with a mean age of
55 years (median 54 years, range 31-87). Three patients had
hypertension, and 1 had non-insulin-dependent diabetes.
Eight patients had received radiation therapy for posterior
uveal melanoma, 1 for lacrimal gland adenoid cystic carcinoma (ACC), and 1 for adenocarcinoma of the skull base.
For the patients with melanoma, the mean apical tumor
height and mean largest tumor basal diameter was 5.2 mm
(range 2-11.3) and 11.6 mm (range 7-17), respectively. All
patients had a history of anti-VEGF therapy (bevacizumab
1.25 mg and/or ranibizumab 0.5 mg), and were receiving active therapy at the time of study enrollment.
The mean time from radiation to development of radiation retinopathy and initiation of anti-VEGF therapy was
34.2 months (range 3-69) and the mean time from radiation retinopathy to study enrollment was 29.4 months
(11-50) (Tab. I). Thus, the mean time of previous antiVEGF therapy prior to study initiation was about 2.5
years, and all patients had received at least 11 months
of anti-VEGF therapy prior to treatment with high-dose
therapy.
© 2013 Wichtig Editore - ISSN 1120-6721
Finger and Chin
Fig. 1 - Patient 2 with recalcitrant radiation retinopathy following plaque
brachytherapy for uveal melanoma.
(Top left) Despite 12 months of anti–
vascular endothelial growth factor
therapy, macular edema persists with
a central foveal thickness (CFT) =
436 µm on optical coherence tomography (OCT). (Top right) Prehigh-dose fluorescein angiogram in
arteriovenous phase demonstrates
persistent macular and retinal edema. (Bottom left) After 12 monthly
injections of 2.0 mg ranibizumab, the
macula resumes a normal contour on
OCT, with a CFT = 228 µm. (Bottom
right) After 12 monthly injections
of 2.0 mg ranibizumab, fluorescein
angiogram in arteriovenous phase
demonstrates a marked reduction in
macular and retinal edema.
Radiation history
All uveal melanoma patients underwent palladium-103
brachytherapy over 5-7 days. Mean dose to tumor apex
was 80 Gy (range 58.8-89.4) and mean dose to fovea was
81 Gy (30.6-137.6) (Tab. I).
The lacrimal gland ACC patient (patient 1) had undergone
proton beam radiation therapy (72 CGE/36 fractions), and
the skull base adenocarcinoma patient (patient 3) had
undergone intensity modulated radiation therapy (IMRT)
6 MV photons at 200 cGy for 25 fractions (total dose
50 Gy).
Treatment
Seven patients completed the 1-year study and received
all 12 injections (Fig. 1). Group 1 received a mean of 10.2
injections over a mean 10.2 months. Group 2 received a
mean of 10.8 injections over a mean 10.8 months. There
were no significant differences in the number of injections
received between groups 1 and 2, since all subjects received treatment for each month they were enrolled. That
is, no subject was able to lengthen the treatment frequency
to greater than 1 month.
Three patients were discontinued from the study per principal investigator (P.T.F.) discretion due to worsening retinopathy despite monthly therapy. They elected to receive
alternate treatment (one each at months 7, 8, and 9). Of the
3 patients who discontinued the study, 2 were from group 1
and 1 was from group 2. This was not found to be significant
in that the groups were treated with the same number of
injections (monthly) despite the creation of 2 study groups
(arms) for the FDA protocol. One patient had undergone
IMRT (skull base adenocarcinoma) and 2 had undergone
plaque brachytherapy. Including those withdrawn from the
study, the mean follow-up period was 9 months.
Primary outcome: safety and tolerability
Ranibizumab 2.0 mg was well-tolerated for up to 1 year of
monthly treatment. There were no cases of ocular or systemic allergy, endophthalmitis, elevated blood pressure,
vascular ischemic events, or other severe adverse event
as noted at each visit. There were no cases of death or
metastasis during the study.
