# Survival and Health Care Burden of Children With Retinoblastoma in Europe

Gianni Virgili, Riccardo Capocaccia, Laura Botta, Damien Bennett, Theodora Hadjistilianou, Kaire Innos, Henrike Karim-Kos, Claudia Kuehni, Ursula Kuhnel, Cinzia Mazzini, et al.

<figure><img src="image_1.png" /></figure>

► To cite this version:

Gianni Virgili, Riccardo Capocaccia, Laura Botta, Damien Bennett, Theodora Hadjistilianou, et al. Survival and Health Care Burden of Children With Retinoblastoma in Europe. JAMA Ophthalmology, 2024, 142 (11), pp.1062. 10.1001/jamaophthalmol.2024.4140. inserm-05114711

HAL Id: inserm-05114711

https://inserm.hal.science/inserm-05114711v1

Submitted on 16 Jun 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Survival and health care burden of children with retinoblastoma in Europe

Virgili, G., Capocaccia, R., Botta, L., Bennett, D., Hadjistilianou, T., Innos, K., Karim-Kos, H., Kuehni, C. E., Kuhnel, U., Mazzini, C., Canete Nieto, A., Paapsi, K., Parravano, M., Ronckers, C. M., Rossi, S., Stiller, C., Vicini, G., Visser, O., Gatta, G., & EUROCARE-6 Working Group (2024). Survival and health care burden of children with retinoblastoma in Europe. *JAMA Ophthalmology*, E1-E9. Advance online publication.
https://doi.org/10.1001/jamaophthalmol.2024.4140

**Published in:**
JAMA Ophthalmology

**Document Version:**
Peer reviewed version

**Queen's University Belfast - Research Portal:**
Link to publication record in Queen's University Belfast Research Portal

**Publisher rights**

Copyright 2024 the authors.

This is an accepted manuscript distributed under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

**General rights**

Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights.

**Take down policy**

The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact openaccess@qub.ac.uk.

**Open Access**

This research has been made openly available by Queen's academics and its Open Research team. We would love to hear how access to this research benefits you. – Share your feedback with us: http://go.qub.ac.uk/oa-feedback
# Survival and health care burden of children with retinoblastoma in Europe from 2000 to 2013

Gianni Virgili, MD<fnref n="1" />,<fnref n="2" />, Riccardo Capocaccia, MSc<fnref n="3" />, Laura Botta, MSc<fnref n="4" />, Damien Bennet, MD<fnref n="5" />, Theodora Hadjistilianou, MD<fnref n="6" />, Kaire Innos, PhD<fnref n="7" />, Henrike Karim-Kos, PhD<fnref n="8" />, Claudia E. Kuehni, MD<fnref n="9" />, Ursula Kuhnel, MSc<fnref n="9" />, Cinzia Mazzini, MD<fnref n="1" />, Adela Canete Nieto, MD<fnref n="4" /> <fnref n="10" /> <fnref n="11" />, Keiu Paapsi, MSc<fnref n="7" />, Mariacristina Parravano, MD<fnref n="2" />, Cécile M. Ronckers, MSc<fnref n="12" />, Silvia Rossi, MSc¹³, Charles Stiller, MSc¹⁴, Giulio Vicini, MD<fnref n="1" />, Otto Visser, PhD¹⁵, Gemma Gatta, MD<fnref n="4" />, and the EUROCARE-6 Working Group*

<footnote n="1">¹ AOU Careggi, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, Florence, Italy.</footnote>

<footnote n="2">² IRCCS-Fondazione Bietti, Rome, Italy.</footnote>

<footnote n="3">³ Editorial board, Epidemiologia & Prevenzione, Milan, Italy (Consultant)</footnote>

<footnote n="4">⁴ Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.</footnote>

<footnote n="5">⁵ Director, Northern Ireland Cancer Registry, School of Medicine, Dentistry and Biomedical Sciences, Centre for Public Health.</footnote>

<footnote n="6">⁶ Unit of Ophthalmology and Referral Center for Retinoblastoma, Department of Surgery, Policlinico "Santa Maria alle Scotte", Siena, Italy.</footnote>

<footnote n="7">⁷ National Institute for Health Development - Tervise Arengu Instituut, Tallinn, Estonia</footnote>

<footnote n="8">⁸ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Research and Innovation, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands.</footnote>

<footnote n="9">⁹ Childhood Cancer Registry of Switzerland, Institut of Social and Preventiv Medicine, University of Berne.</footnote>

<footnote n="10">¹⁰ Spanish Registry of Childhood Tumours (RETI-SEHOP), University of Valencia, Faculty of Medicine, 46010 Valencia, Spain.</footnote>

<footnote n="11">¹¹ Paediatric Oncology Department, La Fe Hospital, 46026 Valencia, Spain.</footnote>

<footnote n="12">¹² German Childhood Cancer Registry (GCCR) | Division of Childhood Cancer Epidemiology (EpiKiK) IMBEI, University Medicine at the Johannes Gutenberg-University.</footnote>
¹³ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

¹⁴ NHS England Leeds United Kingdom NHS England, Leeds, United Kingdom.

¹⁵ Visser Department of Research and Innovation, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands.

