Background: Retinoblastoma, although rare, is one of the most common intraocular malignancies worldwide. Its prognosis has improved significantly in the past few decades, thanks to modern treatments, like systemic, intra-arterial, and intravitreal chemotherapy. However, regarding survival, there are significant differences between high- and low-income countries, eye salvage is still a challenge worldwide, and treatment-related toxicity needs to be carefully and sufficiently managed. Summary: To appraise the strength of supporting evidence, we performed a systematic review of randomized controlled trials investigating any therapeutic protocol for retinoblastoma. Four trials with 174 participants (188 eyes) were eligible, all pertaining to different intravenous chemotherapy regimens. Vincristine, etoposide, and carboplatin (VEC) appear superior to a 5-drug combination for stage III retinoblastoma. Moreover, etoposide and carboplatin as neoadjuvant chemotherapy followed by thermochemotherapy seem to offer better local control than vincristine and carboplatin. However, increasing carboplatin dose in the VEC protocol failed to improve treatment efficacy. Key Messages: Retinoblastoma is a success story of modern medicine. However, only intravenous chemotherapy has been studied through randomized trials, while evidence for the most novel retinoblastoma treatments has mainly stemmed from observational studies. International collaborations for multicenter randomized trials could overcome difficulties and increase certainty and precision in the field.

Retinoblastoma is the most common primary intraocular cancer of childhood, despite being a rare malignancy in general, with an incidence of one in 15,000–20,000 live births, corresponding to 8,000–9,000 new cases per year worldwide [1‒4]. The oncogenesis is initiated by mutations in both alleles of the RB1 gene, which was the first tumor-suppressor gene to be described [5, 6]. Based on the time of occurrence of the first mutation, hereditary and nonhereditary forms of the disease can develop [7].

The disease is lethal if left untreated, mainly due to local and systemic metastases [8]. However, modern therapeutic schemes have dramatically improved prognosis, at least in high-income-countries (HICs), leading to an overall survival rate of 98% and an eye salvage rate of 70%, while the respective rates in the 1980s were 87% and 34% [9]. Tragically, in low- (LICs) and middle-income-countries (MICs), where the main burden of the disease lies, the prognosis is much worse, and enucleation is often the only option, due to restricted accessibility to treatment, older age, and higher proportion of advanced disease at presentation [2, 4, 9, 10]. The worst outcomes are observed in Africa, where the mortality rate reaches 70%, in contrast with less than 5% in Europe, Northern America, Oceania, and Japan [2, 11].

Current treatment modalities include systemic, intra-arterial, intravitreal, intracameral and periocular chemotherapy, focal consolidation therapies (cryotherapy, transpupillary thermotherapy), plaque radiotherapy, and enucleation, based on the stage and focus of the disease as well as social factors [12‒14]. The use of external-beam radiotherapy is very restricted in most HICs because of its numerous side effects, and most importantly the secondary cancer risk in patients with germline disease [12].

Despite recent advances in retinoblastoma management that drastically increased survival, eye salvage and vision preservation rates are yet far from perfect, mainly in patients with advanced disease [13]. Moreover, treatment-related toxicity should not be underestimated, as ocular and systemic side effects are often serious and difficult to manage [12, 15].

As retinoblastoma is a rare malignancy, it is expected that the conduct of randomized controlled trials (RCTs) is challenging, and evidence regarding the available treatments is based on other study designs like cohort studies, chart reviews and case reports. The utilization of the most important selective treatment options primarily relies on such observational studies [16‒18]. In an attempt to assess the existing evidence base, a recent systematic review focused on RCTs comparing systemic chemotherapy with and without adjuvant laser therapy for post-equatorial retinoblastoma yielded no results [19]. Furthermore, an umbrella review of RCT meta-analyses on pediatric malignancies found a notable absence of meta-analyses on retinoblastoma [20]. As of today, no RCT meta-analyses exploring any retinoblastoma treatment have been conducted. Since RCTs and their meta-analyses are considered to provide the highest level of evidence [21], it is intriguing to investigate the extent and depth of randomized evidence in this domain. To deepen our understanding of the evidence supporting retinoblastoma treatments, we have undertaken a systematic review focusing on RCTs related to any therapeutic option in the field.