Secondary outcome: treatment effect at 1 year
Initial median BCVA was 20/45 (range 20/20-20/200) and
final median BCVA was 20/60 (range 20/20-20/125). At the
conclusion of the study, 70% were found to have stable
(n = 3) or improved (n = 4) BCVA. The mean change in BCVA
as compared to baseline was +3.3 letters at 6 months and
+0.7 letters (range −9 to +8) at 1 year. This represents
essentially equivalent BCVA compared to baseline. Three
patients lost letters of acuity at 1 year.
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High-dose ranibizumab for radiation retinopathy
Fig. 2 - Change in central foveal thickness (CFT) pre- and post-highdose 2.0-mg ranibizumab. Time “0 months” represents the baseline
CFT prior to study intervention.
ever, the remaining 2 (patients 6 and 8) showed a slight
increased trend in CFT, and the median increased change
in one patient was statistically significant (p<0.05).
Figure 3 shows the time-dependent cumulative decrease
curves of CFT plotted by the Kaplan-Meier method. Overall, 60% (6/10) of patients experienced a decrease in
CFT of at least 10% after the first injection. Further, the
proportions of patients with (at least 10%) decreased CFT
increased to 70% and 80% after 6 months and 1 year
(Fig. 3). If the outcome was defined as a decrease in CFT
of at least 15% and 20%, the 1-year proportions of decreased CFT were 60% and 50%, respectively (Fig. 3).
Clinical assessments of retinopathy (exudates, retinal
hemorrhage, microaneurysm) using comparative color
photography and fluorescein angiography were made
compared to baseline. As a general finding, this subset of
patients with previously treated retinopathy were primarily
noted to have retinal edema and microangiopathy rather
than hemorrhage. Specific comparative results revealed
that compared to baseline, of the 6 patients with baseline
exudate, 1/6 improved, 3/6 were stable, and 2/6 worsened.
For retinal hemorrhage (baseline n = 4), 3/4 improved and
1/4 worsened. For microangiopathy (baseline n = 10), 4/10
improved, 4/10 were stable, and 2/10 worsened. Clinical
assessments of macular edema using color photography
and fluorescein angiography were also made, and 7/10
improved, 1 was stable, and 2 worsened.
Fig. 3 - Cumulative Kaplan-Meier change rates of central foveal
thickness (CFT). This graph demonstrates the cumulative change
rate if the change is defined as a decrease in CFT of at least 10%,
15%, or 20%.
DISCUSSION
When we examined the 12-month OCT findings for each
patient prior to high-dose study intervention, 50% of patients had worsening edema and the other 50% had stable
but persistent edema (Fig. 2). In contrast, at their last study
visit, most patients (80%, 8/10) were found to have stable (n = 2) or improved (n = 6) CFT compared to baseline.
The mean improvement in CFT was −19.3% (range −57
to +15%), with the “−” denoting improvement in edema.
The initial mean CFT was 428 µm (range 192-776); the final
mean CFT was 333 µm (range 190-532).
Overall, 8 of 10 patients showed a decreased change of
CFT at every time point during the study period. Compared
with baseline CFT, the median decreased CFT in each of
these 8 patients was statistically significant (p<0.05). How854
The results of the present study suggest that a higher
dose (2.0 mg) of ranibizumab can benefit patients with
recalcitrant radiation retinopathy who are failing standard
anti-VEGF therapy. Regardless of the radiation source
(proton beam, IMRT, or plaque brachytherapy), most patients experienced improvements in macular edema as
best illustrated on comparative OCT. Even though these
patients were failing standard dosing, the general trend
was an initial improvement in CFT after the first injection (90%), followed by less dramatic improvement, and
then a plateau in CFT. At the conclusion of the study,
most (80%) were found to have a statistically significant
improvement in CFT as compared to baseline. However, the CFT improvement on OCT did not correlate to
significant (less than one line) improvements in visual
acuity.