* Austria: M. Hackl (National CR); Belgium: E. Van Eycken; N. Van Damme (National CR); Bulgaria: Z. Valerianova (National CR); Croatia: M. Sekerija (National CR); Cyprus: V. Scoutellas; A. Demetriou (National CR); Czechia: L. Dušek; D. Krejici (National CR); Denmark: H. Storm (National CR); Estonia: M. Mägi; K. Paapsi; K. Innos* (National CR); Finland: J. Pitkäniemi (National CR); France: J. Clavel; C. Poulalhon (Childhood Haematopoietic malignancies National CR); B. Lacour; E. Desandes (Childhood Solid Tumours National CR); V. Jooste* (Burgundy, Digestive CR); A. Monnereau* (Gironde, Haematological Malignancies CR); Germany: C. Ronckers; M. Ressing (National Childhood CR); A. Katalinic* (Schleswig-Holstein CR); Greece: E. Petridou; G. Markozannes (National Childhood CR); Hungary: M. Garami; Z. Jakab (National Childhood CR); Iceland: H. Birgisson (National CR); Ireland: D. Murray (National CR); Italy: G. Mazzoleni; F. Vittadello (Alto Adige CR); F. Cuccaro (Barletta-Andria-Trani CR); R. Galasso (Basilicata CR); G. Sampietro (Bergamo CR); S. Rosso (Biella CR); C. Gasparotti; G. Maifredi (Brescia CR); M. Ferrante; A. Torrisi (Catania-Messina-Enna CR); A. Sutera Sardo (Catanzaro CR); M.L. Gambino; M. Lanzoni (Province of Varese and Como CR); P. Ballotari; E. Giacomazzi (Cremona and Mantova CR); S. Ferretti (Ferrara CR); A. Caldarella; G. Manneschi (Firenze-Prato CR); G. Gatta*; M. Sant*; P. Baili*; F. Berrino*; L. Botta; A. Trama; R. Lillini; A. Bernasconi; S. Bonfarnuzzo; C. Vener; F. Didonè; P. Lasalvia; L. Buratti; G. Tagliabue (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan); D. Serraino; M. Taborelli (Centro di Riferimento Oncologico, IRCCS, Aviano for the Friuli Venezia Giulia CR); R. Capocaccia* (Epidemiologia & Prevenzione Board); R. De Angelis*; E. Demuru; F. Cerza; F. Di Mari; C. Di Benedetto; S. Rossi*; M. Santaquilani; S. Venanzi; M. Tallon (Istituto Superiore di Sanità, Rome); L. Boni (Genova CR); S. Iacovacci (Latina CR); A.G. Russo; F. Gervasi (Province of Milan and Lodi CR); G. Spagnoli (Modena CR); L. Cavalieri d'Oro (Monza and Brianza CR); M. Fusco; M.F. Vitale (Napoli 3 South CR); M. Usala (Nuoro CR); W. Mazzucco (Palermo CR); M. Michiara (Parma CR); G. Chiranda (Piacenza CR); C. Sacerdote; M. Maule (Piemonte, Childhood CR); G. Cascone; E. Spata (Ragusa CR); L. Mangone (Reggio Emilia CR); F. Falcini (Romagna CR); R. Cavallo (Salerno CR); D. Piras (Sassari CR); Y. Dinaro; M. Castaing (Siracusa CR); A.C. Fanetti (Sondrio CR); S. Minerba (Taranto CR); G. Candela; T. Scuderi (Trapani CR); R.V. Rizzello (Trento CR); F. Stracci (Umbria CR); M. Rugge (Veneto CR); A. Brustolin (Viterbo CR); Latvia: S. Pildava (National CR); Lithuania: I. Vincerzevskiene (National CR); Malta: M. Azzopardi (National CR); Norway: T.B. Johannesen* (National CR); Poland: J. Didkowska; U. Wojciechowska (National CR); M. Bielska-Lasota*; Portugal: A. Pais (Central Portugal CR); M.J. Bento; R. Calisto (Northern Portugal CR); A. Lourenço; A. Mayer (Southern Portugal CR); Slovakia: C. Safaei Diba (National CR); Slovenia: V. Zadnik; T. Zagar (National CR); Spain: C. Sánchez-Contador Escudero; P. Franch
Sureda (Balearic Islands, Mallorca CR); A. Lopez de Munain; M. De-La-Cruz (Basque Country CR); M.D. Rojas; A. Aleman (Canary Islands CR); A. Vizcaino (Castellon CR); F. Almela (Comunitat Valenciana, Childhood CR); R. Marcos-Gragera; A. Sanvisens (Girona CR); M.J. Sanchez (Granada CR); M.D. Chirlaque Lopez; A. Sanchez-Gil (Murcia CR); M. Guevara*; E. Ardanaz (Navarra CR, CIBERESP); A. Cañete; R. Peris-Bonet (Spanish Childhood (RETI-SEHOP) CR); J. Galceran; M. Carulla (Tarragona CR); Switzerland: C.E. Kuehni; U. Kuehnel (National Childhood CR); Netherlands: O. Visser*; H. Karim-Kos (National CR); UK-England: S. Stevens ; C. Stiller (National CR); UK-Northern Ireland: D. Bennett (National CR); A. Gavin*; UK-Scotland: D. Morrison (National CR); UK-Wales: D. W. Huws* (National CR);

**Word Count:**

2746

**Key-words:**

Retinoblastoma, incidence, survival, children

**Running head:**

Incidence and survival of retinoblastoma in Europe

**Address for reprints:**

Mariacristina Parravano

IRCCS-Fondazione Bietti, Rome, Italy

Email: mcparravano@gmail.com Phone: +390685356727

1

2

**Key-points:**

3

4

**Question**

5

What are the incidence and survival of European children with retinoblastoma (RB)?

6

7

**Findings**

8

9

10

11

12

13

14

**Meaning**
In Europe, RB incidence was stable between 2000 and 2013. Incidence and survival estimates will inform surveillance, which could be improved if registries collect standardized RB stage at diagnosis.

18

## Abstract

20

### Importance

22

The results of this study improve the knowledge on the epidemiology of retinoblastoma (RB)

25

### Objective

To estimate the incidence and survival of RB in European children, and the occurrence of second primary tumors (other than RB) in these patients

29

### Design

Cohort study using population-based data from European cancer registries adhering to the EUROCARE-6 project

33

### Setting

Population-based study with data collection between 2000 and 2013

36

### Participants

European children (0-14 years) with RB diagnosed

39

### Exposures

Diagnosis of RB with ICD-O morphology coded 9510 – 9514 (retinoblastoma) and malignant behavior (fifth digit of morphology code=3) according to the third edition of the International Classification of Diseases for Oncology (ICD-O-3)

44

### Main Outcome Measures

Annual incidence (per million children aged 0-14), 5-year survival (%), and the Standardized Incidence Ratio (SIR) of subsequent malignant neoplasms (SMNs)

48

### Results
We included 3,262 patients from 81 registries, of which 1,706 boys and 1,556 girls.

3,098 patients were considered in trend analysis after excluding registries with
incomplete time coverage: 940 in 2000-3, 703 in 2004-6, 744 in 2007-9, and 856 in
2010-13. The estimated overall EU incidence rate (per 1,000,000 children aged 0-14;
95%CI) was 4.0 (3.9 to 4.1). Rates among countries varied from <2 to >6/million/year.

No time trend of incidence was observed in any area.

The overall European 5-year survival was 97.8% (95.5%- 98.9%; 3180 cases). Five-year survival was lower in Estonia and Bulgaria (<80%) and 100% in several countries.

Twenty-five SMNs were recorded during follow-up (up to 14 years), with an SIR 8.2,
with cases occurring at mean ages between 1.3 and 8.9 years across different sites.

An increased risk was found for hematological tumors (SIR=5) and bone and soft
tissue sarcomas (SIR=29)

62

## Conclusions and Relevance

This European study showed RB incidence remained stable at 4.0 per 1,000,000 children aged 0 to 14 from 2000 to 2013, but estimates varied among countries and differences in survival across countries also persist. These data might be used to monitor RB management and occurrences of second tumors. The findings suggest future registry studies should aim to collect standardized RB stage at diagnosis and treatment to interpret disparities and potentially to improve surveillance.

70
71 **Introduction**

72 Retinoblastoma (RB) is a very rare cancer in infancy and childhood, with
73 estimates of new patients diagnosed annually worldwide ranging from approximately
74 4,400 to 19,000 cases.¹,² In Europe (EU28), the number of new annual diagnoses is
75 patient lower, with 277 cases and a prevalence in the adult population of 5,329
76 individuals who were diagnosed with retinoblastoma in childhood.³,⁴ RB is very
77 aggressive and life-threatening if left untreated, but it is almost always curable if
78 detected at an early stage when the disease is confined to the eye.⁵ Early diagnosis
79 and prompt treatment are vital in order to preserve the patient's life, eyes and vision.
80 Furthermore, a risk of subsequent malignant neoplasms (SMN) following a first
diagnosis was reported,⁶⁻⁹ requiring a dedicated surveillance program for these
81 children. External beam radiation therapy was standard RB therapy until it became
82 clear that patients faced an increased but small SMN risk while also affecting the eye
83 and anatomy of the orbit itself. Currently, radiation therapy is mostly avoided due to
84 fear of SMNs and the availability of newer treatment alternatives, such as intra-arterial
85 and intravitreal chemotherapies.¹⁰ With the abandonment of EBRT, the risk for SMN s
86 should decrease further.¹¹A global cross-sectional study including half RB cases
87 worldwide in 2017 found that children from low- and middle-income countries (LMICs),
88 where the main global RB burden lies,¹ presented at an older age with more advanced
89 disease, and demonstrated a smaller proportion of familial history of retinoblastoma.
90 This is likely because a rather high proportion of affected patients do not reach
91 reproductive age with consequent inability to transmit the genetic heritage to the next
92 generation.² The same study group showed profound inequity in survival of children
93 depending on the national income level of their country of residence. In high-income
94 countries, death from retinoblastoma is rare, whereas in low-income countries
95 estimated 3-year survival is just under 60%.¹² Although essential treatments are
available in nearly all countries, early diagnosis and treatment in low-income countries
are key to improving survival outcomes.

