Metastatic Death Following Ophthalmic Artery Chemotherapy for Retinoblastoma: A Systematic Review and Meta-analysis

Nattawut Leelakanok, Ph.D.1, La-ongsri Atchaneeyasakul, M.D.2, Dittapong Songsaeng, M.D.3, Janthima Methaneethorn, Ph.D.4,5, Kleebsabai Sanpakit, M.D.6, Jassada Buaboonnam, M.D.6

1Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand, 2Department of Ophthalmology, Faculty of

Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 3Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 4Pharmacokinetic Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand, 5Center of Excellence for Environmental Health and Toxicology, Naresuan University, Phitsanulok, Thailand, 6Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

INTRODUCTION

Retinoblastoma, which typically develops before the age of five, is the most common malignant intraocular tumor in children.1 The mean incidence ranges from 11.2-12.4 per 1 million in children younger than five.2,3 Current treatment modalities include enucleation, chemotherapy, local therapy with laser photocoagulation, cryotherapy, and radiotherapy. Irrespective of the chosen

therapeutic approach, the objective of the treatment is to preserve patients’ lives, ocular globes, and vision. Systemic chemotherapies, such as the combination of carboplatin, etoposide, vincristine, or vincristine, doxorubicin, and cyclophosphamide, have been used as adjuvant and salvage therapies. Although they carry a relatively low risk of neutropenic death and platinum-induced ototoxicity,4,5 these regimens include topoisomerase II inhibitors and

Corresponding author: Jassada Buaboonnam E-mail: onco008@yahoo.com

Received 4 December 2023 Revised 8 January 2024 Accepted 17 January 2024 ORCID ID:http://orcid.org/0000-0002-5240-1071 https://doi.org/10.33192/smj.v76i3.266573

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

may elevate the risk of second malignant neoplasms, particularly acute myeloid leukemia (AML).6,7 External beam radiotherapy has previously been used as salvage therapy to prevent enucleation -- the surgical removal of the eyeball and optic nerve -- in patients with treatment- resistant retinoblastoma. It has yielded satisfactory results, however, this approach may elevate the risk of secondary malignant neoplasms.8,9 To resolve these issues, direct chemotherapy administration has gained attention. Originating in Japan, ophthalmic Artery Chemotherapy (OAC) is now widely used as both a primary and salvage therapy, with promising results.10,11 However, enucleation remains a necessary step for patients with affected eyes unresponsive to treatments. Delayed enucleation, often due to parental hesitancy12 or treatment-related factors,13 can lead to disease progression. Moreover, there is a risk of distant metastasis from retinoblastoma due to potential micrometastasis, even when the localized disease is under control. These reasons raise concerns about OAC and increase the likelihood of metastasis of the retinoblastoma. Given the unclear risk of metastatic death associated with OAC, conducting a systematic review and meta-analysis on this mortality aspect could be valuable for physicians managing retinoblastoma patients.

MATERIALS AND METHODS

Data sources and research methodology

A comprehensive literature review was conducted using databases such as Medline, Scopus, ScienceDirect, and CINAHL from inception to November 2023. The search focused on keywords like intraarterial infusion, retinoblastoma, and death, utilizing Medline’s suggested synonyms to broaden the search scope. The search was limited to English-language published articles. Detailed search methodologies are outlined in Electronic Supplementary Material 1. Additionally, references from relevant reviews, articles, letters, and protocols were examined for applicable studies. Contacting experts in the field was not performed.

Inclusion and exclusion criteria

The meta-analysis included studies that met the following criteria: (1) human studies, (2) clear indication of OAC as the treatment method, and (3) explicit reporting of deaths during the study period. Studies were excluded if they were (1) not research articles, (2) failed to report the total number of patients treated with OAC, (3) did not provide data on the total number of metastatic deaths post-OAC, (4) included populations overlapping other studies, and/or (5) involved participants who had previously or were concurrently undergoing intravenous

chemotherapy. The systemic review process is depicted in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram, shown in Fig 1.

