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Ocular oncology
Risk factors for cataract in retinoblastoma management
  1. Shichong Jia,
  2. Xuyang Wen,
  3. Jie Yu,
  4. Min Zhou,
  5. Ludi Yang,
  6. Yiyi Feng,
  7. Xiaoyu He,
  8. Renbing Jia,
  9. Jiayan Fan,
  10. Xianqun Fan
  1. Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  1. Correspondence to Professor Xianqun Fan, Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; fanxq{at}sjtu.edu.cn; Dr Jiayan Fan; fanjiayan1118{at}126.com; Dr Renbing Jia; renbingjia{at}sjtu.edu.cn

Abstract

Aims To investigate the risk factors for cataract following eye-preserving therapies for retinoblastoma.

Methods This retrospective, single-centre cohort study included patients diagnosed with retinoblastoma receiving eye-preserving therapies between January 2017 and June 2021. Cataract by the end of the follow-up was the main outcome.

Results Cataract was found in 31 of 184 (16.8%) included eyes during a mean follow-up of 27.6 months. The cataract and control groups were similar regarding patients’ laterality, sex and disease stage. Eyes in the cataract group were more likely to present with endophytic retinoblastoma (p=0.02) and greater intraocular pressure (p=0.001). Competing risk regression analysis (univariate Fine-Gray model) showed that the growth pattern (p=0.01), intraocular pressure (p=0.01), number of intra-arterial chemotherapy (IAC) cycles (p=0.001), melphalan dose per IAC cycle (p=0.001) and number of intravitreous chemotherapy (IvitC) cycles (p=0.001) were associated with cataract occurrence. Multivariate analysis included higher intraocular pressure (p=0.003), a higher melphalan dose per IAC cycle (p=0.001) and an increasing number of IvitC cycles (p=0.04) as independent risk factors for cataract.

Conclusions Repeated IAC and/or IvitC with melphalan were the most common eye-preserving therapies that induced cataract formation. The toxic effect of melphalan was an essential factor in cataract development, as indicated by the association of cataract occurrence with the melphalan dose.

  • Child health (paediatrics)
  • Retina

Data availability statement

Data are available on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bjo-2022-321723

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Cataract is an important complication cause of enucleation in retinoblastoma patients. However, the risk factors for cataract were rarely discussed.

    WHAT THIS STUDY ADDS

    • The tumour growth pattern, the number of intra-arterial chemotherapy (IAC) cycles, melphalan dose per IAC cycle and the number of intravitreous chemotherapy (IvitC) cycles were associated with cataract occurrence.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Repeated IAC and/or IvitC with melphalan were the most common eye-preserving therapies that induced cataract formation. The toxic effect of melphalan was an essential factor in cataract development, as indicated by the association of cataract occurrence with the melphalan dose.

    Introduction

    Retinoblastoma is the most common primary intraocular tumour in children and represents 4% of all paediatric malignancies.1–3 With the continued efforts of clinicians, retinoblastoma treatment has undergone a major shift from radiotherapy to systemic chemotherapy and then to in situ chemotherapy, which has greatly improved the survival and globe salvage rates.4 The purpose of treatment has also evolved from saving lives to preserving the globe and eyesight. Currently, external beam irradiation has been discontinued because of its radiation toxicity,5 6 while intravenous chemotherapy (IVC), intra-arterial chemotherapy (IAC), intravitreous chemotherapy (IvitC), photocoagulation and cryotherapy constitute the main methods in retinoblastoma management.7

    In the postradiotherapy era, different centres have reported vitreous haemorrhage, eyelid oedema, ptosis, ophthalmic artery (OA) occlusion, chorioretinal atrophy, tropia and cataract as ocular complications among retinoblastoma patients.4 8–11 Cataract impedes the normal development of visual function and the improvement of visual acuity in children, and affects the accurate monitoring of intraocular tumours through fundus examination during follow-up.12 13 However, cataracts occurring after eye-preserving therapies for retinoblastoma have always been reported by case series and the risk factors for the cataracts have rarely been discussed. The purpose of this study was to review patients who received regular eye-preserving therapies for retinoblastoma in our hospital to identify potential procedure- related and/or treatment-related risk factors for cataract occurrence.