Several single-country studies on the epidemiology of RB have been conducted
during the last decades,¹³⁻²⁸ the majority of population-based studies showing fairly
stable incidence or, in Europe, an increased trend over the period 1978–1997. ²⁹ In
high-income countries, the evolution of treatment modalities, as well as the early
detection of tumors and the access to specialized centers, has resulted in survival rates
exceeding 95%, also allowing globe salvage in many cases.²⁹ In Europe, 15-year
survival for retinoblastoma has been reported to be 97%, with a cure fraction of
99%.⁴,³⁰

Approximately 40% of RB cases worldwide are heritable, resulting from a
germline mutation in RB1 gene.⁵,⁶ Survivors of heritable retinoblastoma have a
increased risk of SMNs, particularly bone and soft tissue sarcomas, uterine
leiomyosarcoma, melanomas, and radiotherapy-related central nervous system (CNS)
tumors.⁷⁻⁹ While annual skin examination is recommended for RB survivors, there is
still a debate on the use of whole-body magnetic resonance imaging (MRI) including
the search of pinealoblastoma.³¹

To our knowledge, the last Europe-wide study on the frequency and outcome of
RB using data from population-based cancer registries was conducted using incident
data up to 2002.³² In order to improve the knowledge on the epidemiology of this rare
tumor in Europe, we conducted a comprehensive study on incidence, survival, and
SMN occurrence in children with RB diagnosed between 2000 and 2013, using
population-based data from European cancer registries participating in the
EUROCARE-6 project.

121

122

123 Methods
124

125 *Data collection*

126 We obtained data on 3262 paediatric patients (0-14 years) diagnosed with RB in
127 Europe between 2000 and 2013 from 81 cancer registries of 31 European countries
128 participating in the EUROCARE-6 study, with a follow-up to December 2014. The year
129 2013 was the most recent available, while the years before 2000 was covered by a
130 substantially lower number of CRs, with more than 40% fewer cases. We analyzed
131 malignant cases with ICD-O morphology coded 9510 – 9514 (retinoblastoma) and
132 malignant behavior (fifth digit of morphology code=3) according to the third edition of
133 the International Classification of Diseases for Oncology (ICD-O-3).³³ We did not select
134 specific topography codes to overcome any possible incorrect site coding, since the
135 origin of RB is restricted to embryonic ocular tissue, but can be metastatic and may
136 also arise as a trilateral tumor, i.e. including both eyes and intracranial tissues, usually
137 in the pineal or, in about a quarter of cases, suprasellar region.³⁴ Finally, for our
138 analyses, carried out on individual data, we used the following information on RB
139 patients: sex, date of birth and/or age at diagnosis, date of diagnosis, vital status and
140 date of death, date of last vital status ascertainment, geographic region/cancer registry,
141 occurrence of a following primary tumor (other than RB) after RB with a follow-up to a
142 maximum of 14 years. Bilateral tumors were considered as a single case. Given the
143 rarity of the disease we aggregated countries in 5 European regions. The definition of
144 region was already specified in Gatta et al.,³⁵ with the inclusion of Cyprus in Southern
145 Europe, Czech Republic in Eastern Europe and the exclusion of Sweden from Northern
146 Europe.

147

148 *Statistical analyses*

149 Crude incidence rates were estimated as the number of cases per 1,000,000 persons
150 per year with 95% confidence interval (95%CI). To be comparable with the large
majority of population-based incidence studies, the case incidence year was that of the year of diagnosis. Incidence rate was calculated as the number of cases divided by the number of person-years in the geographical area, sex, age, for the given year period.

Incidence rates, age-adjusted for the European Standard population**, were calculated by sex, age-group, and country/region. Incidence trends of adjusted rates by period of diagnosis (i.e. 2000-3, 2004-6, 2007-9 and 2010-13) were calculated from 3098 cases, after excluding 24 registries that did not cover all the four periods. Patients across periods were 913 in 2000-2003, 670 in 2004-6, 720 in 2007-9, and 795 in 2010-13.

Complete survival analysis was estimated from 2380 cases, estimating survival up to 5 years, irrespective of the date of diagnosis. Five-year observed survival was provided by the actuarial method with the period approach by age-group, sex, country/region and period of diagnosis (i.e. 2000-3, 2004-6, 2007-9 and 2010-13); observed, i.e.

absolute survival is used instead of relative survival for European children, since only few other deaths from other causes occurred. Incidence and observed survival trends were estimated for Europe as a whole and for single countries. Z tests comparing the first and last point of the trends were conducted.

The number of SMNs among the cohort of RB survivors was compared with their expected number estimated from the overall European pool incidence rates, matched by site, sex and age. The common endpoint for both expected and observed second tumors was 31-12-2013.

The confidence intervals for the observed-to-expected ratios were calculated based on the chi-squared distribution, in accordance with Sahai et al.³⁶ SIRs were determined when the 95%CI did not include 1. Excess risk (ER) was estimated as the difference between observed and expected incidence rates.

## Results
We included 3,262 patients from 81 registries, of which 1,706 were boys and 1,556 girls. Out of 2712 cases with information on laterality, 769 (28.4%) had bilateral lesions. The majority of cases were diagnosed within 5 years of age (96%), and 42% were diagnosed in the first year of life (not in Table 1).

Table 1 shows the main data quality indicators by country. Overall, only 1 case was diagnosed from death certificates only (DCO). Sixty-five percent were microscopically verified (MV), although the proportions varied from 16% to 100%. Sixty-six cases of tumour of retina without microscopical diagnosis were not included in the study. Most cases were recorded in Denmark, Italy and Poland. This potential source of bias will be considered in the Discussion. The quality of follow-up for vital status was good, since only 4% of cases were censored before 5 years of follow-up.
189 Incidence

190 The overall EU incidence rate (age-standardized per 1,000,000 person-years age 0-14,
191 95%CI) was estimated to be 4.0 (3.9 to 4.1, 3,262 cases) in the period 2000-2013.