Protocol

The present review was conducted according to a prespecified protocol and complies with the updated recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [22].

Literature Search

We searched PubMed, Cochrane Library and ClinicalTrials.gov from inception to March 10, 2023, for RCTs assessing the association between any therapeutic intervention and an outcome related to retinoblastoma using a predefined search strategy (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000536410). In addition, we manually searched the reference lists from the included articles for additional studies.

Study Selection

Record screening and study selection were performed by two independent reviewers (G.L., N.A.). We included RCTs performed in humans and investigating the safety and efficacy of any retinoblastoma treatment protocol, with no restrictions regarding age, gender, ethnicity, comorbidities of the participants, characteristics of the disease, or outcome assessed, and without any date and language restrictions. When other cancer types were also investigated, we included studies in which >80% of the population were retinoblastoma patients. Observational and non-randomized interventional studies, case series, and case reports were excluded from this review.

Data Extraction

From each eligible RCT, information was extracted by two independent reviewers (G.L., N.A.) on first author, year of publication, country, funding, recruitment period, population, age of the participants, follow-up duration, intervention, control, and outcomes examined, the number of included patients and eyes, the number of events and nonevents on both intervention and control groups, and the p values of the effect sizes. The results for all outcomes (all measures at all time points) for which a comparison between the treatment arms was made were extracted. In case of missing information, an effort was made to directly reach the study investigators.

Risk of Bias

Risk of bias in the included trials was assessed by two independent reviewers (G.L., N.A.) using the version 2 of the Cochrane risk-of-bias assessment tool for randomized trials [23], which covers the following five domains: bias arising from the randomization process; bias due to deviations from intended interventions; bias due to missing outcome data; bias in measurement of the outcome; bias in selection of the reported result. In each domain, bias is judged as low, high, or with some concerns. An overall bias judgment is also made.

Synthesis of Results

A statistical synthesis of the results was initially planned but was not feasible due to the heterogeneity of the studies regarding population and treatments investigated. Instead, we chose to present the results of the included studies narratively.

Study Selection and Characteristics

Out of the 332 entries initially retrieved, 4 trials published from 2015 to 2022 were finally included in the present study (shown in Fig. 1) [24‒27]. The study characteristics are presented in Table 1. A list of the excluded studies can be found in online supplementary Table 2. Three of the included studies were prospective randomized comparative studies [24, 26, 27], and one was a prospective randomized trial with no formal statistical comparison of the two arms [25]. All of them pertained to the comparison of different regimens or doses for intravenous chemotherapy. No RCTs regarding other treatment options were retrieved.

Fig. 1.

PRISMA flow diagram of study selection. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. https://doi.org/10.1371/journal.pmed1000097. For more information, visit www.prisma-statement.org.

Fig. 1.

PRISMA flow diagram of study selection. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. https://doi.org/10.1371/journal.pmed1000097. For more information, visit www.prisma-statement.org.

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Table 1.