Data extraction and evaluation

The selected articles were systematically organized using the EndNote X7, Thomson Reuters, New York, USA citation management. Initial steps involved removing duplicates, followed by a review of titles and abstracts by the first author, focusing on specific words, such as “report” to exclude case reports. Following this, the remaining abstracts were reviewed. For data abstraction, a structured form was designed by the first author and validated by the fourth author. This information was utilized to gather information on aspects such as study design, location, patient demographics, treatment characteristics, follow- up duration, and detailed mortality descriptions within each study. The first and last authors independently extracted this information, resolving any discrepancies through consensus. The evaluation of the risk bias in the studies was determined using a methodology proposed by Murad et al 2018.14 This involved translating positive answers (e.g., “yes” or “clear evidence”, or “no alternative explanation”) into a numerical value of one. Total scores of 1-3, 4-5, and 6-8 were categorized as “good”, “fair”, and “poor”, respectively.

Statistical methods

A binary random-effects model, following the DerSimonian-Laird approach, was implemented using OpenMetaAnalyst software, tailored for Windows 8.15 The I2 statistic was used to assess the heterogeneity of the underlying population. The interpretation of I2 was as the followings: 0-25% indicated insignificant heterogeneity, 26-50% indicated low heterogeneity, 51-75% indicated moderate heterogeneity, and >75% indicated high heterogeneity.16 We performed meta- regression using the random effects model to further investigate factors affecting the heterogeneity of the meta-analysis.

RESULTS

Study characteristics

A systematic search across various literature databases yielded 219 unique articles. After applying the inclusion and exclusion criteria, nine articles were selected for systematic review and meta-analysis (Table 1). These studies were conducted in China,17-20 Egypt,21 Switzerland,22 Turkey,23,24 and the United States,25 which demonstrates a diverse racial composition of the participants. In this meta-analysis, 596 participants

Fig 1. PRISMA diagram for the systematic review.

TABLE 1. Description of included studies

Data are presented as median (max-min) or mean±standard deviation

Abbreviations: CMT: chemotherapy, OAC – Ophthalmic artery chemotherapy, ICRB: International Classification of Retinoblastoma, ND: No data

(635 eyes) were studied. Among these, 89.9% (n = 536 patients) were diagnosed with unilateral retinoblastoma. The size of the studies included was small, with a median participant count of 72 (range: 16-140). The participant group showed a balanced gender distribution, with males comprising a median of 54.5% (range: 47.2-59.9%). All subjects were pediatric patients, with ages spanning from 11 to 34 months. The median follow-up period ranged from 1.5-3.7 years. The overall quality of the articles was considered fair, with a median risk of bias score of 5. In brief, all included studies had clear inclusion criteria, adequate exposure and outcome ascertainment, and sufficient follow-up time. There were no challenge/ rechallenge of the ophthalmic artery chemotherapy and dose-response relationship related to metastatic death observed from all included studies. A detailed summary of the study quality can be found in Table 2.

Metastatic mortality rates

Metastatic mortality rates were assessed among 596 patients, with at least 24 instances of metastasis identified.17-20,25 The most common site of metastasis was the brain, followed by bones. The average duration from the start of ophthalmic artery chemotherapy to

metastasis onset was 25.5 months in one study.25 For patients with metastasis, the post-OAC survival time ranged from 10.2 to 27.3 months according to Chen et al,17 and 8.4 to 23.0 months per Wen et al’s findings.18 The rate of enucleation following ophthalmic artery chemotherapy was 16.2% (95% confidence interval: 9.4%- 22.9%, I2 = 84.87, n = 108/635 eyes, N = 9). We also found 20 instances of metastatic deaths in the included studies. The meta-analysis revealed a pooled weighted metastatic death rate, or the mortality rate considering the study size, of 2.5% (95% confidence interval: 0.8%-4.2%, n = 20/596 patients, N = 9), and this rate was statistically different from zero (p < 0.05) (Fig 2). The heterogeneity of the studies was moderate (I2 = 51.42%) so the use of

the pooled rate estimates should be with caution.