192 Rates were lower than 2 in Cyprus, Denmark, and Austria, whereas they were higher
193 than 6 in Belgium (Figure 1). Incidence rates did not differ by sex (boys 4.2, 95% CI 3.9
194 - 4.5; 1,706 cases; girls: 3.9, 95% CI 3.7 - 4.1; 1,556 cases) while rates were higher in
195 infants and in ages 0-4 (10.6, 95% CI 10.2 - 11.0, 3,127 cases), compared to ages 5-9
196 (0.4, 95% CI 0.3 - 0.5, 122 cases). Table 1 provides the corresponding incidence rate
197 by country. Supplementary Figure 1 (eFigure1) shows incidence trends from 2000-
198 2013. Rates did not vary between the four incidence periods in any European region.

199 However, the Eastern European region had lower incidence rates than other regions
200 throughout the study.

201

202 Survival

203 Figure 2 shows 5-year survival for all registries, with numerical data presented in
204 Supplementary Table 1 (eTable1). The overall EU average was estimated to be 97.8%
205 (95.5%- 98.9%; 3180 cases). Five-year survival was 100% in 10 countries, including
206 three countries of Northern Europe and three of the four UK nations, but less than 70%
207 in Bulgaria.

208 Table 2 shows 5-year survival by age-bands and sex over the three periods. Survival
209 remained very high across all subgroups. Five-year survival improved in the age group
210 1-4 years (overall).

211

212 Risk of subsequent malignant neoplasms

213 Table 3 shows the observed and expected number of SMNs for each site (only first 2
digits of the ICD-O code), with Absolute Excess Risk (AER) reported per 10,000
214 children. The table also shows the time interval at which SMNs were diagnosed. An
215
216 increased risk was found for hematological tumors and sarcomas. Out of the 3 cases of

217 CNS cancer, 2 had a morphological codification as glioma not otherwise specified

218 (NOS), primitive neuroectodermal tumor (PNET, 2 cases) and pineoblastoma of

219 ventricle (1 case). Another pineoblastoma was included in the endocrine glands

220 category. A table with further specification of SMNs is given as Supplemental Table 2

221 (eTable2).

222
223 Discussion

224

225 This population-based estimate of RB incidence and survival in Europe
226 described cases diagnosed since the year 2000. Incidence rates of 4.0 per
227 1,000,000 children were noted among those aged 0-14 in the period 2000-2013,
228 with a large variability of incidence across countries. The European 5-year survival
229 was 98%, with disparities across countries. Furthermore, for Europe we provided the
230 risk of a subsequent tumour after RB within 14 years of diagnosis.

231 Incidence rates reported in non-European countries were higher in South America, US
232 (white Hispanics), East and South East Asia, with world age-standardized incidence
233 rates between 5.1 and 6.0 per million. Rates were lower than Europe in North Africa
234 and among US native Americans (2.2 and 1.8, respectively).²⁹ Our data shows low
235 incidence rates in small countries like the Nordic and the Baltic countries and Austria.

236 Furthermore, the rate would increase only in Denmark if 66 tumours of the retina
237 without pathological diagnosis were included in the analysis, without affecting the range
238 of values. Migration to countries with centers of excellence may be a reason for low
239 case ascertainment,³⁷ though most of the small countries with low recorded incidence
240 have a retinoblastoma centre³⁸ or have active members of the European
241 Retinoblastoma Group³⁹. Genetic differences across populations should also be
242 considered.

243 Risk factors that have been associated with RB include advanced parental age,
244 use of assisted reproductive technology, human papillomavirus infection, diet, sunlight
245 exposure, direct fetal x-ray exposure, and parental exposure to hazardous occupational
246 substances. Of particular interest, paternal employment as a welder, mechanist, or
247 related metal works have been associated with an increased risk of sporadic RB, as
248 among farmers and other workers involved in agriculture.⁴⁰,⁴¹ Finally, our study does
249 not confirm a previous finding of increased trend in incidence found in a subset of
250 European registries in 2017 ⁴²; however, the methods used to compute incidence were
251 different from the ones in our study. Furthermore, the population of patients was
252 different at the numerator in the two studies, as sampling was hospital-based in Stacey
253 et al.⁴²

254 Childhood cancer survival differences across European countries were reported
255 in international population-based studies³,⁴ with lower survival in Eastern European
256 countries and higher in Northern and Central countries in the same period as ours.
257 Compared with all the other pediatric tumors, RB represents a disease with a curability
258 of 99%, because currently available treatments are effective for localized and regional
259 spread lesions and most metastatic tumors.⁴ A diagnosis of early stage RB should be
260 more likely in those countries, mainly in Europe and in other high-income ones. Many
261 high-income countries have established neonatal or early pediatric screening
262 programs, such as assessing the pupillary red reflex, which may allow an early
263 diagnosis of RB.⁴² The absence of these programs may affect the incidence rates of
264 RB in children leading to delayed onset and late stage at diagnosis.²,⁴³,⁴⁴

265 We also estimated the occurrence of SMNs up to a maximum of 14 years since
266 diagnosis in survivors, and found an AER of nearly 11 per 10,000 children for all
267 tumors. Higher risks were found for hematological malignancies and tumors of head
268 and neck (all rhabdomyosarcomas), brain and bone and soft tissues. We also found
269 that 25 cases of SMN were more frequent in bilateral retinoblastoma which are almost
270 all heritable RB (14/21). Subsequent malignant neoplasms in heritable RB children are
271 due to the presence of a mutation in the RB1 tumor suppressor gene and to
272 therapeutic choices. In a review by Fabius et al.,⁴⁴ the SIR for secondary malignancies
273 varied between 11.4 and 20.4 among survivors with heritable RB and 1.2 to 1.85
274 among those with non-heritable RB. In Fabius et al.,⁴⁴ age at onset of SMN was below
275 10 years for most cases of leukemia and lymphoma, adolescence for sarcomas,
276 whereas melanomas and carcinomas appeared in young adults. Central Nervous

277 System tumors were found both in adolescents and young adults in that study. The

278 length of follow-up in our study was limited to 14 years, not yet sufficient to investigate

279 SMN occurrence in adolescents and young adults. Among studies not using

280 population-based data, Schonfeld 2021⁴⁵ have estimated that 1 in 3 patients with

281 hereditary RB will develop SMN by the age of 50, as opposed to none with non-

282 hereditary RB.

283 Despite high survival rates in industrialized countries, children surviving RB

284 have low quality of life and reported difficulties in activities of daily living.⁴⁶ Flegg at

285 al.,⁴⁷ conducted a research prioritization initiative with engagement of people affected

286 by RB, clinicians and researchers to determine the top 10 RB research priorities in

287 Canada. They found that achieving an earlier diagnosis, which should increase the

288 proportion diagnosed with earlier stage disease, and conducting second cancer

289 screening for heritable RB survivors were the top priorities. Other priorities concerned

290 long-term follow-up, including of second cancers, and the formation of international

291 consortia and registries. Surveillance using EUROCARE-6 can contribute to reach

292 these goals.

