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Clinical science
Therapeutic effect of modified double-dose photodynamic therapy in circumscribed choroidal haemangioma
  1. Hyeong Ju Byeon1,
  2. Ji Hwan Lee1,
  3. Junwon Lee1,
  4. Eun Young Choi1,
  5. Yong Joon Kim1,
  6. Sung Chul Lee2,
  7. Christopher Seungkyu Lee1
  1. 1Department of Ophthalmology, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea
  2. 2Department of Ophthalmology, Konyang University College of Medicine, Daejeon, South Korea
  1. Correspondence to Dr Christopher Seungkyu Lee, Ophthalmology, Yonsei University College of Medicine Department of Ophthalmology, Seodaemun-gu 03722, Seoul, The Republic of Korea; sklee219{at}yuhs.ac

Abstract

Aims To retrospectively compare the therapeutic effect of modified double-dose photodynamic therapy (PDT) with standard-dose PDT in patients with circumscribed choroidal haemangioma (CCH).

Methods Thirty-nine patients with CCH were categorised in two groups by PDT type. The standard-dose group (n=12) was treated with 6 mg/m2 verteporfin and a 689 nm laser for 83 s. The modified double-dose group (n=27) received one vial of verteporfin (15 mg), and the dose was calculated for each patient based on body surface area, then irradiance time was adjusted according to calculated verteporfin dose to achieve a ‘double’-dose effect. Treatment outcomes (foveal centre thickness, subretinal fluid, tumour thickness and diameter) were measured at baseline and 1 year post-treatment; subretinal fluid levels were also measured at 1, 3 and 6 months post-treatment.

Results No differences in baseline characteristics were found between the two groups. The modified double-dose group showed a greater reduction in tumour thickness (45.3% vs 20.6%, p=0.013) and tumour volume (60.0% vs 30.0%, p=0.006) at 1 year post-treatment. Recurred or non-complete resolution patients in the standard-dose group tended to show much increased subretinal fluid than those in the modified double-dose group at 1-year post-treatment.

Conclusion Modified double-dose PDT is an effective and safe protocol for symptomatic CCH management, greater tumour regression and potentially better resolution of subretinal fluid compared with standard PDT.

  • choroid
  • neoplasia
  • retina

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/bjophthalmol-2021-319832

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    Introduction

    Choroidal haemangioma is a benign choroidal vascular tumour that can occur as a circumscribed tumour or a diffuse tumour often associated with Sturge-Weber syndrome. Circumscribed choroidal haemangioma (CCH) occurs unilaterally in almost all cases and appears as a round or oval orange-red mass in the peripapillary area or posterior pole. Visual loss can occur when the tumour involves the fovea or when secondary retinal detachment develops. Particularly when total retinal detachment persists, neovascular glaucoma can develop, and the subsequent pain may ultimately require enucleation.1 2

    Symptomatic CCH with serous retinal detachment has been managed with various treatment modalities, including argon laser photocoagulation, transpupillary thermotherapy, plaque radiotherapy and external beam radiotherapy. However, photodynamic therapy (PDT), which is widely accepted as a primary treatment,3–5 selectively damages vascular endothelial cells while preserving normal neuroretinal tissue; thus, PDT can be safely applied to subfoveal symptomatic CCH lesions.4 5 The standard PDT protocol was originally designed to treat choroidal neovascularization in age-related macular degeneration, but CCH is composed of non-proliferating normal endothelium.6 To enhance PDT efficacy against CCH, the standard PDT protocol has been modified in several ways, including shortening verteporfin infusion time, doubling irradiation time and doubling the verteporfin dose.4 7–10 However, doubling the irradiation time from 83 s to 166 s can be burdensome for both physicians and patients, as holding the contact lens steadily throughout irradiation is difficult, especially with more than one irradiation site and for patients who have difficulty cooperating. Double-dose PDT led to better treatment response than standard-dose PDT in CCH management,10 but doubling the verteporfin dose from 6 mg/m2 to 12 mg/m2 almost always requires more than one vial (15 mg) of Visudyne® (Novartis, Basel, Switzerland) in typical adult patients, thus doubling the cost of an already expensive drug.

    In this paper, we present the treatment results of a modified double-dose PDT protocol that we devised, which combines the double-time protocol and double-dose protocol to overcome the limitations of either method while preserving their “doubling” effects. In our modified double-dose protocol, one vial (15 mg) of Visudyne® is infused to a patient, and the dose per square metre is calculated according to the patient’s body surface area (BSA), which would usually be more than the standard 6 mg/m2 but less than the double dose of 12 mg/m2. Then, additional irradiation time is calculated to compensate for the difference in dose relative to the double dose and added to the standard 83 s.

