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Intra-Arterial Chemotherapy for Retinoblastoma: 8-Year Experience from a Tertiary Referral Institute in Thailand

Rojanaporn, Duangnate MD*; Chanthanaphak, Ekachat MD; Boonyaopas, Rawi MD*; Sujirakul, Tharikarn MD*; Hongeng, Suradej MD; Na Ayudhaya, Sirintara Singhara MD

The Asia-Pacific Journal of Ophthalmology: May 2019 - Volume 8 - Issue 3 - p 211–217
doi: 10.22608/APO.2018294
Original Clinical Study
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Purpose: To study the safety and efficacy of intra-arterial chemotherapy (IAC) as a treatment for intraocular retinoblastoma in Thailand.

Design: Retrospective, interventional case series.

Methods: In this study, IAC was performed as primary or secondary treatment for patients with intraocular retinoblastoma using melphalan with or without additional topotecan or carboplatin. Survival rate, globe salvage rate, and treatment complications were recorded and analyzed.

Results: Of 27 eyes of 26 patients with retinoblastoma, 7 (26%) had IAC as primary treatment and 20 (74%) had IAC as secondary treatment. The eyes were classified by International Classification of Retinoblastoma (ICRB) as group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Catheterization was successful in 75 (94%) of 80 sessions. The median number of IAC sessions was 3 (range, 1-7). At a mean follow-up of 32 months (range, 3-95 months), the overall globe salvage rate was 52%, with 100% in groups B and C, 75% in group D, and 9% in group E. Complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), strabismus (n = 2, 7%), and transient ischemic attack (n = 1, 4%). The overall survival rate was 96% (n = 25).

Conclusion: Our experience suggests that IAC is a safe and effective treatment for patients with ICRB group B, C, D, and some group E retinoblastoma. Careful patient selection and experienced surgeons are critical for achieving the best treatment outcome.

From the *Department of Ophthalmology,

Department of Radiology, and

Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

Submitted July 30, 2018; accepted November 7, 2018.

Supported by Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Thailand. The authors declare no competing financial interests.

Reprints: Ekachat Chanthanaphak, Department of Radiology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok, Thailand. E-mail: potter_ra@hotmail.com.

Management of intraocular retinoblastoma is challenging. Multiple treatment modalities have been used in managing this fatal malignancy, including enucleation, external beam radiotherapy, and intravenous chemotherapy, as well as a variety of focal treatments (eg, plaque brachytherapy, cryotherapy, thermotherapy, and laser photocoagulation). Intra-arterial chemotherapy (IAC) is a relatively new technique for the management of advanced retinoblastoma. First introduced in 2004 by Yamane et al,1 the treatment was performed by infusing melphalan into the ipsilateral carotid artery of an eye with retinoblastoma. In 2008, Abramson et al2 began infusing the chemotherapeutic agent directly into the ophthalmic artery. Although there have been several reports of impressive results from IAC,3-7 the procedure requires a skillful radiointerventionist or neurointerventionist to implement. As a result, studies involving IAC have mainly originated from developed countries. We report the outcome of our usage of IAC at a university hospital in Thailand and discuss the role of IAC in the management of intraocular retinoblastoma.

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METHODS

This was a retrospective, nonrandomized, noncomparative interventional case series. Approval from the Institutional Review Board of the Ramathibodi Hospital, Mahidol University was obtained. Because this retrospective study was carried out using patient data in an anonymous manner, the requirement for written informed consent from individual patients was waived. Medical records were reviewed for all patients with retinoblastoma who were treated at Ramathibodi Hospital, Bangkok, Thailand, with IAC as their primary or secondary treatment modality (after the failure of other treatment modalities) from January 2009 to November 2017.

Patient data were reviewed for demographic information, clinical findings, management methods, treatment outcomes, and complications. These included sex, hereditary pattern (familial, sporadic), age at diagnosis, age at first IAC, treatment before and after IAC, number of IAC sessions, number of successful IAC cannulations, type of chemotherapeutic agents used, dosage of each session, and ocular and systemic complications of IAC.

Detailed ocular examination was performed under general anesthesia to identify laterality (unilateral or bilateral), tumor growth pattern (exophytic, endophytic, or combined exophytic-endophytic), total number of tumors per eye, size of the tumor(s), and statuses of the following tissues: anterior chamber, iris, ciliary body, optic nerve, choroid, and vitreous. Each tumor was measured for its largest basal dimension and thickness in millimeters (mm), using indirect ophthalmoscopy and ultrasonography. Associated vitreous seeding (number of quadrants) and subretinal seeding (number of quadrants) parameters were documented. Clinical findings were documented via fundus drawing, fundus photography using RetCam imaging (Massie Industries, Dublin, CA, US), fluorescein angiography, and ultrasonography. Eyes were classified using the International Classification of Retinoblastoma (ICRB).8

During the treatment period, follow-up eye examinations were performed under general anesthesia every 2 to 6 weeks. During each examination, the main solid tumor response was defined as a complete response (no degree of residual viable tumor), a partial response (some degree of residual viable tumor), no response (no change or enlarged viable tumor), or recurrence (recurrence of tumor after an initial response). The statuses and viabilities of vitreous and subretinal seedings were documented. A general physical examination and complete blood count were documented at each visit by a pediatric oncologist.