© 2013 Wichtig Editore - ISSN 1120-6721
Finger and Chin
Recent studies have also demonstrated that high-dose ranibizumab has beneficial potential (11, 12). Fung et al (11)
(pilot study) studied 9 eyes with recalcitrant age-related
macular degeneration (AMD) over 6 months and noted an
improvement in BCVA and CFT using 2.0 mg ranibizumab as compared to 0.5 mg. The multicenter Super-dose
Anti-VEGF (SAVE) trial studied 2.0 mg ranibizumab for
87 patients with recalcitrant AMD (those failing standard
1.25 mg bevacizumab or 0.5 mg ranibizumab monthly
dosing for at least 9 months) (12). They found that the high
dose led to statistically significant improvements in visual acuity and macular anatomy within the first 3 months
of treatment. However, similar to the present study, their
longer-term results failed to demonstrate significant improvement in visual acuity (in press 2013). Therefore, the
higher dose of 2.0 mg ranibizumab is not expected to
become commercially available.
It is important to note that the patients enrolled in our
study were selected with advanced, recalcitrant disease
and thus poor prognosis for vision. These cases included
those with large tumors, a relatively high macular radiation
dose, and/or a subfoveal or juxtapapillary tumor location.
Of these 3 factors, the only controllable factor is radiation
dose. At The New York Eye Cancer Center, we work closely
with our radiation oncologists to employ the lowest possible curative dose and dose rates. We also counsel patients that the role of anti-VEGF therapy is not to reverse
the damage created by radiation; rather its role is to suppress a progressive disease and thus preserve vision for as
long as possible. From this perspective, this study showed
that high-dose ranibizumab was effective in being able to
maintain or improve visual acuity in 70% of patients for a
mean of 9 months.
As high-dose (2.0 mg) ranibizumab was not available at
the conclusion of the study, these patients had elected to
continue treatment with high-dose bevacizumab. More recently, off-label high-dose bevacizumab, including 2.0 mg
and 2.5 mg bevacizumab, has become available through
the use of larger dose volumes (0.08 mL and 0.1 mL, respectively). However, the increased drug volume can cause
transient increased intraocular pressures with resultant
temporary decreased vision.
Any study of intravitreal anti-VEGF therapy must consider
the well-documented intraocular risks, including but not
limited to endophthalmitis, uveitis, and vitreous hemorrhage. In addition, there has been concern in AMD studies over the broad inhibition of VEGF-A in which frequent
dosing may lead to geographic atrophy and poor visual
outcome (13); however, this must be weighed against the
natural course of radiation retinopathy.
Weaknesses of this study include that it is a small case
series with no control group and thus no statistically significant comparison. Though a nonhomogenous group
including both melanoma and nonmelanoma etiologies,
all study patients had secondary unilateral radiation retinopathy.
Reviewers have pointed out that without therapeutic intervention, radiation retinopathy can run a course that leads
to reabsorption of retinal exudates and hemorrhages and
decreased macular thickness over time. However, untreated long-term radiation retinopathy almost invariably leads
to permanent visual field defects and loss of useful vision.
Herein, we have shown that 2.0 mg monthly ranibizumab
was tolerated for 1 year. Decreased CFT and stable vision
was noted in most cases. These agents may offer select
patients with recalcitrant retinopathy the potential to prolong useful vision when standard therapy fails. However,
the safety, longer-term tolerability, and effectivity of high
doses of anti-VEGF agents requires further investigation.
ACKNOWLEDGMENT
Study drug and funding for statistical analysis was supplied
by Genentech, Inc., South San Francisco, California, USA.
Financial Support: Support for statistical assistance and ranibizumab 2.0 mg were provided by Genentech, Inc., South San Francisco,
California, USA. Research supported in part by The Eye Cancer Foundation, Inc. (http://eyecancerfoundation.net).
Conflict of Interest Statement: Dr. Finger holds United States Patent
#7,553,486, “Anti-VEGF Treatment for Radiation Induced Vasculopathy,” issued on June 30, 2009. None of the authors has conflict of
interest with this submission.
Meeting Presentation: Presented in part at the American Society of
Retinal Specialists, 2012 (paper); Retina Society, 2012 (paper); and
American Academy of Ophthalmology, 2012 (poster).
Address for correspondence:
Paul T. Finger, MD
The New York Eye Cancer Center
115 East 61st Street
New York, NY 10065
USA
[email protected]
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High-dose ranibizumab for radiation retinopathy
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