    Methods

    A retrospective chart review was performed for consecutive patients with unilateral or bilateral retinoblastoma who received eye-preserving therapies between January 2017 and June 2021. Exclusion criteria were opaque media from haemorrhage in the anterior chamber, vitreous or subretinal space, the invasion of the postlaminar optic nerve, sclera, orbit or anterior chamber, extraocular disease, intracranial metastatic disease and neovascular glaucoma at diagnosis. Eyes returned for evaluation later than 35 days after the last treatment/follow-up or evaluated by a different ophthalmologist were also excluded. This study was conducted in accordance with the Declaration of Helsinki.

    The patients’ medical records and fundus photography at presentation and during follow-up were carefully reviewed to obtain demographic data, tumour characteristics and treatments. The International Intraocular Retinoblastoma Classification (IIRC) was applied for tumour staging based on clinical presentation. Treatments included IVC, IAC, IvitC, intracameral chemotherapy, photocoagulation and cryotherapy. Vindesine, etoposide and carboplatin were the chemotherapeutic agents used in IVC cycles and chemotherapy cycles were provided every 4 weeks.14 The surgical procedures and drug regimen in IAC cycles have been described in detail in our published article.10 In brief, a super-selective microcatheter was introduced to an ostial position and chemotherapeutic drugs were injected into the OA. Chemotherapeutic medications included melphalan, topotecan and carboplatin, and the drugs were administered at a dosage dependent on age (melphalan at 3.0–7.5 mg; topotecan at 1 mg; carboplatin at 20 mg). If OA catheterisation was unavailable, we adopted the alternative external carotid artery branch approach or balloon approach on the basis of the anatomical condition. During the treatment, IvitC was applied for the control of vitreous seeds. The intravitreous injections in our centre were performed following the procedure described previously by Francis.15 Following induction of anaesthesia, the intraocular pressure was lowered by digital massage to a target pressure of less than 21 mm Hg. Intravitreous melphalan (10–30 µg in 0.01–0.1 mL) was injected with a 30-gauge needle. Intravitreal injection site was based on the age of the patient that distance posterior to the limbus that has been improved infants and children patient safety.16 Before needle withdrawal, the injection site was sealed and sterilised with cryotherapy. The ocular surface was submerged in irrigating sterile water for 3 min. The injection site was sealed and sterilised by cryotherapy before removal of the needle. Commonly used drugs for intravitreous injections were melphalan and topotecan, and the dose was 10–30 µg, dependent on eye size and tumour volume. Intracameral chemotherapy was applied to treat aqueous seeding, and the desired final melphalan concentration was 15–20 μg/mL.17 The choice of local adjuvant therapy (cryotherapy or photocoagulation) was customised and adapted to the tumour size and location.

    The treated eyes were retrospectively divided into two groups. The cataract group comprised eyes that were found to develop cataract during follow-up, while the control group comprised eyes that did not develop cataract by the end of the follow-up. Cataracts were evaluated under general anaesthesia with a handheld slit lamp as well as a retcam anterior segment photographic system.

    Statistical analysis

    Categorical variables were compared using the χ2 test or Fisher’s exact test, while quantitative variables were compared using an unpaired t-test or Wilcoxon rank-sum test. Cumulative incidence function was applied to describe the occurrence of cataract over time after treatment in the presence of enucleation as a competing risk. Risk factors for cataract were analysed using a competing risk regression (Fine-Gray model). Variables with a p<0.05 in the univariate analyses were included in the multivariate analysis. HRs with corresponding 95% CIs were used to describe the impact of risk factors. For all tests, a value of p<0.05 was considered to be statistically significant, and all analyses were performed with SPSS (V.22.0) and Stata (V.15.0).