293 Limitations of this investigation include the partial availability of RB stage.

294 A wider use of the Toronto guidelines in childhood cancer registration ⁴⁸ will

295 improve the registration of clinical variables such as stage at diagnosis,

296 treatment and other prognostic factors. Another limitation is the latency in data

297 collection, which is inherent in large-scale, centralized studies. Moreover, not all

298 registries provided data across all periods, leading to incidence and survival

299 trends being based on registries with incident data throughout the study time-

300 frame, which are the majority. All these limitations may reduce the certainty of

301 the evidence of our estimates.
302 Strengths of this investigation include its relatively large number of cases
303 evaluated and a standardized Europe-wide data collection. According to the
304 recommendations of the ENCR, code 9510 can be used for retinoblastomas
305 without requiring histological confirmation. This could potentially explain the
306 differences between countries regarding histological verification and the column of
307 tumors of the retina without morphological codification of retinoblastoma. These are
308 likely to be cases receiving medical treatment and not registered, by mistake, as
309 retinoblastoma. Only Denmark would double its rate after their inclusion,
310 appearing more similar to the other Nordic countries. A further limitation of our
311 study is that the results may be influenced by, or associated to the specific
312 ethnic group genetic predisposition.

313

314 Conclusions

315 We found stable incidence of 4.0 per 1,000,000 children among those aged 0-
316 14 in the period 2000-2013, with a large variability of incidence across
317 countries. High survival for children with RB were noted in Europe, with higher
318 risk with respect to the children population of SMNs in RB survivors.

319 Multinational initiatives that collect RB stage and primary treatment, linking
320 clinical and cancer registries, are warranted to improve RB surveillance.

321

Acknowledgment

Funding

This research was funded by the European Commission through the Consumers, Health,
Agriculture and Food Executive Agency (Chafea); Grant No. 2000111201; Information
network on rare cancers -RARECARENet.
Funding from the European Commission (Work Programme 2017, Grant Agreement 801520 HP-JA-2017, "Innovative Partnership for Action Against Cancer") was used to prepare and clean the EUROCARE-6 database. The salary of LB was granted by the Italian Association of Cancer Research (AIRC) under Investigator Grant 2020 ID.24933 (Principal Investigator GG).

For the Bietti Foundation the research for this paper was financially supported by the Italian Ministry of Health and Fondazione Roma. The funders had no role in the design or conduct of this research.

**Conflict of Interest:**

Mariacristina Parravano has the following disclosures: ABBVIE (S), BAYER (S); NOVARTIS (S), ROCHE (S), ZEISS (S) outside the submitted work.

None for all other authors.

**Access to data and data analysis:**

Virgili G. and Gatta G. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis
323 References

324

1. Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Atun R. Estimating the total incidence of global childhood cancer: a simulation-based analysis. *Lancet Oncol*. Apr 2019;20(4):483-493. doi:10.1016/S1470-2045(18)30909-4

325

326

327

2. Fabian ID, Abdallah E, Abdullahi SU, et al. Global Retinoblastoma Presentation and Analysis by National Income Level. *JAMA Oncol*. May 01 2020;6(5):685-695. doi:10.1001/jamaoncol.2019.6716

328

329

330

3. Surveillance of Rare Cancers in Europe (RARECARE) http://rarecarenet.istitutotumori.mi.it/analysis.php. Accessed December 28th, 2023.

331

332

333

4. Botta L, Gatta G, Capocaccia R, et al. Long-term survival and cure fraction estimates for childhood cancer in Europe (EUROCARE-6): results from a population-based study. *Lancet Oncol*. Dec 2022;23(12):1525-1536. doi:10.1016/S1470-2045(22)00637-4

334

335

336

337

5. Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. *Br J Ophthalmol*. Sep 2009;93(9):1129-31. doi:10.1136/bjo.2008.150292

338

339

340

6. Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. *Nat Rev Dis Primers*. Aug 27 2015;1:15021. doi:10.1038/nrdp.2015.21

341

342

7. Woo KI, Harbour JW. Review of 676 second primary tumors in patients with retinoblastoma: association between age at onset and tumor type. *Arch Ophthalmol*. Jul 2010;128(7):865-70. doi:10.1001/archophthalmol.2010.126

343

344

345

8. Tonorezos ES, Friedman DN, Barnea D, et al. Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma. *Ophthalmology*. Nov 2020;127(11):1549-1557. doi:10.1016/j.ophtha.2020.05.024

346

347

348

9. Jiménez I, Laé M, Tanguy ML, et al. Craniofacial second primary tumors in patients with germline retinoblastoma previously treated with external beam radiotherapy: A retrospective institutional analysis. *Pediatr Blood Cancer*. Apr 2020;67(4):e28158. doi:10.1002/pbc.28158

349

350

351

352

10. Raval V, Parulekar M, Singh AD. Emerging New Therapeutics for Retinoblastoma. *Ocul Oncol Pathol*. Nov 2022;8(3):149-155. doi:10.1159/000524919

353

354

11. Francis JH, Roosipu N, Levin AM, et al. Current Treatment of Bilateral Retinoblastoma: The Impact of Intraarterial and Intravitreous Chemotherapy. *Neoplasia*. Aug 2018;20(8):757-763. doi:10.1016/j.neo.2018.05.007

355

356

357

12. Group GRS. The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. *Lancet Glob Health*. Aug 2022;10(8):e1128-e1140. doi:10.1016/S2214-109X(22)00250-9

358

359

360

13. Moll AC, Kuik DJ, Bouter LM, et al. Incidence and survival of retinoblastoma in The Netherlands: a register based study 1862-1995. *Br J Ophthalmol*. Jul 1997;81(7):559-62. doi:10.1136/bjo.81.7.559

361

362

363

14. Saw SM, Tan N, Lee SB, Au Eong KG, Chia KS. Incidence and survival characteristics of retinoblastoma in Singapore from 1968-1995. *J Pediatr Ophthalmol Strabismus*. 2000;37(2):87-93. doi:10.3928/0191-3913-20000301-07

364

365

366

15. Seregard S, Lundell G, Svedberg H, Kivelä T. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. *Ophthalmology*. Jun 2004;111(6):1228-32. doi:10.1016/j.ophtha.2003.10.023

367

368

369
370 16. Leal-Leal C, Flores-Rojo M, Medina-Sansón A, et al. A multicentre report from the Mexican Retinoblastoma Group. *Br J Ophthalmol*. Aug 2004;88(8):1074-7.
371 doi:10.1136/bjo.2003.035642

373 17. MacCarthy A, Birch JM, Draper GJ, et al. Retinoblastoma in Great Britain 1963-2002. *Br J Ophthalmol*. Jan 2009;93(1):33-7. doi:10.1136/bjo.2008.139618

375 18. Moreno F, Sinaki B, Fandiño A, Dussel V, Orellana L, Chantada G. A population-based study of retinoblastoma incidence and survival in Argentine children. *Pediatr Blood Cancer*. Sep 2014;61(9):1610-5. doi:10.1002/pbc.25048

378 19. Park SJ, Woo SJ, Park KH. Incidence of retinoblastoma and survival rate of retinoblastoma patients in Korea using the Korean National Cancer Registry database (1993-2010). *Invest Ophthalmol Vis Sci*. May 01 2014;55(5):2816-21.
381 doi:10.1167/iovs.14-14078

382 20. Li SY, Chen SC, Tsai CF, Sheu SM, Yeh JJ, Tsai CB. Incidence and survival of retinoblastoma in Taiwan: a nationwide population-based study 1998-2011. *Br J Ophthalmol*. Jun 2016;100(6):839-42. doi:10.1136/bjophthalmol-2015-307211

