Reply

Drs Abramson and Shields’ letter addresses our 2 American Joint Committee on Cancer Ophthalmic Oncology Task Force (AJCC-OOTF) publications. Our research aimed to answer the question: can high-risk clinical factors uniquely stratified within the AJCC staging system predict high-risk pathology features and thus the risk for metastatic retinoblastoma (RB)? Their letter and our reply can be used to contrast the 2 worlds of RB. One is the high-resource world of Abramson and Shields, where every possible primary and rescue treatment is available no matter the cost. The second is our results, derived from 41 centers in 18 countries on 6 continents, that more accurately represents what happens to children with RB around the world.1Tomar A.S. Finger P.T. Gallie B. et al.Global retinoblastoma treatment outcomes: association with national income level.Ophthalmology. 2021; 128: 740-753Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Ours includes high-, middle-, and low-resource environments where attempts emulating Abramson and Shields’ published eye-saving methods are performed without available rescue therapies. This may result in a greater incidence of metastatic RB and death. As reflected in our research, it is under those circumstances where primary enucleation of AJCC staged high-risk eyes is more likely to save the lives of most of the world’s children with RB. On the one hand, Abramson and Shields are quick to decry our conclusions because they might cause the loss of eyes, but they do not consider that they might just save lives. Perhaps high-resource centers promoting results commonly unattainable in the rest of the world are the real “danger.” Abramson and Shields criticize our 2 publications for including many different treatments. Quite the contrary, we consider this a foundational element of our conclusions because it comprises the best available local care, selected based on the clinical, socioeconomic, and parental considerations in each individual case from centers around the world, where most cases of RB occur. Consider that the incidence of RB depends on population size and birth rate.2Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death.Br J Ophthalmol. 2009; 93: 1129-1131Crossref PubMed Scopus (501) Google Scholar Because of the lack of national registries, mathematical estimates have been used to predict trends in the incidence of RB. One such report used an RB incidence of 1 in 16 642 live births per year and found an annual incidence of 264 new RB children in North America, 464 in Europe, 615 in Latin America, 2293 in Africa, and 4258 in Asia.3Munier F.L. Beck-Popovic M. Chantada G.L. et al.Conservative management of retinoblastoma: challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity.”.Prog Retin Eye Res. 2019; 73100764Crossref PubMed Scopus (108) Google Scholar Clearly, Asia and Africa carry the highest RB burden (83%). There, advanced RB is the most common presentation, and primary enucleation of AJCC high-risk eyes will most likely save lives.1Tomar A.S. Finger P.T. Gallie B. et al.Global retinoblastoma treatment outcomes: association with national income level.Ophthalmology. 2021; 128: 740-753Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,3Munier F.L. Beck-Popovic M. Chantada G.L. et al.Conservative management of retinoblastoma: challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity.”.Prog Retin Eye Res. 2019; 73100764Crossref PubMed Scopus (108) Google Scholar In addition, high-risk pathological features are seen in > 50% of children in moderate- and low-resource countries, compared with < 20% of enucleated eyes in high-resource countries.4Chantada G.L. Qaddoumi I. Canturk S. et al.Strategies to manage retinoblastoma in developing countries.Pediatric Blood Cancer. 2011; 56: 341-348Crossref PubMed Scopus (93) Google Scholar Our prior global RB outcome analysis showed that enucleated eyes with high-risk pathology (pT3 and pT4) from high-resource countries were more likely to survive than low-resource ones.1Tomar A.S. Finger P.T. Gallie B. et al.Global retinoblastoma treatment outcomes: association with national income level.Ophthalmology. 2021; 128: 740-753Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar This was attributed to the relative lack of stem cell treatment facilities, external beam radiation therapy, and salvage techniques in the latter. To make matters worse, pathology results can be delayed, incomplete, or absent. The lack of ophthalmic pathology services places emphasis on identifying high-risk clinical features that predict high-risk pathology features and thus facilitate potentially life-saving clinical decisions. Although our findings most likely have their maximum effect in Africa and Asia, they also apply to high-risk RB children in high-resource countries. Although resource-rich centers are more likely to detect intraocular recurrence and metastatic disease promptly and apply life-saving measures, the risks of eye-sparing treatments remain. To be clear, RB specialists even in high-resource countries have voiced their concerns about the costs (physical, emotional, and financial) of multiple, sequential therapies to save eyes that may never provide useful vision and increase the risk for metastatic disease. Our results show that clinical findings uniquely stratified in AJCC RB staging predict the presence of high-risk pathology and, thus, risk for metastatic disease no matter where the child might live. Drs Abramson and Shields’ concern that massive choroidal invasion, extension into the optic nerve beyond the lamina cribrosa, and scleral invasion can rarely be detected before enucleation is also unwarranted; these features are not needed to assign high-risk AJCC clinical RB stages that were used to predict such pathology findings in our studies. In addition, our finding is particularly important where ophthalmic pathology services are lacking and where a clinical decision to attempt to save a high-risk, poor prognosis eye may sacrifice a child’s life.4Chantada G.L. Qaddoumi I. Canturk S. et al.Strategies to manage retinoblastoma in developing countries.Pediatric Blood Cancer. 