Intra-arterial chemotherapy was performed under general anesthesia by neurointerventionists. The right femoral artery was punctured and a 4-French arterial sheath (Terumo Corporation, Tokyo, Japan) was inserted. Heparinization was administered at a dose of 30 U/kg, and a 4-French headway catheter (CathNet-Science, Paris, France) was then guided into the ipsilateral internal carotid artery of the targeted eye. A cerebral angiogram was performed to visualize the cerebral vasculature, ophthalmic artery origin, and retinal stain. After completion of roadmapping, a 0.4-mm tip flow-related microcatheter (1.2-French Magic microcatheter, Balt Therapeutics, Montgomery, France) and a 0.008-inch (0.20-mm) hydrophilic microguidewire (Mirage, EV3, US) were catheterized into the ophthalmic artery. Once the microcatheter was stabilized within the ophthalmic artery, angiography was performed to verify and confirm vascularization of the entire globe, and the chemotherapeutic agent was delivered directly into the ophthalmic artery (superselective IAC technique) (Fig. 1A). The chemotherapeutic agent would then be infused over a duration of 20 minutes.

FIGURE 1.

FIGURE 1.

In the event that the cannulation of the ophthalmic artery was determined to be unsuccessful, the neurointerventionist would change the technique to selective IAC. In cases where the ophthalmic artery was supplied by a branch of the external carotid artery (ECA)—in particular, the meningo-ophthalmic artery—a 1.2-French Magic microcatheter (Balt Therapeutics, Montgomery, France) would be inserted into the ECA branch with infusion of the chemotherapeutic agent. In cases where the ophthalmic artery was not supplied by an ECA branch, temporary balloon occlusion of the supraclinoid portion of the internal carotid artery would be performed using a 5-French arterial sheath (Terumo Corporation, Tokyo, Japan), 5-French Softtip XF headway (Boston Scientific, US), and Magic B1 Balloon (Balt Therapeutics, Montgomery, France) (Fig. 1B). The chemotherapeutic agent would then be infused over a duration of 5 minutes or less.

Each IAC session was performed 4 to 6 weeks apart. The main chemotherapeutic agent used was melphalan. The dosage was calculated according to the patient's age and the stage of the tumor, as described previously by Gobin et al3 and Shields et al.9 In brief, 3 mg was given if the patients aged 2 years or younger, 5 mg for 2 to 5 years, and 7.5 mg for those older than 5 years. Additionally, topotecan (0.3 or 0.4 mg) or carboplatin (30 mg) was given in cases showing poor response to melphalan monotherapy.

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RESULTS

Overall, 27 eyes of 26 patients with intraocular retinoblastoma were treated with IAC over an 8-year period at our institution. Patient characteristics are summarized in Table 1. A majority of patients (96%) exhibited sporadic retinoblastoma. All 27 eyes were classified according to the ICRB: group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Intra-arterial chemotherapy was performed as the primary treatment in 7 eyes (26%) (4 and 3 eyes in ICRB group D and E, respectively) and as the secondary treatment in 20 eyes (74%) (3, 1, 8, and 8 eyes in ICRB group B, C, D, and E, respectively). Previous treatments in the secondary treatment group included systemic chemotherapy with vincristine, etoposide, and carboplatin in all 20 eyes (100%), and external beam radiotherapy in 1 eye (5%). There were 12 patients (46%) who received concurrent systemic chemotherapy during the course of IAC. The overall success rate of cannulation for IAC was 94%, with 89% for superselective IAC and 11% for selective IAC. The mean number of IAC sessions for each eye was 2.7. Melphalan (3-7.5 mg) was used as the primary chemotherapeutic agent in all eyes; additional treatment consisted of topotecan (0.3 or 0.4 mg) in 4 eyes and carboplatin (30 mg) in 1 eye. Two (29%) and 13 (65%) of patients receiving IAC as primary and secondary treatment modality respectively needed additional treatments (Table 2). The mean follow-up period was 32 months (median, 25 months; range, 3-95 months). The overall globe salvage was achieved in 14 eyes (52%), with 100%, 100%, 75% and 9% in ICRB group B, C, D (Fig. 2), and E, respectively (Table 3). Kaplan-Meier survival analysis of globe salvage is shown in Figure 3.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

TABLE 3

FIGURE 2.

FIGURE 2.