385 21. Fernandes AG, Pollock BD, Rabito FA. Retinoblastoma in the United States: A 40-Year Incidence and Survival Analysis. *J Pediatr Ophthalmol Strabismus*. May 01 2018;55(3):182-188. doi:10.3928/01913913-20171116-03

388 22. Retinoblastoma CftNRO. The National Registry of Retinoblastoma in Japan (1983-2014). *Jpn J Ophthalmol*. Jul 2018;62(4):409-423. doi:10.1007/s10384-018-0597-2

391 23. Darwich R, Ghazawi FM, Rahme E, et al. Retinoblastoma Incidence Trends in Canada: A National Comprehensive Population-Based Study. *J Pediatr Ophthalmol Strabismus*. Mar 19 2019;56(2):124-130. doi:10.3928/01913913-20190128-02

394 24. Nummi K, Kivelä TT. Retinoblastoma in Finland, 1964-2014: incidence and survival. *Br J Ophthalmol*. Jan 2021;105(1):63-69. doi:10.1136/bjophthalmol-2019-315744

397 25. MacCarthy A, Birch JM, Draper GJ, et al. Retinoblastoma: treatment and survival in Great Britain 1963 to 2002. *Br J Ophthalmol*. Jan 2009;93(1):38-9.
399 doi:10.1136/bjo.2008.139626

400 26. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975-2004. *Br J Ophthalmol*. Jan 2009;93(1):24-7. doi:10.1136/bjo.2008.143842

402 27. Bowman RJ, Mafwiri M, Luthert P, Luande J, Wood M. Outcome of retinoblastoma in east Africa. *Pediatr Blood Cancer*. Jan 2008;50(1):160-2. doi:10.1002/pbc.21080

405 28. Chawla B, Hasan F, Azad R, et al. Clinical presentation and survival of retinoblastoma in Indian children. *Br J Ophthalmol*. Feb 2016;100(2):172-8.
407 doi:10.1136/bjophthalmol-2015-306672

408 29. Steliarova-Foucher E, Colombet M, Ries LAG, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. *Lancet Oncol*. Jun 2017;18(6):719-731. doi:10.1016/S1470-2045(17)30186-9

411 30. MacCarthy A, Draper GJ, Steliarova-Foucher E, Kingston JE. Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project. *Eur J Cancer*. Sep 2006;42(13):2092-102.
414 doi:10.1016/j.ejca.2006.06.003

415 31. Friedman DN, Hsu M, Moskowitz CS, et al. Whole-body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and
417 young adult survivors of germline retinoblastoma: An update. *Pediatr Blood Cancer*. Jul 2020;67(7):e28389. doi:10.1002/pbc.28389

419 32. Gatta G, Ferrari A, Stiller CA, et al. Embryonal cancers in Europe. *Eur J Cancer*. Jul 2012;48(10):1425-33. doi:10.1016/j.ejca.2011.12.027

421 33. Fritz A. ICD-O-3 terminology approved for use with cases diagnosed January 1, 2014 and after. *J Registry Manag*. 2013;40(3):140-3.

423 34. de Jong MC, Kors WA, de Graaf P, Castelijns JA, Moll AC, Kivelä T. The Incidence of Trilateral Retinoblastoma: A Systematic Review and Meta-Analysis. *Am J Ophthalmol*. Dec 2015;160(6):1116-1126.e5. doi:10.1016/j.ajo.2015.09.009

426 35. Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a population-based study. *Lancet Oncol*. Jan 2014;15(1):35-47. doi:10.1016/S1470-2045(13)70548-5

429 36. Sahai H. Confidence Intervals for the Mean of a Poisson Distribution: A Review. In: Khurshid A, editor. 1993. p. 857-867.

431 37. Karim-Kos HE, Hackl M, Mann G, et al. Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011. *Cancer Epidemiol*. Jun 2016;42:72-81. doi:10.1016/j.canep.2016.03.015

434 38. Fabian ID, Stacey AW, Foster A, et al. Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries. *Br J Ophthalmol*. Oct 2021;105(10):1435-1443. doi:10.1136/bjophthalmol-2020-316613

438 39. Dittner-Moormann S, Reschke M, Abbink FCH, et al. Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG). *Pediatr Blood Cancer*. Jun 2021;68(6):e28963. doi:10.1002/pbc.28963

442 40. Omidakhsh N, Hansen J, Ritz B, et al. Parental Occupation and Risk of Childhood Retinoblastoma in Denmark. *J Occup Environ Med*. Mar 01 2021;63(3):256-261. doi:10.1097/JOM.0000000000002120

445 41. Thompson S, Ritz B, Cockburn M, Heck JE. Prenatal ambient pesticide exposure and childhood retinoblastoma. *Int J Hyg Environ Health*. Aug 2022;245:114025. doi:10.1016/j.ijheh.2022.114025

448 42. Stacey AW, Bowman R, Foster A, et al. Incidence of Retinoblastoma Has Increased: Results from 40 European Countries. *Ophthalmology*. Sep 2021;128(9):1369-1371. doi:10.1016/j.ophtha.2021.01.024

451 43. Koochakzadeh L, Yekta A, Hashemi H, Pakzad R, Heydarian S, Khabazkhoob M. Epidemiological aspect of retinoblastoma in the world: a review of recent advance studies. *Int J Ophthalmol*. 2023;16(6):962-968. doi:10.18240/ijo.2023.06.20

454 44. Fabius AWM, van Hoefen Wijsard M, van Leeuwen FE, Moll AC. Subsequent Malignant Neoplasms in Retinoblastoma Survivors. *Cancers (Basel)*. Mar 10 2021;13(6)doi:10.3390/cancers13061200

457 45. Schonfeld SJ, Kleinerman RA, Abramson DH, Seddon JM, Tucker MA, Morton LM. Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors. *Br J Cancer*. Mar 2021;124(7):1312-1319. doi:10.1038/s41416-020-01248-y

461 46. Wise J, Hayashi R, Wu T, et al. Eye-related quality of life and activities of daily living in pediatric retinoblastoma patients: A single-center, non-controlled, cross-sectional analysis. *Pediatr Blood Cancer*. Aug 2023;70(8):e30479. doi:10.1002/pbc.30479
465 47. Flegg K, Gelkopf MJ, Johnson SA, Dimaras H, Committee CRRABPSS. The top
466 10 retinoblastoma research priorities in Canada as determined by patients, clinicians and
467 researchers: a patient-oriented priority-setting partnership. *CMAJ Open*. 2020;8(2):E420-
468 E428. doi:10.9778/cmajo.20190221

469 48. Gupta S, Aitken JF, Bartels U, et al. Paediatric cancer stage in population-based
cancer registries: the Toronto consensus principles and guidelines. *Lancet Oncol*. Apr
470 2016;17(4):e163-e172. doi:10.1016/S1470-2045(15)00539-2

472
473
474
475 Table 1. Data quality of retinoblastoma cases included in the analysis in the period 2000-2013, by country (absolute numbers, unless otherwise described).