    Results

    Patients and treatment characteristics

    A total of 184 retinoblastoma eyes in 151 consecutive patients treated at our centre were included in this study. The study group selection is summarised in figure 1A. During a mean follow-up of 27.6 months after the retinoblastoma diagnosis, cataract was found in 31 treated eyes (16.8%), which were assigned to the cataract group. The baseline characteristics of eyes in the cataract and control groups are presented in table 1. There was no significant difference in gender, side, laterality or tumour staging between the two groups. However, eyes in the cataract group tended to present with an endophytic growth pattern (p=0.02) and greater intraocular pressure (p=0.001).

    Figure 1
    Figure 1

    (A) Flow chart showing the study group. Of the 282 eyes treated between January 2017 and June 2021, 184 eyes of 151 patients matched the study inclusion criteria. (B, C) Representative images of cataract in retinoblastoma management: (B) appearance; (C) microscopic view. A 36-month-old girl with right retinoblastoma (Group E, IOP: 30 mm Hg) was treated with five cycles of IAC, and 9 months later developed cataracts. IAC, intra-arterial chemotherapy; IOP, intraocular pressure.

    View this table:
    Table 1

    Baseline of 184 eyes (151 patients) treated for retinoblastoma

    Therapeutic modalities included IAC (n=140, 76.1%), IVC (n=108, 58.7%), IvitC (n=60, 32.6%), cryotherapy (n=58, 31.5%), photocoagulation (n=80, 43.5%) and intracameral chemotherapy (n=2, 1.1%), which are presented in table 2. None of the patients previously underwent radiotherapy. A higher proportion of eyes in the cataract group received IAC (p=0.01), and of the eyes that developed cataracts, only 2 (6.5%) had never received IAC. Moreover, eyes in the cataract group received a greater number of IAC cycles (p=0.02). Furthermore, the melphalan dose per IAC cycle was also significantly higher in the cataract group (p<0.001). The cataract group showed a greater number of IvitC cycles (p=0.02). However, there was no significant difference in the drug dose per injection between the two groups.

    View this table:
    Table 2

    Treatment of 184 eyes for retinoblastoma

    Cataract

    Thirty-one eyes of 30 patients developed cataracts, with a mean interval between retinoblastoma diagnosis and cataract presentation of 15.9 months (median: 13.9 months; range: 3.9–44.0 months). The mean age at cataract presentation was 43.7 months (median: 40.0 years; range: 7.6–105.1 years). Among the 31 eyes, vitreous seeds were found in 12 (38.7%) eyes, subretinal fluid was present in 3 (9.7%) eyes, retinal detachment was observed in 11 (35.4%) eyes and subretinal seeds were found in 5 (16.1%) eyes. None of the eyes were found to have tumour contacting the lens at presentation. Initially, eyes were presented with small punctate clouding, vacuoles and crystals under the posterior capsule of the lens. Subsequently, they developed posterior subcapsular cataract and progressed to a wider range. Typical images of cataract are shown in figure 1B,C.

    Cataract surgery was performed when cataract prevented the monitoring of the tumours and 18 (58.1%) eyes received cataract surgery. All such patients underwent lens aspiration plus posterior capsulotomy. Anterior vitrectomy was performed in 8 (25.8%) eyes.

    Risk factors for cataract

    To date and to our knowledge, 48 eyes (26.1%) were enucleated and no patient has demonstrated metastases or has died. Cumulative incidence function showed that the tumour growth pattern (figure 2A), number of IAC cycles (figure 2B), melphalan dose per IAC cycle (figure 2C) and number of IvitC cycles (figure 2D) were associated with cataract occurrence. Competing risk regression analysis (univariate Fine-Gray model) indicated that the growth pattern, intraocular pressure, number of IAC cycles, melphalan dose in IAC and number of IvitC cycles were univariate risk factors for cataract (table 3). Multivariable analysis demonstrated that high intraocular pressure was a risk factor for cataract (p=0.003) (table 3). For the treatment, a higher melphalan dose in each IAC cycle (p=0.001) and an increasing number of IvitC cycles (p=0.04) were both independent risk factors.