2011; 56: 341-348Crossref PubMed Scopus (93) Google Scholar, 5Zhao J. Feng Z.X. Wei M. et al.Impact of systemic chemotherapy and delayed enucleation on survival of children with advanced intraocular retinoblastoma.Ophthalmol Retina. 2020; 4: 630-639Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Our registry studies showed that identifying high-risk clinical features and viewing them through the lens of a universal staging system, here the AJCC clinical RB staging, is best performed at initial tumor staging. Failure to identify high-risk pathology can deprive the child of necessary follow-up and adjuvant treatment to avoid local tumor recurrence, and it risks metastatic disease and death. Although Abramson and Shields agreed with our stratification of metastatic risk based on clinical features, they considered our conclusion, “primary enucleation offered the highest survival rates for patients with advanced intraocular RB,” as potentially dangerous. They use a rationale of a lack of treatment standardization between centers, the nonrandomized study design, variations in local treatments, experience, resources, cultures, and selection bias. However, they omit that no uniform treatment protocol or equitable resource distribution exists to offer every child a similar RB treatment outcome across the globe. Furthermore, they do not address that outcomes are confounded by factors beyond any physician’s control, including parents’ religious beliefs, social stigma, gender bias, abandonment of treatment, and other economic factors. For example, our authors have witnessed parent pressure based on unrealistic hope for eye salvage fed by high-resource center “marketing” to the underprivileged world, where up to 100% local control and survival are not achievable.6Lu J.E. Francis J.H. Dunkel I.J. et al.Metastases and death rates after primary enucleation of unilateral retinoblastoma in the USA 2007-2017.Br J Ophthalmol. 2019; 103: 1272-1277Crossref PubMed Scopus (30) Google Scholar,7Shields C.L. Dockery P.W. Yaghy A. et al.Intra-arterial chemotherapy for retinoblastoma in 341 consecutive eyes (1,292 infusions): comparative analysis of outcomes based on patient age, race, and sex.J AAPOS. 2021; 25: 150.e1-150.e9Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar This results in unnecessary treatments, delay of definitive cure, metastasis, and financial collapse of the family. Such outcomes would not be seen in high-resource countries, where timely follow-up and aggressive local therapies are feasible, even for the smallest recurrences. Clearly this letter and reply contrast the 2 worlds of RB. The incredible advancements seen in the management of RB are not accessible uniformly in the foreseeable future. Many unserved countries and large regions with no trained ophthalmic oncologists or pathologists exist. Our statement, “enucleation is the best treatment for advanced RB eyes” must be considered both in the context of our registry experience and in specific clinical situations.1Tomar A.S. Finger P.T. Gallie B. et al.Global retinoblastoma treatment outcomes: association with national income level.Ophthalmology. 2021; 128: 740-753Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,8Tomar A.S. Finger P.T. Gallie B. et al.A multicenter, international collaborative study for American Joint Committee on Cancer staging of retinoblastoma: part II: treatment success and globe salvage.Ophthalmology. 2020; 127: 1733-1746Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 9Finger P.T. Tomar A.S. Retinoblastoma outcomes: a global perspective.Lancet Glob Health. 2022; 10: e307-e308Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar10Tomar A.S. Finger P.T. Gallie B. et al.A multicenter, international collaborative study for American Joint Committee on Cancer staging of retinoblastoma: part I: metastasis-associated mortality.Ophthalmology. 2020; 127: 1719-1732Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar We consider every child with RB unique, requiring shared clinical and social decision-making by eye cancer specialists, and family members. Further, decisions are based on presenting features, socioeconomic constraints, and available technology. Drs Abramson and Shields conclude by pointing out that intravenous and intra-arterial chemotherapy “can be particularly effective at saving eyes with more advanced RB.” This may be true, but there exists a danger in their statement. Abramson and Shields have revealed no multicenter, international evidence that these treatments are equal to enucleation for saving life. In contrast, our research revealed statistically significant clinical evidence to show that enucleation of high-risk eyes is, globally, more likely to save life. With this letter, the AJCC-OOTF and The Eye Cancer Foundation invite Drs Abramson and Shields to join our efforts to address the inequities in RB care. Because, as a medical community, we must unite and ensure that the tide raises all boats to bring the world’s RB children to safety. Re: Tomar et al.: American Joint Committee on Cancer Ophthalmic Oncology Task Force. High-risk pathologic features based on presenting findings in advanced intraocular retinoblastoma: a multicenter, international data-sharing American Joint Committee on Cancer Study (Ophthalmology. 2022;129:923–932) and Tomar et al.: American Joint Committee on Cancer Ophthalmic Oncology Task Force. Metastatic death based on presenting features and treatment for advanced intraocular retinoblastoma: a multicenter registry-based study. (Ophthalmology. 2022;129:933–945)OphthalmologyVol. 130Issue 3PreviewIt was with great interest and concern that we read the 2 recent articles from a large, worldwide collaborative group on retinoblastoma.1,2 We believe the data given for each article are strong, but are concerned that clinicians worldwide could act on the recommendations inappropriately. Full-Text PDF