477

<table><thead><tr><th rowspan="2">Country</th><th rowspan="2">cases</th><th rowspan="2">DCO</th><th rowspan="2">MV</th><th rowspan="2">Retina, cases unspecified morphology *</th><th rowspan="2">Lost &lt; 5y</th><th rowspan="2">Lost &lt; 5y (%)</th><th colspan="3">Laterality</th></tr><tr><th>One site</th><th>Bilateral</th><th>Unknown</th></tr></thead><tbody><tr><td>Austria National</td><td>28</td><td>0</td><td>82%</td><td>0</td><td>0</td><td>0%</td><td>22</td><td>6</td><td>0</td></tr><tr><td>Belgium National</td><td>104</td><td>0</td><td>77%</td><td>0</td><td>2</td><td>2%</td><td>72</td><td>11</td><td>21</td></tr><tr><td>Bulgaria National</td><td>33</td><td>0</td><td>100%</td><td>0</td><td>0</td><td>0%</td><td>31</td><td>2</td><td>0</td></tr><tr><td>Croatia National</td><td>24</td><td>0</td><td>100%</td><td>0</td><td>3</td><td>13%</td><td>0</td><td>0</td><td>24</td></tr><tr><td>Cyprus National</td><td>1</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>0%</td><td>1</td><td>0</td><td>0</td></tr><tr><td>Czech Republic National</td><td>40</td><td>0</td><td>100%</td><td>2</td><td>0</td><td>0%</td><td>34</td><td>4</td><td>2</td></tr><tr><td>Denmark National</td><td>23</td><td>0</td><td>96%</td><td>21</td><td>1</td><td>4%</td><td>16</td><td>5</td><td>2</td></tr><tr><td>Estonia National</td><td>5</td><td>0</td><td>100%</td><td>0</td><td>0</td><td>0%</td><td>4</td><td>1</td><td>0</td></tr><tr><td>Finland National</td><td>67</td><td>0</td><td>55%</td><td>0</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>67</td></tr><tr><td>France National, Childhood</td><td>695</td><td>0</td><td>62%</td><td>0</td><td>10</td><td>1%</td><td>480</td><td>215</td><td>0</td></tr><tr><td>Germany National, Childhood</td><td>550</td><td>0</td><td>41%</td><td>0</td><td>90</td><td>16%</td><td>360</td><td>186</td><td>4</td></tr><tr><td>Hungarian National, Childhood</td><td>74</td><td>0</td><td>76%</td><td>0</td><td>3</td><td>4%</td><td>48</td><td>24</td><td>2</td></tr><tr><td>Iceland National</td><td>2</td><td>0</td><td>100%</td><td>0</td><td>0</td><td>0%</td><td>2</td><td>0</td><td>0</td></tr><tr><td>Ireland National</td><td>53</td><td>0</td><td>87%</td><td>0</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>53</td></tr><tr><td>Italy (CRs Pool)</td><td>192</td><td>0</td><td>70%</td><td>14</td><td>5</td><td>3%</td><td>45</td><td>20</td><td>127</td></tr><tr><td>Latvia National</td><td>12</td><td>0</td><td>83%</td><td>1</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>12</td></tr><tr><td>Lithuania National</td><td>13</td><td>0</td><td>100%</td><td>0</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>13</td></tr><tr><td>Malta National</td><td>4</td><td>0</td><td>75%</td><td>0</td><td>0</td><td>0%</td><td>0</td><td>0</td><td>4</td></tr><tr><td>The Netherlands National</td><td>170</td><td>0</td><td>75%</td><td>0</td><td>0</td><td>0%</td><td>111</td><td>59</td><td>0</td></tr><tr><td>Norway National</td><td>42</td><td>0</td><td>55%</td><td>0</td><td>0</td><td>0%</td><td>28</td><td>13</td><td>1</td></tr><tr><td>Poland National</td><td>217</td><td>0</td><td>100%</td><td>18</td><td>0</td><td>0%</td><td>78</td><td>34</td><td>105</td></tr><tr><td>Portugal (CRs Pool)</td><td>68</td><td>0</td><td>82%</td><td>0</td><td>0</td><td>0%</td><td>47</td><td>11</td><td>10</td></tr><tr><td>Slovakia National</td><td>26</td><td>0</td><td>100%</td><td>0</td><td>0</td><td>0%</td><td>17</td><td>9</td><td>0</td></tr><tr><td>Slovenia National</td><td>14</td><td>0</td><td>100%</td><td>1</td><td>0</td><td>0%</td><td>11</td><td>3</td><td>0</td></tr><tr><td>Spain (CRs Pool)</td><td>198</td><td>1</td><td>44%</td><td>0</td><td>6</td><td>3%</td><td>134</td><td>9</td><td>1</td></tr><tr><td>Switzerland National, Childhood</td><td>57</td><td>0</td><td>16%</td><td>0</td><td>0</td><td>0%</td><td>39</td><td>18</td><td>0</td></tr><tr><td>England National</td><td>474</td><td>0</td><td>71%</td><td>3</td><td>0</td><td>0%</td><td>323</td><td>128</td><td>23</td></tr><tr><td>Northern Ireland National</td><td>12</td><td>0</td><td>75%</td><td>1</td><td>0</td><td>0%</td><td>6</td><td>3</td><td>3</td></tr><tr><td>Scotland National</td><td>41</td><td>0</td><td>71%</td><td>0</td><td>0</td><td>0%</td><td>29</td><td>6</td><td>6</td></tr><tr><td>Wales National</td><td>23</td><td>0</td><td>70%</td><td>5</td><td>0</td><td>0%</td><td>5</td><td>2</td><td>16</td></tr><tr><td>Northern Europe</td><td>134</td><td>0</td><td>63%</td><td>21</td><td>1</td><td>1%</td><td>46</td><td>18</td><td>70</td></tr><tr><td>Central Europe</td><td>1,618</td><td>0</td><td>56%</td><td>1</td><td>102</td><td>6%</td><td>1,095</td><td>498</td><td>25</td></tr><tr><td>Eastern Europe</td><td>420</td><td>0</td><td>95%</td><td>21</td><td>3</td><td>1%</td><td>212</td><td>74</td><td>134</td></tr><tr><td>Southern Europe</td><td>487</td><td>1</td><td>62%</td><td>14</td><td>14</td><td>3%</td><td>275</td><td>40</td><td>223</td></tr><tr><td>UK_Ireland</td><td>603</td><td>0</td><td>73%</td><td>9</td><td>0</td><td>0%</td><td>363</td><td>139</td><td>101</td></tr><tr><td>European Pool (81 CRs)</td><td>3,262</td><td>1</td><td>66%</td><td>66</td><td>120</td><td>4%</td><td>1,943</td><td>769</td><td>496</td></tr></tbody></table>

478
479 Legend: DCO: death certificate only; MV: microscopic verification.
480 * Not included in the analysis

481 Spain, Portugal, Italy are not nationally covered.

482
483 Spain was covered by Balearic Islands, Mallorca, Basque Country, Canary Islands,
484 Castellon. Comunitat Valenciana, Girona, Granada, Murcia, Navarra, Spanish Childhood
485 (RETI-SEHOP) and Tarragona registries.

486
487 Italy was covered by Alto Adige, Barletta-Andria-Trani, Basilicata; Bergamo, Biella,
488 Catania-Messina-Enna, Catanzaro, Province of Varese and Como, Cremona and
489 Mantova, Ferrara, Firenze-Prato, Friuli Venezia Giulia, Genova, Latina, Province of Milan
490 and Lodi, Modena, Monza and Brianza, Napoli 3 South, Nuoro, Palermo, Parma,
491 Piacenza, Piemonte Childhood, Ragusa, Reggio Emilia, Romagna, Salerno, Sassari,
492 Siracusa, Sondrio, Taranto, Trapani, Trento, Umbria, Veneto and Viterbo registries.