Characteristics of the 4 included randomized controlled trials

First author, yearPopulationInterventionaControlaOutcomesN eyes (N patients)Financial support
Muhammed, [27] (2022) Children with ICRB group D or E retinoblastoma Vincristine, etoposide, and higher dose carboplatin (<36 months: 28 mg/kg; ≥36 months: 840 mg/m2Vincristine, etoposide, and standard-dose carboplatin (<36 months: 18.6 mg/kg; ≥36 months: 560 mg/m2Eye salvage, salvage of meaningful vision, tumor response (regression pattern, tumor diameter, tumor height, subretinal fluid, subretinal seeds, vitreous seeds) 32 (29) Not reported 
Chawla, [24] (2016) Children with IRSS stage IIIa retinoblastoma Vincristine (0.025 mg/kg), etoposide (12 mg/kg), and carboplatin (28 mg/kg) Carboplatin (560 mg/m2, 18.6 mg/kg for children <3 years) and etoposide (100 mg/m2, 3.3 mg/kg for children <3 years), alternating with cyclophosphamide (65 mg/kg), idarubicin (10 mg/m2), and vincristine (1.5 mg/m2, 0.05 mg/kg for children <3 years) Complete response, partial response, no response, progressive disease, overall survival, time from diagnosis to death, optic nerve head infiltration, retrolaminar area infiltration, presence of viable tumor cells, scleral invasion, choroidal invasion, iris or ciliary body infiltration, neutropenia grade 3, neutropenia grade 4, thrombocytopenia grade 3, thrombocytopenia grade 4, anemia grade 3, anemia grade 4 54 (54) Department of Science and Technology, Science and Engineering Research Board, Government of India 
Lumbroso-Le Rouic, [25] (2016) Children with unilateral or bilateral retinoblastoma amenable to conservative management in at least one eye for bilateral cases and requiring an initial neoadjuvant chemotherapy Children >1 year or >10 kg: carboplatin 560 mg/m2, vincristine 1.5 mg/m2 Children >1 year or >10 kg: carboplatin 200 mg/m2, etoposide 150 mg/m2 Treatment failure (need for EBRT or enucleation), eye salvage with EBRT, RBC transfusion, platelet transfusion, neutropenia grade 4, hospitalization between courses 65 (55) Programme Hospitalier de Recherche Clinique (supported by the French Ministry of Health and the French National Cancer Institute) 
Children <1 year and/or <10 kg: carboplatin 18.7 mg/kg, vincristine 0.05 mg/kg Children <1 year and/or <10 kg: carboplatin 6.7 mg/kg, etoposide 5 mg/kg 
Children <2 months: carboplatin 12.5 mg/kg, vincristine 0.05 mg/kg Children <2 months: carboplatin 4.5 mg/kg, etoposide 3.3 mg/kg 
Meel, [26] (2015) Children with ICRB group C or D retinoblastoma Vincristine (1.5 mg/m2), etoposide (150 mg/m2), and carboplatin (750 mg/m2Vincristine (1.5 mg/m2), etoposide (150 mg/m2), and carboplatin (560 mg/m2Eye salvage with focal treatment, eye salvage with STC±EBRT, overall eye salvage, treatment failure, event-free survival, time to disease progression, tumor response (tumor height, vitreous seeds, subretinal seeds) 37 (36) Wellcome Trust, Harvard Catalyst/The Harvard Clinical and Translational Science Center National Institutes of Health Award 1UL1 TR001102-01 
First author, yearPopulationInterventionaControlaOutcomesN eyes (N patients)Financial support
Muhammed, [27] (2022) Children with ICRB group D or E retinoblastoma Vincristine, etoposide, and higher dose carboplatin (<36 months: 28 mg/kg; ≥36 months: 840 mg/m2Vincristine, etoposide, and standard-dose carboplatin (<36 months: 18.6 mg/kg; ≥36 months: 560 mg/m2Eye salvage, salvage of meaningful vision, tumor response (regression pattern, tumor diameter, tumor height, subretinal fluid, subretinal seeds, vitreous seeds) 32 (29) Not reported 
Chawla, [24] (2016) Children with IRSS stage IIIa retinoblastoma Vincristine (0.025 mg/kg), etoposide (12 mg/kg), and carboplatin (28 mg/kg) Carboplatin (560 mg/m2, 18.6 mg/kg for children <3 years) and etoposide (100 mg/m2, 3.3 mg/kg for children <3 years), alternating with cyclophosphamide (65 mg/kg), idarubicin (10 mg/m2), and vincristine (1.5 mg/m2, 0.05 mg/kg for children <3 years) Complete response, partial response, no response, progressive disease, overall survival, time from diagnosis to death, optic nerve head infiltration, retrolaminar area infiltration, presence of viable tumor cells, scleral invasion, choroidal invasion, iris or ciliary body infiltration, neutropenia grade 3, neutropenia grade 4, thrombocytopenia grade 3, thrombocytopenia grade 4, anemia grade 3, anemia grade 4 54 (54) Department of Science and Technology, Science and Engineering Research Board, Government of India 
Lumbroso-Le Rouic, [25] (2016) Children with unilateral or bilateral retinoblastoma amenable to conservative management in at least one eye for bilateral cases and requiring an initial neoadjuvant chemotherapy Children >1 year or >10 kg: carboplatin 560 mg/m2, vincristine 1.5 mg/m2 Children >1 year or >10 kg: carboplatin 200 mg/m2, etoposide 150 mg/m2 Treatment failure (need for EBRT or enucleation), eye salvage with EBRT, RBC transfusion, platelet transfusion, neutropenia grade 4, hospitalization between courses 65 (55) Programme Hospitalier de Recherche Clinique (supported by the French Ministry of Health and the French National Cancer Institute) 
Children <1 year and/or <10 kg: carboplatin 18.7 mg/kg, vincristine 0.05 mg/kg Children <1 year and/or <10 kg: carboplatin 6.7 mg/kg, etoposide 5 mg/kg 
Children <2 months: carboplatin 12.5 mg/kg, vincristine 0.05 mg/kg Children <2 months: carboplatin 4.5 mg/kg, etoposide 3.3 mg/kg 
Meel, [26] (2015) Children with ICRB group C or D retinoblastoma Vincristine (1.5 mg/m2), etoposide (150 mg/m2), and carboplatin (750 mg/m2Vincristine (1.5 mg/m2), etoposide (150 mg/m2), and carboplatin (560 mg/m2Eye salvage with focal treatment, eye salvage with STC±EBRT, overall eye salvage, treatment failure, event-free survival, time to disease progression, tumor response (tumor height, vitreous seeds, subretinal seeds) 37 (36) Wellcome Trust, Harvard Catalyst/The Harvard Clinical and Translational Science Center National Institutes of Health Award 1UL1 TR001102-01 