FIGURE 3.

FIGURE 3.

The observed complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), and strabismus (n = 2, 7%). One patient (4%) developed single episode of transient ischemic attack (TIA), but fully recovered after treatment with intravenous methylprednisolone without any complications; none of our patients developed permanent stroke or cerebral damage. One patient died, putting the overall survival rate at 96% (n = 25). This patient, whose IAC cannulation failed, underwent enucleation and later developed fatal brain metastasis, despite multiple courses of systemic chemotherapy.

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DISCUSSION

Intra-arterial chemotherapy is a challenging procedure, requiring technical skill and specialized facilities. Because of this, a vast majority of studies on the efficacy and safety of IAC were performed in developed countries. On the other hand, there is a shortage of data pertaining to the use of IAC in developing countries. Our study aimed to help rectify this problem by presenting the data collected at our center, currently the only facility in Thailand with the capacity to perform IAC for intraocular retinoblastoma.

At our institution, IAC has been used for the treatment of intraocular retinoblastoma since 2009. It has been performed as both primary treatment (especially in cases of unilateral advanced disease) and secondary treatment (in eyes that have previously failed conventional treatments) to increase the probability of globe salvage. We use both superselective and selective cannulation techniques, but typically prefer the superselective technique, as it avoids the temporary occlusion of the internal carotid artery associated with balloon catheter usage in the selective IAC technique. According to previous studies, the overall success rate of cannulation have ranged from 79% to 100% (Table 4).3-7,10-30 Our success rate of cannulation was 94%, which was comparable to these studies.

TABLE 4

TABLE 4

Although numerous reports have found IAC to be a safe treatment for intraocular retinoblastoma,3-7,10-30 this complex procedure is certainly not without its complications. For instance, a stroke could theoretically be induced by intra-arterial catheterization.31,32 Nevertheless, no study has yet reported the occurrence of stroke in retinoblastoma patients following IAC. In our study, although none of the patients developed a permanent stroke, one had a TIA. This patient received a total of 7 sessions of IAC (3 sessions with melphalan and 4 sessions with carboplatin), and was notable for being the only patient who received carboplatin during the study period. The TIA developed after the patient's final IAC session. After receiving intravenous methylprednisolone, this patient fully recovered and did not exhibit any sequelae. Possible causes of the TIA included vasospasm induced by repetitive IAC cannulation33 and vascular toxicity from carboplatin.34 After this incident, we abandoned the use of carboplatin and no patient has developed TIA since then.

In addition, retinal artery precipitates were found in 2 eyes (7%) after IAC, even though in both cases, fluorescein angiography had shown good vascular perfusion all the way to the periphery. Wilson et al35 followed a study in a non-human primate model and hypothesized that retinal artery precipitates may be the result of complex interactions between multiple inflammatory mediators, the phenomenon of leukostasis, and drug particulates, which were seen on electron microscopy. These mechanisms may also be related to the development of Purtscher-like retinopathy10 and retinal arteriole emboli,11 which have been reported previously. Moreover, melphalan may have a short duration of stable concentration,36,37 thereby contributing to accumulation of drug particulates. The fact is that retinal artery precipitates were only observed in some of our cases, even though in our study, all drugs were consistently carefully prepared and properly administered.

The occurrence of occlusive vasculopathies, such as vessel stenosis or total occlusion, following IAC may be related to ischemic changes in the choroid and retina. In previous studies, the rate of occlusive vasculopathy has ranged from 0% to 38% (Table 4). In our study, 4 eyes (15%) demonstrated occlusive vasculopathy (ophthalmic arterial occlusion), a rate comparable to those found in previous studies. It remains unclear whether occlusive vasculopathy results from rheological disturbances, linked to ophthalmic artery catheterization, or from direct drug toxicity to the choroidal vasculature and/or retinal pigment epithelium.11 Therefore, further study is required to elucidate the cause of occlusive vasculopathy, in order to prevent this sight-threatening complication.

Vitreous hemorrhage, which obscures fundus visualization, can complicate follow-up examinations after IAC. This obstacle is particularly pertinent to advanced cases, which carry the possibility of disease progression. Hence, persistent vitreous hemorrhage may necessitate enucleation. In previous studies, the rate of vitreous hemorrhage has varied from 4% to 41%.5,7,10-13,16,18,19,23,25,28 In our study, vitreous hemorrhage was found in 3 eyes (11%), all of which were enucleated due to concerns regarding tumor progression without the capacity for visualization. Of 3 enu-cleated eyes, residual viable tumors were found in 2. In 2 previous large case series, vitreous hemorrhage was reported in 6% and 4% of eyes following IAC.5,7 Although the exact mechanism of vitreous hemorrhage remains to be elucidated, it has been specu-lated to result from the fragile neovascularization of an ischemic retina, or from toxicity by chemotherapeutic agents.12