    Figure 2
    Figure 2

    Cumulative incidence function for cataract (accounting for enucleation as a competing risk) according to (A) growth patterns; (B) number of IAC cycles; (C) melphalan dose per IAC cycle; (D) number of IvitC cycles. IAC, intravenous chemotherapy; IvitC, intravitreous chemotherapy.

    View this table:
    Table 3

    Results of the univariate and multivariate risk analyses for variables associated with cataract after treatment for retinoblastoma

    Discussion

    Retinoblastoma globe salvage has been greatly improved with multiple breakthrough treatment methods in the conservative management of retinoblastoma in recent years, allowing more eyes to be salvaged. With growing experience with ever-increasing numbers of treatments, several complications have been reported. In this study, we reviewed cataract occurrence in retinoblastoma patients treated at our ocular oncology centre and investigated the risk factors for cataract in retinoblastoma management. We report an incidence of 16.8% (31/184) of eyes that developed cataract after eye preservation therapy. Further analysis showed that the tumour growth pattern, number of IAC cycles, melphalan dose per IAC cycle and number of IvitC cycles were associated with cataract occurrence.

    Cataract occurrence is closely associated with the treatment modalities for retinoblastoma. In the era of external beam radiation therapy, cataract formation was one of the most significant side effects in the treatments.18 It was reported that cataracts occurred in 71.7% of eyes receiving whole-eye radiotherapy, and the incidence of cataracts could still reach 35.3% after lens-sparing radiotherapy.19 Despite a great decline in radiotherapy use owing to advances in selective chemotherapy drug delivery, a number of studies have reported cataract as a common complication during IAC or IvitC cycles for retinoblastoma.

    Suesskind et al reported a case of cataract formation in which a 23-month-old girl developed cataract after receiving repeated IAC with melphalan.20 Three years later, Chen et al reported a cataract incidence of 6.7% after IAC and concluded that cataract was one of the main late complications.21 There are more reports about cataract occurrence after IvitC treatment. Francis et al reported lens opacity as a common toxic effect in intravitreous melphalan injection. Subsequently, four studies reported an incidence of cataract after receiving IvitC of 27.5% (Shields et al), 15.8% (Ji et al), 26.7% (Xue et al) and 30% (Yousef et al).22–26 Over the past decade, IAC and IvitC using various melphalan-based regimens have become established treatment options for retinoblastoma globally. Currently, IAC is employed for retinoblastoma patients as the primary treatment for unilateral or bilateral retinoblastoma, and as a secondary treatment following failure of other treatments. However, there are ocular toxicities that are encountered after IAC therapy that were never observed with systemic chemotherapy. Among all the applied methods, repeated IAC and IvitC are the most common eye-preserving therapies for retinoblastoma that induce cataract formation.

    In the IAC and IvitC techniques, the systemic absorption is minimal, and melphalan is the primary chemotherapeutic agent. Furthermore, melphalan has been systemically used in multiple myeloma treatment for decades.27 Evidence showed that melphalan can cause infertility, myelosuppression and gastrointestinal reaction among other conditions. However, there have been few reports in the literature on cataracts induced after systemic melphalan application. Our results showed that the higher melphalan dose per IAC cycle the greater was the risk for cataract. This indicated that the toxic effects of chemotherapeutic agents may be a possible cause of cataract, because the increasing topical drug concentrations in the eye may be more likely to exceed the maximum threshold that lens epithelial cells and lens fibres can tolerate.28 In addition, damage from chemotherapeutic toxicity gradually accumulated as the IAC cycles increased, which may partially explain why the risk for cataract differed in eyes receiving different numbers of IAC sessions. Similarly, an increasing number of IvitC cycles was a risk factor for cataract because the toxic effect of melphalan may bring the potential of a long-term risk for cataract. Some measures, such as timely adjustment of melphalan doses and substitution of IVC during the IAC cycles, may help to reduce cataract occurrence, and it is necessary to verify the effectiveness of these measures in future clinical practice.