    Materials and methods

    Patient selection

    We retrospectively reviewed medical records of patients with CCH who received PDT at Severance Hospital, Yonsei University College of Medicine, from September 2012 to March 2021. CCH was diagnosed using ophthalmoscopy, fluorescein angiography, indocyanine green angiography and ocular ultrasonography. Patients with CCH with reduced visual acuity or metamorphopsia due to associated subretinal fluid were included. Patients with previous PDT for CCH, porphyria, abnormal liver function or any significant liver disease were excluded. Standard-dose PDT was primarily performed in patients with CCH before 2014, while the modified double-dose protocol was used in more recent patients.

    Photodynamic therapy

    PDT was performed with verteporfin (Visudyne; Norvartis, Basel, Switzerland). In the standard-dose group, verteporfin was infused intravenously at a dose of 6 mg/m2 for 10 min, followed by 689 nm laser irradiation after 5 min. In the modified double-dose group, one vial of Visudyne® containing 15 mg verteporfin was infused intravenously for 10 min; the dose was calculated for each patient based on BSA, and the lesion was irradiated using the 689 nm laser after 5 min. In the standard group, an exposure of 50 J/cm2 at an irradiance of 600 mW/cm2 was applied for 83 s. In the modified double-dose group, an irradiance of 600 mW/cm2 was applied for the time calculated for each patient using the following formula:

    Embedded Image

    For example, an extremely thin patient with a BSA of 1.25 would receive a dose of 12 mg/m2 if 15 mg verteporfin was infused and would receive 83 s of irradiance, representing a purely double-dose case. In contrast, a morbidly obese patient with BSA of 2.5 would receive a dose of 6 mg/m2 if 15 mg verteporfin was infused and would receive 166 s of irradiation, representing a purely double-time case. Laser spot diameter was determined based on indocyanine green angiography to cover the tumour without safety margins. If the tumour size exceeded the maximal laser spot size, consecutive non-overlapping lasers were applied.

    Documentation and measurement

    All patients received a standard ophthalmic evaluation within 1 month before beginning PDT. The standard evaluation includes best-corrected visual acuity (BCVA), slit-lamp examination, fundus examination, B-scan ocular ultrasonography (Ellex, Adelaide, Australia), spectral domain optical coherence tomography (OCT) (Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography/indocyanine green angiography (Heidelberg Engineering, Heidelberg, Germany/Optos, Dumferline, UK). BCVA values using the Snellen chart were converted to the logarithm of the minimum angle of resolution (logMAR) scale for statistical analysis. Foveal centre thickness was defined as the distance between the inner surface of the retina and the inner surface of the retinal pigment epithelium (RPE) using OCT. Subretinal fluid height was measured from the outer surface of the detached retina to the inner surface of the RPE, where its height was tallest on OCT scans. The subretinal fluid ratio was defined as the ratio of post-treatment height to baseline height. Largest tumour basal diameter and tumour thickness were determined using B-scan ocular ultrasonography. The tumour thickness ratio was defined as the ratio of post-treatment tumour height to baseline height. Assuming that CCH is an ellipsoidal mass, tumour volume was calculated using the following formula11:

    Embedded Image

    Tumour location was determined using wide fundus photography (Optos, Dumferline, UK) or fundus photography (Carl Zeiss, Oberkochen, Germany) and OCT. If any part of the tumour was located under the fovea, we defined it as a subfoveal tumour. If the tumour was located in the macula but the fovea was spared, it was defined as a perifoveal tumour. The tumour located outside of the retinal vascular arcade was defined as a peripheral tumour. If the tumour was located around the optic disc, it was defined as a juxtapapillary tumour.

    Recurrence of subretinal fluid

    Recurrence of subretinal fluid was defined as the occurrence of subretinal fluid after complete resolution of subretinal fluid. Subretinal fluid height measured 1 month after PDT was not used for an analysis to lessen possible bias from transient elevation of subretinal fluid shortly after PDT.

    Statistical analysis

    All data were analysed using IBM SPSS Statistics for Windows V.27.0. Distribution patterns of the data were analysed using the Shapiro-Wilk test. For data not normally distributed, the Mann-Whitney U test was used. For data distributed normally, Student’s t-test was applied. To estimate complete resolution and recurrence of subretinal fluid after treatment, Kaplan-Meier analysis was performed; and to compare complete resolution rate between groups, χ2 test was used. All results are presented as the mean values±standard deviation (SD). A p value of less than 0.05 was considered statistically significant.