EBRT, external-beam radiotherapy; ICRB, International Classification of Retinoblastoma; IRSS, International Retinoblastoma Staging System; N, number; RBC, red blood cell; STC, sub-tenon carboplatin.

aDoses are reported per day for each chemotherapy cycle.

A total of 188 eyes (range 32–65, mean 47) from 174 patients were enrolled in the aforementioned studies. Three of the trials were performed in India [24, 26, 27] and one in France [25]. In three RCTs [24, 26, 27], the participants were selected according to disease stage, based either on the International Classification of Retinoblastoma (ICRB) [28, 29] or on the International Retinoblastoma Staging System (IRSS) [30].

Risk of Bias within Studies

The detailed risk of bias assessment for every outcome examined can be found in online supplementary Table 3. The most problematic domains were deviations from intended interventions and the randomization process. Regarding the former, the failure to report masking and analysis details resulted in 69% of the assessments being of high risk of bias. As for the latter, some concerns arose in 88% of the individual outcome assessments, while the remaining 12% were of high risk of bias, mainly due to lack of information pertaining to allocation concealment. Moreover, in the study of Lumbroso-Le Rouic et al. [25], there were more patients with advanced retinoblastoma in the experimental arm, which might have favored the control treatment.

Results of Individual Studies

Two trials [24, 25] randomized patients to receive different protocols for intravenous chemotherapy, while the remainders [26, 27] used the same chemotherapeutic protocol (vincristine, etoposide, and carboplatin [VEC]) and examined the impact of an increase of the carboplatin dose.

Comparison of Different Chemotherapeutic Regimens

Chawla et al. [24] investigated the efficacy and safety of VEC compared to a 5-drug combination including carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. These regimens were used as part of a multimodal treatment including neoadjuvant and adjuvant chemotherapy, external-beam radiotherapy (EBRT), and enucleation. Patients with IRSS stage IIIa retinoblastoma (regional extension with overt orbital disease) were enrolled in the study. VEC was found to be superior in terms of complete response to treatment (56% vs. 20%, p = 0.008) and progressive disease (4% vs. 24%, p = 0.04). Overall survival probability at 4 years was marginally not statistically significant (63% vs. 25%, p = 0.05) but showed a strong trend in favor of VEC. Regarding treatment safety, the risk of grade 4 neutropenia was higher with the 5-drug combination (12% vs. 55%, p = 0.002).