We further investigated the effect of two factors on the proportion of metastatic death: 1) the length of follow-up time, and 2) the percent of patients treated with IAC only in each study. We found that increasing the length of follow-up time slightly lowered the metastatic death rate (β coefficient = -0.002 (95%CI:

-0.005-0.000), N = 9, p = 0.045). In addition, increasing the percentage of patients who received IAC only slightly increased the metastatic death rate (β coefficient = 0.001

TABLE 2. Quality of the included studies.

Fig 2. Forest plot demonstrating the proportion (%) of metastatic death of retinoblastoma treated with ophthalmic artery chemotherapy.

(95%CI: 0.000-0.001), p = 0.021). We therefore concluded that the length of follow-up time, and the percent of patients treated with IAC only affected the heterogeneity of this meta-analysis.

DISCUSSION

Treating retinoblastoma poses the dual challenge of preventing metastasis and preserving vision. With the introduction of OAC, the management of retinoblastoma has undergone drastic changes, with OAC serving both as front-line and salvage therapy. This study’s findings show a metastatic mortality rate of 2.5% among retinoblastoma patients treated with OAC, which closely aligns with the 2.1% (14/655) rate noted in a systematic review.26 The overall mortality rate for retinoblastoma ranges from 1-9%,26,27 with a specific study reporting a 1.7% metastatic death rate following primary enucleation over a follow-up period of 2.1 years (range 0.4-4.8).28 This study also found that the most frequent metastatic deaths were attributed to CNS complications, with post- OAC survival times spanning 8.4 to 27.3 months, which is longer than those reported post-enucleation (6-14 months).28 Despite global improvements in survival rates, including in countries with limited resources, high-risk histopathological features,29 and delayed enucleation30,31 appear to be the leading cause of metastatic deaths in retinoblastoma. While adjuvant systemic chemotherapy is effective in mitigating the risk of metastatic deaths in patients with high-risk histopathological features32 and may theoretically decrease the risk of metastasis in those receiving OAC, evidence from a study of patients treated with a combination of OAC and systemic chemotherapy17 shows that the risk of metastasis cannot be completely eliminiated by systemic chemotherapy (a fact physicians should be aware of). We also noted that CNS was the predominant site for metastasis, which emphasizes the

need for regular imaging to detect metastasis early in patients.

This study has several limitations that need to be addressed. First, our systematic review and meta-analysis found only nine studies focusing on the use of OAC for retinoblastoma treatment without previous or concurrent intravenous (IV) chemotherapy. These strict exclusion criteria, designed to minimize the confounding effects from IV treatments, yielded a smaller case pool. This approach also led to the exclusion of several other studies, such as one by Abramson et al,33 which reported three metastatic deaths among 1,139 patients treated with OAC and other modalities, possibly including IV chemotherapy. Second, even though high-risk pathological features are predictive factors of metastatic death, there is no data on whether eyes unresponsive to OAC harbored high-risk histopathological features. If these patients also had high- risk pathological features, the metastatic death could be affected by high-risk histopathological features instead of only by OAC. Additionally, the median follow-up period in our analysis ranged between 1.5 to 3.7 years. If studies with shorter follow-up times had extended their duration, more metastasis may have been detected. As evidenced by a systematic review that reported seven additional metastatic cases beyond study endpoints in follow-ups, the median follow-up time ranged from 7 to 74 months.26

This systematic review and meta-analysis provides valuable insights into metastatic mortality among retinoblastoma patients treated with OAC. This study also highlights several clinical and research concerns, such as the prevalence of CNS metastasis as a leading cause of death post-OAC, with instances occurring 8.4 to

27.3 months after treatment. This finding highlights the importance of discussing the risk of distant metastasis, especially CNS metastasis, with patients’ parents since

the clinical outcome of patients with extraocular diseases is dismal even when treated with intensive therapy.34,35 Future studies should identify the risk of distant metastasis in those receiving OAC in addition to uncovering more information such as the OAC to be synthesized, and what reporting system (WHO,36 PROCESS,37 or CARE38) should be followed. This systematic review and meta-analysis also revealed that several studies failed to include vital information, including previous and concomitant treatment, enucleation rate post-OAC, number of participants who failed to follow-up, and cause of death (Table 1). Therefore, it was not possible to meta-analyze some information in our study.