    Results

    Baseline characteristics

    Thirty-nine patients were included in this study, with 27 in the modified double-dose group and 12 in the standard-dose group. Twenty-six patients (16 with the modified double dose, 10 with the standard dose) completed 1 year of follow-up examinations. No differences were observed in age, sex, tumour size, tumour location, foveal centre thickness, subretinal fluid and initial visual acuity between the two groups (table 1).

    View this table:
    Table 1

    Baseline characteristics of patients with circumscribed choroidal haemangioma who completed the 1-year follow-up

    In modified double-dose group, average dose of verteporfin was 8.63 mg/m2, ranging from 7.22 mg/m2 to 10.71 mg/m2. Average irradiation time is 117.13 s, ranging from 93 s to 138 s.

    Therapeutic outcomes of modified double-dose versus standard-dose PDT

    In both groups, mean tumour size, foveal centre thickness and subretinal fluid decreased 1 year after treatment (table 2). The modified double-dose group showed greater regression of mean tumour thickness than the standard-dose group (45.3% vs 20.6%, respectively; p=0.013; figure 1). The modified double-dose group had a strong tendency for a greater decrease in tumour diameter (27.2% vs 7.9%, respectively; p=0.058). Additionally, the modified double-dose group showed significantly reduced tumour volume (60.0% vs 30.0%, respectively; p=0.006). For visual acuity, mean logMAR BCVA difference was not statistically different in the two groups (−0.23 vs −0.19, p=0.788).

    View this table:
    Table 2

    Therapeutic outcomes at 1-year follow-up after modified double-dose and standard-dose photodynamic therapy in patients with circumscribed choroidal haemangioma

    Figure 1
    Figure 1

    Representative images of a CCH before (A–D) and 1 year after modified double-dose photodynamic therapy (E–H). (A) Wide-field fundus photograph showing an oval-shaped orange-red mass located at the peripheral area in right eye. (B,C) Optical coherence tomography scans showing 145 µm subfoveal fluid and neuroretinal elevation caused by choroidal lesion with overlying subretinal fluid. (D) Ocular ultrasonography B-scan showing a CCH of 1.78 mm (height)×6.55 mm (base) at 10 o’clock. (E) Flattened CCH with hyperpigmentation on the lesion at 1 year after modified double-dose PDT. (E,F) Complete resolution of subretinal fluid and decreased choroidal tumour. (H) Tumour size at 10 o’clock was measured as 0.80 mm (height)×5.33 mm (base). CCH, circumscribed choroidal haemangioma.

    Aspects of subretinal fluid

    Prolonged presence of subretinal fluid at the foveal area and its recurrence can have a significant effect on visual symptoms. Twenty (74%) of 27 patients receiving modified double-dose PDT and 11 (91%) of 12 patients receiving the standard-dose PDT achieved complete resolution of subretinal fluid at the mean 5.2 and 4.3 months after treatment, respectively. There was no difference in the proportion of patients with complete subretinal fluid resolution at each follow-up period (all p>0.05, figure 2A). After complete resolution, the subretinal fluid recurred in 5% of the modified double-dose PDT group and 27% of the standard-dose group, respectively, within 1 year of treatment.

    Figure 2
    Figure 2

    Graphs showing changes in SRF states during 1 year after treatment. (A) CR rate of SRF at each follow-up. (B) Changes in mean SRF height ratio based on initial SRF height at each follow-up. Error bars indicate the SD. CR, compete resolution; SD, standard deviation; SRF, subretinal fluid.

    Subretinal fluid height in recurred and non-complete resolution patients tends to be greater in the standard-dose group than in the modified double-dose group; at 1 year after the treatment, 30.0% of the standard-dose group showed increased subretinal fluid height from the baseline level, while 6.3% of the modified double-dose group showed increased subretinal fluid height. While the mean subretinal fluid ratio gradually decreased after treatment in the modified double-dose group, it began to increase after 1 month in the standard-dose group, but the difference in their ratios was not statistically significant at each follow-up period (all p>0.05, figure 2B).

    Complications

    All patients tolerated PDT well. We noted no side effects or complications, such as choroidal ischaemia, occlusion of the retinal arterioles or venules, or retinal pigment epithelial deteriorations such as RPE atrophy in both groups.

    Discussion

    In this study, we found that our modified double-dose PDT protocol was more effective than the standard PDT protocol for managing symptomatic CCH with respect to tumour size reduction and subretinal fluid resolution. Unlike the vessel walls of choroidal neovascularization, for which the standard PDT protocol was devised, choroidal haemangioma has non-proliferative endothelial vessel walls that can be histopathologically classified as cavernous, capillary or mixed type.6 Witschel and Font showed that most CCHs contain the cavernous and mixed types, which have large vessels and limited connective tissue.6 Thus, selective action of PDT on CCH may be based on slow blood perfusion compared with normal vessel3 and larger vessel diameter with relative thin vessel wall.12 To occlude large choroidal vessels by vascular thrombosis,13 standard PDT may not be strong enough for optimal treatment of CCH. In addition, standard PDT could be less effective in brown Asian eyes with increased uveal melanin pigments14 compared with blue eyes, potentially making modified double-dose PDT more beneficial in Asian or African patients.