Lumbroso-Le Rouic et al. [25] compared two 2-drug combinations (vincristine-carboplatin and etoposide-carboplatin) for neoadjuvant chemotherapy, followed by local treatments (cryotherapy, thermotherapy, plaque brachytherapy) or thermochemotherapy in patients with unilateral or bilateral retinoblastoma. The authors decided not to perform a statistical comparison between the two arms. Instead, they set a threshold of more than 60% eyes salvaged without EBRT or enucleation, based on previous experience. Both combinations were found to be effective based on this threshold, yet treatment success rate was slightly higher in the etoposide-carboplatin arm (81.2% vs. 69.7%). Systemic adverse events (hematological toxicity) were more frequent in the etoposide-carboplatin arm but were not severe or unexpected.

Comparison of Different Carboplatin Doses in the VEC Protocol

Both Meel et al. [26] and Muhammed et al. [27] administered the VEC combination to all patients, increasing the dose of carboplatin in the intervention arm. The former enrolled patients with ICRB group C (focal seeds) and D (diffuse seeds) retinoblastoma and increased the carboplatin dose from 560 mg/m2 to 750 mg/m2. The latter selected children with group D or E (extensive retinoblastoma) disease, and increased the dose even more, to 840 mg/m2 (and from 18.6 mg/kg to 28 mg/kg for children younger than 3 years of age). Nevertheless, neither of the studies showed an improvement in eye salvage, salvage of meaningful vision, response to treatment, or event-free survival with the higher dose.

In the present work, we embarked into a systematic review seeking to assess all published randomized evidence on therapeutic protocols for retinoblastoma, discuss the findings of the available studies, evaluate their quality, and highlight potential research gaps in the field. Four RCTs were included in our review, all concerning intravenous chemotherapy protocols. Outcomes examined included eye salvage, salvage of meaningful vision, overall and event-free survival, response to treatment based on clinical and histopathologic findings, and adverse events. Few associations were nominally statistically significant at the p = 0.05 level, and all of them pertained to the comparison between two drug combinations performed by Chawla et al. [24]. The VEC protocol, the most used chemotherapeutic protocol for retinoblastoma [12, 13, 31], was associated with lower disease progression and mortality rates as well as less adverse events compared to a 5-drug combination consisting of carboplatin and etoposide, alternating with cyclophosphamide, idarubicin, and vincristine. A further comparison between different protocols showed that etoposide and carboplatin might offer better tumor control than vincristine and carboplatin when used as neoadjuvant chemotherapy, without an increase in severe toxicity [25]. Another investigated approach was increasing the standard carboplatin dose of 560 mg/m2 [32] in the VEC protocol, but in two trials included in our review [26, 27], this failed to improve the efficacy of the treatment.

Of course, the fact that all included studies were small, with an average of 47 eyes per trial, might imply a lack of power to detect significant differences between treatment arms. A post hoc power analysis performed by Meel et al. [26] showed that 1,258 participants were needed to achieve a power of 80%. However, it is practically impossible to conduct so extensive RCTs in the field of pediatric oncology [20, 33, 34], let alone in a rare malignancy like retinoblastoma. Therefore, it is not unexpected that these four small trials constitute the entire randomized evidence about this disease. It is encouraging, however, that there are another four active relevant RCT protocols for systemic and intra-arterial chemotherapy, according to a search in ClinicalTrials.gov (search strategy in online suppl. Table 1.2).

The results from the included RCTs are comparable with these of other non-randomized and observational studies. Chawla et al. [24] reported a cumulative 4-year overall survival of 42% for the included stage IIIa patients (63% in the VEC arm). This falls in the 40–82% range previously reported [35‒39], although a direct comparison is difficult because of differences in the examined populations and treatment protocols. Regarding eye salvage, Lumbroso-Le Rouic et al. [25] found an event-free and an overall eye survival rate of 75% and 78%, respectively, which came in accordance with the findings of a recent German and Austrian study [31]. The 62.5% event-free eye survival rate in patients with group D/E retinoblastoma found by Muhammed et al. [27] was higher than previously reported [29, 31], but this could be explained by the shorter follow-up in this study.