CONCLUSION

In conclusion, while OAC is associated with a risk of metastatic death in retinoblastoma, the risk appears to be on par with the mortality rate associated with the condition. Therefore, it is important to communicate the risk of potential distant metastasis to patients’ parents and pursue further studies to identify the risks of metastasis following OAC treatment.

ACKNOWLEDGMENTS

None.

Funding

This research did not receive any specific grant from any public, commercial, or non-profit funding agencies.

Conflict of interest

None.

REFERENCES

1. Atchaneeyasakul L. Retinoblastoma: What s’ new? Siriraj Med

   J. 2007;59(3):144-5.

2. Seregard S, Lundell G, Svedberg H, Kivelä T. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology. 2004; 111(6):1228-32.

3. Fernandes AG, Pollock BD, Rabito FA. Retinoblastoma in the United States: A 40-Year Incidence and Survival Analysis. J Pediatr Ophthalmol Strabismus. 2018;55(3):182-8.

4. Zhu D, Berry JL, Ediriwickrema L, Wong K, Lee TC, Murphree AL, et al. Long-Term Outcomes of Group B Eyes in Patients with Retinoblastoma Treated with Short-Course Chemoreduction: Experience from Children’s Hospital Los Angeles/University of Southern California. Ocul Oncol Pathol. 2016;2(2):105-11.

5. Sullivan EM, Wilson MW, Billups CA, Wu J, Merchant TE, Brennan RC, et al. Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation. J Pediatr Hematol Oncol. 2014;36(6):e335-e40.

6. Hijiya N, Ness KK, Ribeiro RC, Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current

   findings and issues. Cancer. 2009;115(1):23-35.

7. Gombos DS, Hungerford J, Abramson DH, Kingston J, Chantada G, Dunkel IJ, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmol. 2007;114(7):1378-83.

8. Fontanesi J, Pratt CB, Hustu HO, Coffey D, Kun LE, Meyer D. Use of irradiation for therapy of retinoblastoma in children more than 1 year old: the St. Jude Children’s Research Hospital experience and review of literature. Med Pediatr Oncol. 1995; 24(5):321-6.

9. Abramson DH, Beaverson KL, Chang ST, Dunkel IJ, McCormick B. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol. 2004;122(9):1316-23.

10. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011;129(6):732-7.

11. Abramson DH, Marr BP, Francis JH, Dunkel IJ, Fabius AW, Brodie SE, et al. Simultaneous Bilateral Ophthalmic Artery Chemosurgery for Bilateral Retinoblastoma (Tandem Therapy). PLoS One. 2016;11(6):e0156806.

12. Olteanu C, Dimaras H. Enucleation Refusal for Retinoblastoma: A Global Study. Ophthalmic Genet. 2016;37(2):137-43.

13. Zhao J, Feng ZX, Wei M, Liu G, Solarte CE, Li B, et al. Impact of Systemic Chemotherapy and Delayed Enucleation on Survival of Children with Advanced Intraocular Retinoblastoma. Ophthalmol Retina. 2020;4(6):630-9.

14. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018;23(2):60-3.

15. Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol. 2009;9(80.

16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.

17. Chen Q, Zhang B, Dong Y, Mo X, Zhang L, Xia J, et al. Evaluating primary intra-arterial chemotherapy versus intravenous plus intra-arterial chemotherapy for advanced intraocular retinoblastoma. Cancer Chemother Pharmacol. 2020;85(4):723-30.

18. Wen X, Fan J, Jin M, Jiang H, Li J, Han M, et al. Intravenous versus super-selected intra-arterial chemotherapy in children with advanced unilateral retinoblastoma: an open-label, multicentre, randomised trial. Lancet Child Adolesc Health. 2023;7(9): 613-20.

19. Liang T, Zhang X, Li J, Hua X, Zhao P, Ji X. Intra-Arterial Chemotherapy as Primary Treatment for Advanced Unilateral Retinoblastoma in China. Front Med. 2022;9:855661.