    Debefve et al demonstrated a dose-proportional effect of light energy and drug concentration on vascular occlusion by PDT in a chorioallantoic membrane model.15 Based on this finding, the PDT protocol for CCH was modified to raise the light dose energy via increasing laser exposure time. Double-time PDT was proposed to compensate for the location of CCH in the deep choroidal layer13 16 and its relatively thick endothelial membrane compared with choroidal neovascularisation.3 4 7–9 In addition, decreased verteporfin infusion time was suggested, considering a late-phase choroidal washout.3 8 However, increasing the light dose to 100 J/cm2 in double-time PDT carries the risk of RPE alteration and reduced retinal sensitivity with microperimetry.8 13 Furthermore, holding the contact lens in place for twice as long can be difficult for both the physician and the patient.

    Double-dose PDT was proposed because CCH is composed of large, congested blood vessels.6 10 Compared with standard PDT, double-dose PDT exhibits a superior effect on tumour size reduction without altering the rate of subretinal fluid reduction.10 However, its primary limitation is increased drug costs associated with a double dose. The average BSA is 1.94 m2 for adult men and 1.69 m2 for adult women.17 Thus, double-dose PDT at a dose of 12 mg/m2 requires more than one vial (15 mg) of expensive Visudyne® for almost all patients. To overcome the limitations of double-time and double-dose PDT protocols, we created a modified double-dose PDT protocol that uses only one vial of Visudyne® to raise the dose above the standard dose of 6 mg/m2 and then increases the irradiation time to compensate for the lack of a double dose. Although most CCHs were located in the subfoveal area, modified double-dose PDT was well tolerated without significant complications.

    Modified double-dose PDT appears to show more consistent management of subretinal fluid than standard PDT for as long as 1 year after treatment. Persistent serous leakage can damage the RPE and the outer retinal layer, and repeated events could eventually cause retinal atrophy.7 Both standard-dose and modified double-dose PDT resulted in complete or near-complete resolution of subretinal fluid in most patients, but the recurrence rate and severity of subretinal fluid tended to be greater with standard-dose PDT, especially after 6 months following treatment (figure 2A,B). Although no difference in visual acuity was observed between the two groups at 1 year after treatment, recurrence or aggravation of subretinal fluid requires retreatment or additional treatment and may result in a poorer visual outcome in longer follow-up periods. Additionally, modified double-dose PDT showed an enhanced effect in tumour reduction. Although the primary goal of CCH treatment is not to flatten the tumour completely, better tumour regression may suggest improved resolution of subretinal fluid and decreased recurrence, both of which were true for this study.

    The limitations of this study include its retrospective design and the relatively small number of participants. However, conducting a prospective comparative study of CCH is difficult due to its rarity. Additionally, the patients were not randomised to treatment groups in this study. We primarily performed standard-dose PDT in patients with CCH before 2014 and used the modified double-dose protocol in more recent patients. Thus, selection bias could have been lessened in this respect and no differences in demographics, tumour characteristics and clinical findings were found before treatment between the two groups. Furthermore, there is no constant verteporfin per BSA and laser fluence. One aspect of the modified double-dose protocol to consider is that, according to our formula, patients with a higher BSA would receive treatment similar to double-time PDT, whereas patients with a lower BSA would receive a treatment similar to double-dose PDT. We assessed whether a difference in treatment response occurs according to patient BSA, but no notable difference was observed (results are not shown).

    In conclusion, modified double-dose PDT is an effective and safe protocol for managing symptomatic CCH by yielding greater tumour regression and potentially better controlling of subretinal fluid than standard-dose PDT.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The institutional review board (IRB) of Yonsei University Medical Center approved this study, and the requirement to obtain informed consent from the subjects was waived by the IRB (IRB number 4-2021-0045).

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    Footnotes

    • Contributors All authors participated in the review and editing of the manuscript. JHL, JL, CSL and SL designed this study. HJB, EYC, YJK, CSL and SL collected the data. HJB and CSL analysed and interpreted the data and wrote the manuscript. CSL contributed to the revision of the final manuscript.

    • Funding This research was supported by the Basic Science Research Program through the National Research Foundation of Korea under 2019R1A2C2002393 (CSL).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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