Another observation from our study is that three of the trials [24, 26, 27] were performed in India, the country with the highest number of new cases per year in the world (>1,500) [3]. India is a lower-middle-income country, based on the World Bank classification [40]. As discussed earlier, there is a huge gap in terms of retinoblastoma prognosis between HICs and LICs/MICs because of restricted accessibility to diagnosis and treatment [2, 4, 9, 10], although the discrepancies seem to have narrowed in the past decade, at least to some extent [9]. Patients in LICs and MICs are typically diagnosed at an older age and with more advanced disease. Specifically, in two recent international studies [4, 10], the median age at diagnosis was 30.5 months in LICs, compared to approximately 20 months in MICs and 14 months in HICs. Statistically significant differences were also observed in terms of tumor staging, including distant metastasis and extraocular disease [4, 10]. Naturally, these differences impact treatment outcomes, with MICs showing 1.6- to 2.2-fold higher treatment failure rates than HICs. A positive association of overall survival and globe salvage with education level has also been demonstrated [9]. These observations come in accordance with the aforementioned Indian studies that included children with IRSS Stage III and ICRB Group C-E disease, presenting at an age of 15–35 months on average. In our review, eye salvage rates reported by Meel et al. (27% and 43% for event-free and overall survival, respectively) [26] were lower than these of trials from HICs [25, 31, 41] but comparable with other lower-middle-income countries reports [9].

Current indications for intravenous chemotherapy include bilateral or germline disease, positive family history, optic nerve, choroidal or scleral invasion, and extraocular retinoblastoma [12, 13]. Multiple combinations of 2–5 chemotherapeutic agents including vincristine, carboplatin, etoposide, cyclophosphamide, doxorubicin, and idarubicin have been used as neoadjuvant or adjuvant treatment [25, 31, 36, 42]. Although no definitive consensus has been reached, triple therapy with VEC is the combination of choice in most centers [12, 43], having shown better results compared to other protocols in terms of efficacy and safety [24, 31]. The standard doses are: vincristine 1.5 mg/m2, day 1 of each cycle; etoposide 150 mg/m2, days 1 and 2; carboplatin 560 mg/m2, day 1 [43]. Hematologic toxicity is, of course, a concern, and Lumbroso-Le Rouic et al. [25] tried to reduce it by replacing etoposide with vincristine in a 2-drug combination with carboplatin. Toxicity was, indeed, reduced, but the tumor control was less optimal, and the authors concluded that omitting etoposide is not necessary, as no severe adverse events were observed. Regarding long-term concerns pertaining to infertility, hearing loss, and secondary neoplasms, there seems to be no reason to be deterred from using systemic chemotherapy, as these adverse events are rare with standard medication doses [12, 43]. However, lifelong monitoring is essential for all childhood cancer survivors, including retinoblastoma patients [44]. This involves surveillance for new and recurrent retinoblastoma tumors, secondary neoplasms, and late treatment effects, along with visual rehabilitation and psychosocial support. Ophthalmology and oncology follow-up are recommended at varying intervals based on age, treatment received, disease laterality, presence of germline mutation, and high-risk clinical or pathological characteristics [45]. Due to an increased subsequent cancer risk in adult survivors of heritable retinoblastoma, annual melanoma-focused skin examination and prompt assessment of any sarcoma-related symptoms are recommended [46].

Although intravenous chemotherapy is the only retinoblastoma treatment tested with randomized trials, other therapeutic options should not be forgotten, as a multimodal management is almost always required [13, 39]. Selective delivery of chemotherapeutic agents has proven to be a valuable asset in the management of the disease, increasing globe salvage in eyes with advanced or recurrent disease [47‒51], despite the associated risks [15, 52]. Intra-arterial chemotherapy is now the first choice for unilateral, non-germline retinoblastoma [14, 53]. For neonates and young infants, a bridge intravenous chemotherapy has been described until they reach the required age and weight (3 months, 6 kg) for intra-arterial delivery [54]. Intravitreal chemotherapy, on the other hand, has emerged as a globe salvage therapy in the presence of vitreous seeding, and sub-Tenon delivery is indicated to increase local dose in advanced bilateral or recurrent tumors [12, 14]. Lastly, intracameral chemotherapy is employed in cases with aqueous seeding or involvement of the anterior chamber, while intrathecal and intraventricular delivery has been used for leptomeningeal retinoblastoma, although research on the topic is limited [55, 56]. Combinations of the former with brachytherapy and focal consolidation therapies have also been applied with promising results [57, 58]. Despite these breakthroughs, these treatment modalities remain to be tested in prospective, randomized protocols to increase certainty regarding their use.