20. Qi D, Gang S, Shengli S, Yuebing L, Jing Z, Jing L, et al. Comparison of clinical outcomes of ophthalmic artery chemotherapy with systemic vein-eye artery chemotherapy for retinoblastoma in children. CEJO. 2022;40(11):1-6.

21. Othman MH, Hassan F, Ibrahim HM, Ahmed EA, Yassa G, Abdel-Rahman MS, et al. Ophthalmic artery chemosurgery for retinoblastoma: an initial 3-year experience from two major institutes in Egypt. Egypt J Radiol Nucl Med. 2020;51(1):79.

22. Munier FL, Mosimann P, Puccinelli F, Gaillard MC, Stathopoulos C, Houghton S, et al. First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective

    review of 20 years of treatment. Br J Ophthalmol. 2017;101(8): 1086-93.

23. Tuncer S, Sencer S, Kebudi R, Tanyıldız B, Cebeci Z, Aydın K. Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey. Acta Ophthalmol. 2016;94(7):e644-e51.

24. Batu Oto B, Sarıcı AM, Kızılkılıç O. Superselective intra-arterial chemotherapy treatment for retinoblastoma: clinical experience from a tertiary referral centre. Cancer J Ophthalmol. 2020;55(5): 406-12.

25. Yannuzzi NA, Francis JH, Marr BP, Belinsky I, Dunkel IJ, Gobin YP, et al. Enucleation vs Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma: A Retrospective Analysis. JAMA Ophthalmol. 2015;133(9):1062-6.

26. Yousef YA, Soliman SE, Astudillo PPP, Durairaj P, Dimaras H, Chan HSL, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol. 2016;134(5):584-91.

27. Naseripour M. “Retinoblastoma survival disparity”: The expanding horizon in developing countries. Saudi J Ophthalmol. 2012;26(2):157-61.

28. Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmol. 1987;94(4):371-7.

29. Lu JE, Francis JH, Dunkel IJ, Shields CL, Yu MD, Berry JL, et al. Metastases and death rates after primary enucleation of unilateral retinoblastoma in the USA 2007-2017. Br J Ophthalmol. 2019;103(9):1272-7.

30. Atchaneeyasakul LO, Wongsiwaroj C, Uiprasertkul M, Sanpakit K, Thephamongkhol K, Trinavarat A. Prognostic factors and

    treatment outcomes of retinoblastoma in pediatric patients: a single-institution study. Jpn J Ophthalmol. 2009;53(1):35-9.

31. Sitorus RS, Moll AC, Suhardjono S, Simangunsong LS, Riono P, Imhof S, et al. The effect of therapy refusal against medical advice in retinoblastoma patients in a setting where treatment delays are common. Ophthalmic Genet. 2009;30(1):31-6.

32. Honavar SG, Singh AD, Shields CL, Meadows AT, Demirci H, Cater J, et al. Postenucleation Adjuvant Therapy in High-Risk Retinoblastoma. Arch Ophthalmol. 2002;120(7):923-31.

33. Abramson DH, Shields CL, Jabbour P, Teixeira LF, Fonseca JRF, Marques MCP, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40.

34. Antoneli CBG, Steinhorst F, de Cássia Braga Ribeiro K, Novaes PERS, Chojniak MMM, Arias V, et al. Extraocular retinoblastoma: A 13-year experience. Cancer. 2003;98(6):1292-8.

35. Jubran RF, Erdreich-Epstein A, Butturini A, Murphree AL, Villablanca JG. Approaches to Treatment for Extraocular Retinoblastoma: Children’s Hospital Los Angeles Experience. J Pediatr Hematol Oncol. 2004;26(1):31-4.

36. Abou Chakra CN, Pariente A, Pinet M, Nkeng L, Moore N, Moride Y. Case series in drug safety: a review to determine characteristics and quality. Drug Saf. 2010;33(12):1081-8.

37. Agha RA, Fowler AJ, Rajmohan S, Barai I, Orgill DP. Preferred reporting of case series in surgery; the PROCESS guidelines. Int J Surg. 2016;36(Pt A):319-23.

38. Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep. 2013;2(5):38-43.