Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

Dedicated to A. Linn Murphree my paragon and mentor, and to Akihiro Kaneko who pioneered modern targeted chemotherapy of intraocular retinoblastoma
https://doi.org/10.1016/j.preteyeres.2019.05.005Get rights and content

Abstract

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a “state of metastatic grace” never to be violated.

Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy.

Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the “state of metastatic grace”, with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.

Introduction

Retinoblastoma is the archetype of developmental tumors and is responsible for 17% of neonatal (Halperin, 2000), 13% of infantile (Vasilatou-Kosmidis, 2003), 6% and 3% of all pediatric cancers under age 5 and 15 years, respectively (Broaddus et al., 2009; Group et al., 2013). Left untreated, this malignancy is rapidly recognizable as a protruding mass. Within the limitations of retrospective diagnosis (Kivela and Polkunen, 2003), it is thus not surprising to find retinoblastoma already mentioned in the medical literature at the turn of the XVIth and XVIIth centuries by Pawius in the Netherlands (Pawius, 1657) and Hildanus in Switzerland (Hildanus, 1682) respectively. According to the Hippocratic theory of four humors still in use at that time, ocular tumors were thought to result from a causal chain, of which the patient's constitution and hygiene was the first link (causa primitiva), triggering black bile overflow (causa antecedens) pouring into the eye after its transfer to the brain (causa coniuncta) (Koelbing, 1954). The advocated treatment was a combination of poultice, leech and purge to eliminate the flood of melancholic humor. This approach was supplanted by enucleation, made possible by the advent of anesthesia in the middle of the XIXth century, leading to the first success in terms of patient survival. This surgical period lasted more than 50 years, until the radiosensitivity of retinoblastoma was discovered by Hilgartner in 1903 (Hilgartner, 1903), allowing for the first time a conservative (globe-preserving) management of the disease. Since then, and for the next 90 years, external beam irradiation became the first line treatment, complemented by focal therapeutic modalities such as cryotherapy, xenon photocoagulation and brachytherapy for less advanced diseased eyes. In 1996, following the recognition of a radio-induced neoplasm predisposition in germline carriers, chemoreduction replaced radiotherapy, which use was relegated to treat chemo-resistant disease in only eyes as an alternative to enucleation. The introduction of this whole-body therapy failed, however, to improve eye preservation in advanced disease, while exposing children to systemic toxicity. This was explained by the pharmacokinetics of the perfused drugs not reaching tumoricidal concentrations in the various intraocular seeding compartments. To overcome these limitations, the concept of targeted chemotherapy using intra-arterial and intravitreal drug delivery was pioneered in Japan by Akihiro Kaneko already 30 years ago (Kaneko and Takayama, 1990; Yamane et al., 2004). In 2008, the technique of intra-arterial chemotherapy, revisited by Abramson (Abramson et al., 2008), became rapidly adopted and proved its efficacy to control retinal and subretinal tumors, but not vitreous seeds. The latter fully surrendered only to intravitreal chemotherapy, which became available in 2012 following the description of a safety-enhanced injection technique (Munier et al., 2012a). Aqueous seeding, the very last intra-ocular sanctuary to resist virtually all available treatment modalities, became manageable only since 2015 with the description of a technique adapted to safely inject into the anterior and posterior chambers (Munier et al., 2015), now successfully implemented in the current management of aqueous disease (Munier et al., 2017a, 2018). To date, the appropriate combination of all these modalities has enabled unprecedented eye survival rates, even for advanced retinoblastoma, contributing at the same time to the eradication of external beam irradiation in the treatment of intraocular retinoblastoma without jeopardizing patient survival.

Section snippets

Epidemiology

Retinoblastoma is a cancer of early childhood, habitually described as a rare tumor. Statistical evidence, however, suggests that it is likely the most common eye cancer worldwide (Kivela, 2009). As a developmental cancer, its incidence is highly dependent on age (Table 1), and therefore difficult to establish. To date, the most stable estimates are derived by assigning incident retinoblastomas to the year the patient was born, a method known as birth cohort analysis (Li et al., 2016; Park et

Presenting features

Retinoblastoma is the only pediatric cancer presenting with recognizable signs, allowing awareness campaigns to be credited with significant shortening of the time to diagnosis as shown in Switzerland (Wallach et al., 2006). Similarly, the implementation of a national educational program in Honduras allowed to significantly reduce the proportion of patients with extraocular spread at diagnosis within less than a decade (Leander et al., 2007). This unique feature of retinoblastoma has the

Retinoblastoma genesis

Like any cancer, the biological and clinical behavior of retinoblastoma is dictated by the unique features of the cancer cells and their interactions with the host. In turn, the cancer cell features are largely determined by the intrinsic gene expression program of the retinoblastoma cell-of-origin in combination with changes to the cell-of-origin signaling circuitry that are induced by oncogenic mutations. However, in contrast to most cancers, the genetic changes that initiate retinoblastoma

Retinoblastoma genetics and genetic counseling

In this part are described the different variants of heritable (50%) and non-heritable (50%) (MacCarthy et al., 2009) presentations of retinoblastoma, as well as their implications for the patient's family members, based on family history, laterality at presentation, and current genetic tests.

Clinical growth and seeding patterns

The retinoblast undergoing malignant transformation initiates a primary intraretinal tumor, which has not only the capacity to metastasize but also, unlike other cancers, to generate secondary tumors by seeding. Clinical features of retinoblastoma retinal growth and seeding patterns are reviewed below.

Conservative management of intraocular retinoblastoma

With the emergence of new therapies over the last 20 years, the management of retinoblastoma has also become more complex. The first rule remains the defense of life, which presupposes a permanent arbitration between pursuit of conservative therapy and secondary enucleation. This being said, one of the most important keys to success is continuous adaptation of the therapeutic strategy to the different eye compartments involved. The right decision-making implies a solid knowledge of the

Future directions and conclusion

Historically, therapeutic innovation in the conservative management of retinoblastoma was driven independently of randomized clinical trials, often in the absence of preclinical studies, mostly due to the orphan nature of the disease. Over the last decade, virtually all steps forward were taken by challenging orthodoxy with new administration routes of known drugs subsequently evaluated in non-randomized retrospective studies. In the future, therapeutic breakthroughs should benefit from an

Funding

The authors have no financial interest in any aspect of this article.

No conflicting relationship exists for any author.

Co-authors'contributions

FLM: Design and redaction of the manuscript, iconography selection of and sketch conception; MBP: 3.6, 7.2; GC: 3.3, 3.7, 7.2; DC: 4; TK: 2, 3.5, 3.6; DL: 5; PM: 3.2.4; ACM: 3.8, 7.4; AMC: 8.1, 8.2; AM: 6.1, 6.2, 6.3; PS: 7.1; CB: data analysis; PD: 8.5, 8.6; SH: data management - editing; FP: 7.2.2; YV: 3.5; MCG: 3.2, 7.3.1, 7.3.2; CS: Redaction and harmonization of the whole manuscript.

Acknowledgements

My gratitude goes to Professor Claude Gailloud who founded and Dr Aubin Balmer who further developped the Retinoblastoma Clinic in Lausanne. The iconography illustrating this paper was obtained thanks to the collaboration of Marc Curchod (eye pictures), Yann Leuba (montage) and Isabel de Dioz (drawings) from the Centre d’Imagerie Oculaire at Jules-Gonin Eye Hospital. Our gratitude extends to Laurent Gouban and Cédric Blanchard, librarian and assistant-librarian at Jules-Gonin Eye Hospital

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