Discussion

The last three decades have witnessed huge developments in the management of retinoblastoma, with several new modalities becoming available. This has necessitated a rethink of the classification of intraocular disease from the R-E classification that predicted globe salvage in the era of EBRT1 to the ICRB, which was developed in the era of chemotherapy.2 This study bridges an era in our centre after the establishment of IVC for retinoblastoma,4 ,14–16 when EBRT was used for salvage, to the emergence of IAC for salvage. This was a large cohort of 64 group D eyes followed up for a median time of nearly 5 years with an eye salvage rate of 63%. This is significantly higher than previous similar studies.3 ,17–25 Before IAC, Shields et al3 reported a globe salvage rate of 47% in group D eyes treated by primary IVC, the highest success rate achieved in the pre-IAC era. Of note, Shields et al3 used the Philadelphia version of the IRCB, whereas we used slightly different criteria to define D eyes, according to the Children's Hospital Los Angeles scheme,2 and it was shown that such discrepancies may adversely impact attempts to compare treatment outcomes.26 Nevertheless, this does not fully explain the disparity in salvage rates between the two studies.

A previous study from our centre, from 1995 to 2003, on group D heritable retinoblastoma treated with primary IVC, with median follow-up of 30 months, found that 11/18 eyes (61%) were salvaged, with 5 eyes requiring salvage with EBRT.23 Since then, the role of EBRT has been relegated to being akin to treatment failure, especially with increased risk of second cancers in patients with germline retinoblastoma.27 Interestingly, in this study, salvage EBRT was used in five eyes, all in the early cases, prior to the use of IAC, and in all, treated eyes were eventually enucleated. Presumably, the longer follow-up in this report allowed for more definitive outcomes. These findings, in addition to the known risk associated with EBRT,27 strengthen the approach that EBRT should have a diminished role in treating intraocular retinoblastoma.

IAC and more recently IViC injections are important adjuncts and are important in achieving the relatively high salvage rate in the present cohort. Interestingly, neither was found to be a significant protective factor for eye salvage. As for IViC, this is not surprising, as it was first used in the current cohort in 2014 and only in four eyes. IAC however was first introduced in 2009 and used in 20 eyes in this study. A reasonable explanation would be that IAC was used as a salvage treatment initially in more resistant cases, and 11 of these had to undergo secondary enucleation.

Yousef et al,8 in a systematic review on IAC, reported a total of 67% success rate, when used as second-line therapy, but for all eye groups, clearly different to this study that concentrates on D eyes only. Eye salvage for advanced retinoblastoma in their analysis was found to be 57%, when IAC was used as first and second line and for ICRB groups D and E.8 Shields et al28 reported 67% eye retention in a small case series of six D eyes treated with primary IVC followed by IAC. Abramson et al recently published their results on D eyes treated with first-line IAC (n=47) and reported 85.1% success rate.9 In their study, the median follow-up time was 30 months, in 12 (24%) eyes it was under a year, and in 7 (14%) 2–6 months. In our study, nearly 60% of secondary enucleations were performed after the first year of follow-up and nearly 40% after the second year, so it is possible that later relapse might lead to more enucleations and a lower overall globe salvage. Conversely, it is possible that we may be able to increase our globe retention rates by earlier use of salvage IAC, as our initial cases were treated with this modality as a last resort. Overall then, results from the present and other studies show that IAC, when indicated, is a powerful tool as an adjunct to primary IVC for group D retinoblastoma, enabling retention of a greater number of eyes compared with IVC alone or with the use of additional local consolidation.

We tried to understand whether certain features would subclassify group D into eyes that were more likely to succeed with IVC or would be higher risk for enucleation. None of the variables emerged as significant risk factors for secondary enucleation. This is not surprising, as per definition, D eye tumours hold common features, including tumour size and the presence of retinal detachment and seeding. To note, in two relatively large cohort studies on retinoblastoma eyes treated by primary IVC,20 ,29 group D eyes were analysed as part of a larger cohort containing additional ICRB groups and no subanalysis was performed. In the literature, there are no reports of specific risk factors for secondary enucleation of D eyes treated initially with IVC.