As reported in previous studies,7,13,15,19,20 strabismus, as another complication of IAC, may manifest as third or sixth cranial nerve palsy and typically resolves spontaneously within a few months.38 In our study, 2 eyes (7%) showed strabismus due to third cranial nerve palsy. Notably, strabismus has been hypothesized to result from iatrogenic injury during catheter advancement into the ophthalmic artery.13 Thus, we investigated the relevance of catheter depth in the ophthalmic artery to the incidences of strabismus and ophthalmic artery occlusion following IAC. Interestingly, we found no significant correlation between catheter depth and either complication (P value, odds ratio, confidence interval: strabismus, 0.15, 1.18, 0.94-1.49; ophthalmic artery occlusion, 0.08, 1.17, 0.98-1.39). Because both patients showed strabismus after their second or third course of IAC, we suspect the strabismus might have been related to toxicity of the chemotherapeutic agents, which could have induced vasospasm and led to a transient ischemic process within the cranial nerves.

It is difficult to compare the efficacy of IAC among previous reports, as they had used a variety of retinoblastoma staging systems and treatment modalities. We summarized other large case series and compared them with our study in Table 4. In other studies, globe salvage rates for primary IAC, secondary IAC, and the overall course of treatment were 43%-100%, 55%-100%, and 54%-100%, respectively (Table 4). Globe salvage was more likely to be achieved in patients with less advanced disease, according to ICRB classification, with a salvage rate of 75%-100% in ICRB groups A-C, 45%-100% in group D, and 30%-91% in group E (Table 4). In our study, globe salvage rates in primary IAC, secondary IAC, and the overall course of treatment were 57%, 50%, and 52%, respectively, which were lower than those reported in other studies. However, when compared the different stages of ICRB, our results were comparable, except in group E (100% in groups A-C, 75% in group D, and 9% in group E). Hence, a plausible explanation for our lower rates of overall globe salvage may be the different composition of ICRB stages among our patient cohort. Also note that almost half of our patients (41%) were in ICRB group E, which has been associated with very poor globe salvage rates even after multiple intensive treatments. It should be noted that 4 of the enucleations were performed due to uncontrolled vitreous seeding. Although all 4 eyes could potentially have benefited from intravitreal chemotherapy, this treatment only became available at our center in time for the treatment of one of these eyes. Nevertheless, with these new combined treatment modalities, we anticipate positive prospects of salvaging more ICRB group E eyes in the future.

In general, enucleation is indicated in patients with ICRB group E retinoblastoma, hence it is always recommended to them. However, in Thailand, where samsara is a common Buddhist belief, enucleation is assumed to affect one's well-being in the next life, making the procedure highly stigmatized. Therefore, in cases where parents have strongly objected to enucleation, IAC was offered as an alternative, despite very poor chances of globe salvage. This was done primarily to maintain contact with the patient for further treatment and follow-up, in an effort to prevent metastasis or death. Additionally, it was often found that enucleation became more acceptable to these parents after the failure of IAC treatment.

In Thailand, IAC is very useful because it can serve as both primary and secondary, or adjunctive treatment for intraocular retinoblastoma. In addition, IAC allows us to salvage globes that might have required enucleation in the past, especially in patients with ICRB group D retinoblastoma. However, scarcity of resources, limited budget, and requirement of specialized facilities and technical expertise, stand in the way of its implementation in many developing countries. Consider, for example, that one session of IAC using melphalan can cost up to US$2200, while one cycle of chemoreduction cost US$250, and enucleation cost US$1000. At our hospital, we are currently managing to circumvent these budgetary constraints by creating a special fund, supported by our administration and other foundations. This solution may serve as a guide for other developing countries with plans to initiate IAC treatment in the future.

In conclusion, our findings indicate that IAC is a safe and effective treatment for patients with ICRB group B, C, and (in some cases) D retinoblastoma. This is, however, generally not true for patients with ICRB group E retinoblastoma, for whom enucleation is still required in the majority of our cases. Our results may aid in the counseling of parents, allowing them to understand and accept enucleation as the best option for their child. Moreover, our results further illustrate the importance of promoting awareness of retinoblastoma on a national scale, in order to implement better surveillance and facilitate earlier recognition and treatment, with overall improvement in clinical outcomes. Lastly, our results confirm the importance of careful patient selection, and the involvement of an experienced surgeon, as mandatory considerations for achieving the best treatment outcome for IAC in patients with intraocular retinoblastoma.

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ACKNOWLEDGMENTS

We thank Ryan Chastain-Gross, PhD, from Edanz Group (www.edanzediting.com/ac) for editing the draft of this manuscript.

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Keywords:

developing country; eye; intra-arterial chemotherapy; retinoblastoma; treatment

© 2019 by Asia Pacific Academy of Ophthalmology