While significant progress has been made in improving retinoblastoma prognosis, ongoing efforts are focused on identifying new methods that offer enhanced safety and efficacy. In preclinical studies, the topical instillation of cell-penetrating peptide-conjugated melphalan has demonstrated efficacy comparable to intravitreal melphalan, with the added advantage of reducing the risk of metastasis [59]. Furthermore, the current trend in research has shifted toward exploring non-chemotherapeutic alternatives, including targeting specific molecular pathways such as MDMX-p53 and OTX2, immunotherapy, and genetic modulation through oncolytic adenoviruses [56, 60, 61]. These innovative approaches signify a broader exploration of treatment avenues beyond traditional chemotherapy. It is essential to acknowledge that further research and clinical trials are necessary to validate the results of these promising strategies in human patients.

This systematic review intends to provide an overview of all randomized evidence in the management of retinoblastoma. The results from the included studies should be interpreted with caution, as they lack power and are prone to systematic bias. Nevertheless, the information provided is a valuable resource in the field of systemic chemotherapy and highlights the differences between the various available protocols. However, larger RCTs and meta-analyses investigating the safety and efficacy of all treatment modalities are needed to augment and expand high-level evidence in the field. Conducting RCTs in pediatric populations can prove challenging due to the rarity of the disease, limited commercial interest, stringent regulations, and ethical issues [20, 33, 34, 62]. Addressing ethical considerations, the adequacy of parental informed consent is a major concern, influenced by emotional distress, reduced comprehension of scientific terms, insufficient information about alternative treatment options, and the complex doctor-parent relationship, particularly due to the intertwinement between research and clinical care in pediatric oncology [63, 64]. The inclusion of child “assent” after providing developmentally appropriate information adds another layer to the ethical discussion [62, 65]. Offering manageable and understandable yet complete pieces of information over a period of time can facilitate truly informed consent [63]. Early-phase clinical trials present additional ethical challenges, given the limited potential for direct benefit and scarce data from adult studies. These obstacles may hinder the conduct of large-scale RCTs in pediatric oncology settings. Nonetheless, recent efforts to address relevant logistical challenges have paved the way for the feasibility of multicenter trials [66], which could be the solution to ensure the enrollment of an adequate number of participants. Such collaborative efforts, either at the national or international level, have proven valuable in addressing important clinical questions in pediatric oncology in recent years, specifically concerning the treatment of hematologic malignancies [67‒70], osteosarcoma [71], and glioma [72], as well as supportive interventions [73], emphasizing the significance of cooperation to provide more accurate answers in the field.

Limitations

The present work is not free of limitations. Non-randomized interventional studies were excluded from this review. Although we acknowledge their value in a field where the conduct of RCTs is very challenging, we believe that their inclusion exceeds the scopes of our systematic review, as we wanted to focus only on the highest level of evidence that stems from randomized trials.

Retinoblastoma is a success story of modern medicine, with almost perfect survival and improved globe salvage rates, at least in HICs. A personalized multimodal approach including systemic and local treatment applications is necessary in most cases. Systemic chemotherapy for retinoblastoma has been meticulously studied, with the available randomized trials showing that standard-dose VEC protocol might be the best choice when intravenous treatment is indicated.

However, most of the information regarding the most novel therapeutic techniques is not based on randomized evidence and is derived from other study designs that are inherently more prone to bias. Acknowledging the difficulties connected to the conduct of large RCTs in such a rare pediatric malignancy, we believe that international collaborations between centers specializing in retinoblastoma could overcome the challenges and increase the certainty and precision in the field to provide patients with the best possible care.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

No financial support was received for this work.

Georgios Lavasidis: conceptualization, methodology, investigation, visualization, and writing – original draft. Kyriaki Papaioannou, Nikolaos E. Bechrakis, and Petra Ketteler: supervision and writing – review and editing. Nikolaos Anagnostou: investigation, writing – original draft. Evangelia Ntzani: methodology, supervision, project administration, and writing – review and editing. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

The data that support the findings of this study are not publicly available due to complexity but are available from the corresponding author upon reasonable request.

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