Eight eyes resulted with early treatment failure and eventually secondary enucleation. Salvage IAC was not available for all, but when used for two of these cases, it also failed to achieve a beneficial effect. There is only scant literature on retinoblastoma that does not respond to IVC and that necessitates immediate change in management. In a retrospective analysis by Gunduz et al,30 unresponsive disease was defined as persistence of retinal tumours, vitreous or subretinal seeds after the second IVC cycle, with no appreciable sign of regression. Recurrent disease was defined as regrowth of tumours any time after an initial favourable response. Of 105 eyes (all R-E classification groups), 10 (10%) eyes were unresponsive to treatment. On statistical analysis, however, unresponsive cases were combined with recurrent ones, precluding specific insight into the former subgroup. Interestingly, in this study, eyes with unifocal tumours and those with relatively larger horizontal corneal diameters (in both eyes) were found to be at significant risk for early treatment failure. We have no reasonable explanations for these associations. It should also be mentioned that detection of numerous tumours, usually in cases of genetic disease, is not always possible, especially in D eyes, as in most a total retinal detachment can limit a clear view and ultrasound is only partially helpful in such cases.

In three eyes (5%), no additional treatments to IVC were needed to reach tumour control and in more than half TTT and/or cryotherapy were given after completion of the chemotherapy cycles. There is no consensus on the use of adjuvant therapies. In some reports, routine use of consolidating local modalities was superior to chemotherapy alone,31 but caution is sometimes necessary in case of adverse impact.32 ,33 This argues for adjuvant treatments given only when indicated, as they may also have an adverse impact on the treated eyes.

The extraocular complications and adverse events related to IVC reported in this study are in the spectrum found in the literature.34 This is also the case regarding IAC.13 For both modalities, no serious or life-threatening events were recorded, but twice there was an anaphylactic reaction to systemic carboplatin that responded to conservative management.

Metastatic disease from intraocular retinoblastoma did not occur in any of the cases, an inherent protective feature of IVC over primary IAC.8 The high globe retention rates reported with primary IAC for group D retinoblastoma (85%) are impressive, but there was a 6% metastatic rate in that study.9 In the IVC era, metastatic rates have been low, so the metastatic risks of primary IAC may temper the enthusiasm for this technique in some centres.

Limitations of this study include mainly its retrospective and non-randomised design. Nearly 40% of eyes during the study period underwent primary enucleation (hence were excluded from this analysis of chemotherapy-treated eyes). This could potentially result in selection bias if the more advanced group D eyes were enucleated. Although not the subject of the current report, we compared the primary enucleation with the primary IVC cohort (data not shown), and found that the enucleation cases were selected not for more advanced or complicated disease, but rather older age of presentation and usually unilateral disease. These reservations should be taken into account when interpreting the results of this study. Additional limitations are inherent to the clinical examination of group D retinoblastoma eyes and include, in some cases, difficulty in assessing the number of tumours and the presence of subretinal seeds in case of a large retinal detachment. With regard to insufficient tumour response cases, the definite criterion to be included in this subgroup was change in management during or immediately after IVC. There are several tumour features that can change in respond to treatment and these include, among others, size, colour, vascularisation, degree of calcification, number of tumours and density. It is the combination of all of the above features summed up on clinical examination that dictates whether change of management is required.

In summary, in this large cohort of group D retinoblastoma eyes, primary IVC, followed by additional local therapies, tailored as per clinical need, was found to be an efficient and safe approach, achieving an eye salvage rate of 63% in a median follow-up time of nearly 5 years. In this time period, no case of metastatic spread from intraocular retinoblastoma was recorded and no cases of death. These results are an improvement on those reported previously for group D eyes treated with primary IVC, and are partly a result of IAC, that was added as a salvage modality, replacing EBRT. With the recent addition of IViC, both locally delivered chemotherapy modalities, used as powerful adjuncts to primary IVC, are expected to further improve eye salvage rates and control of the disease, replacing the use of EBRT.