Progress in Retinal and Eye Research 73 (2019) 100764 Contents lists available at ScienceDirect Progress in Retinal and Eye Research journal homepage: www.elsevier.com/locate/preteyeres Conservative management of retinoblastoma: Challenging orthodoxy T without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity” ∗ Francis L. Muniera, , Maja Beck-Popovicb, Guillermo L. Chantadac,d,e, David Cobrinikf,g, Tero T. Kiveläh, Dietmar Lohmanni, Philippe Maederj, Annette C. Mollk, Angel Montero Carcabosod,e, Alexandre Moulina, Paula Schaiquevichl,m, Ciara Bergina, Paul J. Dysonn, Susan Houghtona, Francesco Puccinellio, Yvan Vialp, Marie-Claire Gaillarda, Christina Stathopoulosa a Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland b Unit of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland c Hemato-Oncology Service, Hospital JP Garrahan, Buenos Aires, Argentina d Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain e Institut de Recerca Sant Joan de Deu, Barcelona, Spain f The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA g USC Roski Eye Institute, Department of Biochemistry & Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA h Department of Ophthalmology, Ocular Oncology and Pediatric Ophthalmology Services, Helsinki University Hospital, Helsinki, Finland i Eye Oncogenetics Research Group, Institute of Human Genetics, University Hospital Essen, Essen, Germany j Unit of Neuroradiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland k UMC, Vrije Universiteit Amsterdam, Department of Ophthalmology, Cancer Center Amsterdam, Amsterdam, Netherlands l Unit of Clinical Pharmacokinetics, Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina m National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina n Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland o Interventional Neuroradiology Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland p Materno-Fetal Medicine Unit, Woman-Mother-Child Department, University Hospital of Lausanne, Switzerland ARTICLE INFO ABSTRACT Dedicated to A. Linn Murphree my paragon and Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with mentor, and to Akihiro Kaneko who pioneered ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first modern targeted chemotherapy of intraocular successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage retinoblastoma 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. Keywords: Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of Retinoblastoma improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic Treatment Intra-arterial chemotherapy chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 Intravitreal chemotherapy years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely Intracameral chemotherapy intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, de- Complication finitive eradication of radiotherapy and reduction of systemic chemotherapy. Metastasis Here we intend to review the relevant knowledge susceptible to improve the conservative management of retino- Liquid biopsy blastoma 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. ∗ Corresponding author. Head of Ocular Oncology, Pathology and Genetics, Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Avenue de France 15, 1000, Lausanne 7, Vaud, Switzerland. E-mail address: [email protected] (F.L. Munier). https://doi.org/10.1016/j.preteyeres.2019.05.005 Received 17 February 2019; Received in revised form 25 May 2019; Accepted 29 May 2019 Available online 05 June 2019 1350-9462/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). F.L. Munier, et al. Progress in Retinal and Eye Research 73 (2019) 100764 1. Introduction chemotherapy using intra-arterial and intravitreal drug delivery was pioneered in Japan by Akihiro Kaneko already 30 years ago (Kaneko Retinoblastoma is the archetype of developmental tumors and is and Takayama, 1990; Yamane et al., 2004). In 2008, the technique of responsible for 17% of neonatal (Halperin, 2000), 13% of infantile intra-arterial chemotherapy, revisited by Abramson (Abramson et al., (Vasilatou-Kosmidis, 2003), 6% and 3% of all pediatric cancers under 2008), became rapidly adopted and proved its efficacy to control retinal age 5 and 15 years, respectively (Broaddus et al., 2009; Group et al., and subretinal tumors, but not vitreous seeds. The latter fully surren- 2013). Left untreated, this malignancy is rapidly recognizable as a dered only to intravitreal chemotherapy, which became available in protruding mass. Within the limitations of retrospective diagnosis 2012 following the description of a safety-enhanced injection technique (Kivela and Polkunen, 2003), it is thus not surprising to find retino- (Munier et al., 2012a). Aqueous seeding, the very last intra-ocular blastoma already mentioned in the medical literature at the turn of the sanctuary to resist virtually all available treatment modalities, became XVIth and XVIIth centuries by Pawius in the Netherlands (Pawius, 1657) manageable only since 2015 with the description of a technique and Hildanus in Switzerland (Hildanus, 1682) respectively. According adapted to safely inject into the anterior and posterior chambers to the Hippocratic theory of four humors still in use at that time, ocular (Munier et al., 2015), now successfully implemented in the current tumors were thought to result from a causal chain, of which the pa- management of aqueous disease (Munier et al., 2017a, 2018). To date, tient's constitution and hygiene was the first link (causa primitiva), the appropriate combination of all these modalities has enabled un- triggering black bile overflow (causa antecedens) pouring into the eye precedented eye survival rates, even for advanced retinoblastoma, after its transfer to the brain (causa coniuncta)(Koelbing, 1954). The contributing at the same time to the eradication of external beam ir- advocated treatment was a combination of poultice, leech and purge to radiation in the treatment of intraocular retinoblastoma without jeo- eliminate the flood of melancholic humor. This approach was sup- pardizing patient survival. planted by enucleation, made possible by the advent of anesthesia in th the middle of the XIX century, leading to the first success in terms of 2. Epidemiology patient survival. This surgical period lasted more than 50 years, until the radiosensitivity of retinoblastoma was discovered by Hilgartner in Retinoblastoma is a cancer of early childhood, habitually described 1903 (Hilgartner, 1903), allowing for the first time a conservative as a rare tumor. Statistical evidence, however, suggests that it is likely (globe-preserving) management of the disease. Since then, and for the the most common eye cancer worldwide (Kivela, 2009). As a devel- next 90 years, external beam irradiation became the first line treatment, opmental cancer, its incidence is highly dependent on age (Table 1), complemented by focal therapeutic modalities such as cryotherapy, and therefore difficult to establish. To date, the most stable estimates xenon photocoagulation and brachytherapy for less advanced diseased are derived by assigning incident retinoblastomas to the year the pa- eyes. In 1996, following the recognition of a radio-induced neoplasm tient was born, a method known as birth cohort analysis (Li et al., 2016; predisposition in germline carriers, chemoreduction replaced radio- Park et al., 2014; Seregard et al., 2004). therapy, which use was relegated to treat chemo-resistant disease in only eyes as an alternative to enucleation. The introduction of this 2.1. Incidence whole-body therapy failed, however, to improve eye preservation in advanced disease, while exposing children to systemic toxicity. This The incidence of retinoblastoma depends on the size of the popu- was explained by the pharmacokinetics of the perfused drugs not lation and the birth rate (Kivela, 2009). Around 7980 retinoblastomas reaching tumoricidal concentrations in the