    The possibility of cataract formation by radiation exposure during fluoroscopy has been indicated.20 The total radiation exposure increases with an increasing number of IAC cycles. By evaluating the radiation applied to the lens per procedure, it was calculated that the threshold for the onset of radiation-induced cataract will be exceeded if IAC is performed for more than eight cycles, which reflects the risk posed by the radiation accumulated in the increasing IAC cycles.29 In our cohort, 29 cataract eyes received a median of 4 IAC cycles (range: 1–9), and only 1 patient received a total of 9 IAC treatments for recurrent tumours after 6 months who had received four IAC cycles, and ultimately developed cataracts 2 months later. Furthermore, we did not find any correlation between cataract and the radiation dose per cycle in our patients who received IAC. Therefore, a radiation-related cataract would be less probable than a toxic effect of melphalan, and ocular complication should be taken into consideration as a limitation of the number of feasible repeated treatments.

    In addition to potential treatment-related risk factors, another variable affecting cataract occurrence was the autologous characteristics of the tumour, which may be associated with mechanical stress caused by tumour growth and biochemical alterations brought about by the tumour. Posterior pole tumours were widely accepted as one of the potential causes of paediatric cataracts.30 According to the speculation of Suesskind et al, endophytic tumour would induce circumscribed lens opacities where the tumour cells come into contact with the lens surface.20 However, none of the tumours in our cohorts touched the lens. In addition, bioactive growth factors produced by retinoblastoma cells can also induce cataractous changes; for example, transforming growth factor beta produced by retinoblastoma cells has been associated with various ocular changes, including cataract formation and neovascularisation.31 Unfortunately, limited by the lack of laboratory studies, it is difficult to clarify the specific mechanism of tumour in cataract progression. Moreover, competing risk regression model reflected that IIRC group was not associated with the cataract incidence (table 3). On the other hand, group E eyes in our study were not presented with an increasing number of IAC cycles and a higher melphalan dose in each cycle, which implied that more drugs were not a reflection of underlying disease. Therefore, the current data supported that the cataract incidence was more correlated with melphalan dose, rather than disease burden. A large series from multiple centres are necessary to verify our findings.

    In this retrospective single-centre study, there were several sources of bias: retrospective nature (in which the methodology could not be controlled), single centre (in which the sample size was restricted and selection bias was inevitable) and the Chinese population (reflecting results only from one part of the wider population). It is necessary to verify our findings in a large series from multiple ocular oncology centres with long-term follow-up.

    In conclusion, this report demonstrated that cataract seen in retinoblastoma patients might be related to the growth pattern, intraocular pressure, the number of IAC cycles, melphalan dose per IAC cycle and the number of IvitC cycles. The toxic effect of melphalan is an essential factor in cataract development, as indicated by the association of cataract occurrence with the melphalan dose. Protective methods should be attempted for those eyes to minimise the risk of cataract complications.

    Data availability statement

    Data are available on reasonable request.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • SJ, XW and JY contributed equally.

    • Contributors Conception and design: XF, JF and RJ. Collection and assembly of data: SJ, XW and JY. Data analysis and interpretation: all authors. Guarantors: XF, JF and RJ

    • Funding This work was supported by grants from the National Natural Science Foundation of China (grant number: 81872339), Science and Technology Commission of Shanghai (grant number: 20DZ2270800), the Shanghai Science and Technology Development Fund (grant number: 19QA1405100), Shanghai Youth Top-notch Talent Support Programme, Shanghai Key Clinical Specialty, Shanghai Eye Disease Research Center (grant number: 2022ZZ01003), Clinical Research Plan of SHDC (grant number: SHDC2020CR1009A), Cross research of Shanghai Ninth People's Hospital (grant number: JYJC202230) and Shanghai Ninth People' s Hospital Excellent Youth Fund Program (grant number: JYYQ003).

    • Competing interests None declared.

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