493
494 Portugal was covered by Central Portugal, Northern Portugal and Southern Portugal
495 registries.

496
497

498 Table 2: 5-year survival (%) and 95% CI by age, sex and period.

499

<table><thead><tr><th rowspan="2">Sex</th><th colspan="3">2003 Estimate</th><th colspan="3">2006 Estimate</th><th colspan="3">2009 Estimate</th><th colspan="3">2013 Estimate</th></tr><tr><th>Survival</th><th colspan="2">95%CI</th><th>Survival</th><th colspan="2">95%CI</th><th>Survival</th><th colspan="2">95%CI</th><th>Survival</th><th colspan="2">95%CI</th></tr></thead><tbody><tr><td>Male</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 years</td><td>98</td><td>95</td><td>99</td><td>99</td><td>95</td><td>100</td><td>99</td><td>95</td><td>100</td><td>99</td><td>96</td><td>100</td></tr><tr><td>1-4 years</td><td>96</td><td>93</td><td>98</td><td>96</td><td>92</td><td>98</td><td>97</td><td>93</td><td>99</td><td>99</td><td>96</td><td>100</td></tr><tr><td>5-9 years</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td></tr><tr><td>10-14 years</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td></tr><tr><td>Total</td><td>97</td><td>95</td><td>98</td><td>97</td><td>95</td><td>99</td><td>98</td><td>96</td><td>99</td><td>99</td><td>97</td><td>100</td></tr><tr><td>Female</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 years</td><td>99</td><td>95</td><td>100</td><td>98</td><td>93</td><td>99</td><td>99</td><td>94</td><td>100</td><td>98</td><td>94</td><td>99</td></tr><tr><td>1-4 years</td><td>96</td><td>92</td><td>98</td><td>93</td><td>89</td><td>96</td><td>97</td><td>92</td><td>99</td><td>98</td><td>95</td><td>100</td></tr><tr><td>5-9 years</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>91</td><td>51</td><td>99</td><td>100</td><td>n.e.</td><td>n.e.</td></tr><tr><td>10-14 years</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td></tr><tr><td>Total</td><td>97</td><td>95</td><td>99</td><td>95</td><td>92</td><td>97</td><td>98</td><td>95</td><td>99</td><td>98</td><td>96</td><td>99</td></tr><tr><td>Male and female</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 years</td><td>99</td><td>97</td><td>100</td><td>99</td><td>96</td><td>99</td><td>99</td><td>97</td><td>100</td><td>99</td><td>97</td><td>100</td></tr><tr><td>1-4 years</td><td>96</td><td>94</td><td>97</td><td>95</td><td>92</td><td>97</td><td>97</td><td>94</td><td>98</td><td>99</td><td>97</td><td>99</td></tr><tr><td>5-9 years</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>95</td><td>0.70</td><td>0.99</td><td>100</td><td>n.e.</td><td>n.e.</td></tr><tr><td>10-14 years</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td><td>100</td><td>n.e.</td><td>n.e.</td></tr><tr><td>Total</td><td>97</td><td>96</td><td>98</td><td>96</td><td>95</td><td>98</td><td>98</td><td>96</td><td>99</td><td>99</td><td>98</td><td>99</td></tr></tbody></table>

500

501 Legend: 95%CI= 95% confidence interval; n.e. = not estimable.

502
503 Table 3.

504 Subsequent malignant neoplasms after the diagnosis of retinoblastoma: observed and
505 expected number of neoplasms for each site, with excess risk reported as cases per
506 10,000 children per year. The table also shows the time interval at which subsequent
507 malignant neoplasms were diagnosed and number of diagnosed children for four periods
508 of follow-up.

509

510

<table><thead><tr><th>Tumor site</th><th>Observed</th><th>Expected</th><th>O/E</th><th>p-value</th><th>CI Lower</th><th>CI Upper</th><th>Excess Risk</th><th>Mean Age at Event</th><th>FU 6-11 months</th><th>FU 12-59 months</th><th>FU 60-119 months</th><th>FU 120+ months</th></tr></thead><tbody><tr><td>All Sites but Eye</td><td>25</td><td>3.06</td><td>8.2</td><td>0,00</td><td>5.3</td><td>11.7</td><td>10.68</td><td>6.43</td><td>0</td><td>11</td><td>12</td><td>2</td></tr><tr><td>Nose, Nasal Cavity and Middle Ear</td><td>2</td><td>0.01</td><td>253.6</td><td>0.00</td><td>30.7</td><td>916.0</td><td>0.97</td><td>3.37</td><td>0</td><td>2</td><td>0</td><td>0</td></tr><tr><td>Bones and Joints</td><td>8</td><td>0.12</td><td>64.9</td><td>0.00</td><td>28.0</td><td>127.8</td><td>3.83</td><td>2 digits unless &lt;0.01</td><td>0</td><td>0</td><td>6</td><td>2</td></tr><tr><td>Soft Tissue including Heart</td><td>2</td><td>0.22</td><td>9.2</td><td>0.01</td><td>1.1</td><td>33.3</td><td>0.87</td><td>7.21</td><td>0</td><td>0</td><td>2</td><td>0</td></tr><tr><td>Kidney and Renal Pelvis</td><td>1</td><td>0.2</td><td>5.1</td><td>0.5</td><td>0.1</td><td>28.4</td><td>0.39</td><td>5.66</td><td>0</td><td>0</td><td>1</td><td>0</td></tr><tr><td>Brain</td><td>3</td><td>0.43</td><td>6.9</td><td>0.00</td><td>1.4</td><td>20.3</td><td>1.25</td><td>5.68</td><td>0</td><td>2</td><td>1</td><td>0</td></tr><tr><td>Endocrine System</td><td>2</td><td>0.18</td><td>11.2</td><td>0.00</td><td>1.4</td><td>40.3</td><td>0.89</td><td>5.87</td><td>0</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Non-Hodgkin Lymphoma</td><td>1</td><td>0.2</td><td>5</td><td>0.50</td><td>0.1</td><td>28.1</td><td>0.39</td><td>2.91</td><td>0</td><td>1</td><td>0</td><td>0</td></tr><tr><td>Leukemia</td><td>5</td><td>0.97</td><td>5.2</td><td>0.00</td><td>1.7</td><td>12.0</td><td>1.96</td><td>5.08</td><td>0</td><td>4</td><td>1</td><td>0</td></tr><tr><td>Acute Lymphocytic Leukemia</td><td>1</td><td>0.77</td><td>1.3</td><td>0.76</td><td>0.0</td><td>7.2</td><td>0.11</td><td>1.25</td><td>0</td><td>1</td><td>0</td><td>0</td></tr><tr><td>Acute Myeloid Leukemia</td><td>2</td><td>0.13</td><td>15.7</td><td>0.00</td><td>1.9</td><td>56.7</td><td>0.91</td><td>7.58</td><td>0</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Acute Monocytic Leukemia</td><td>2</td><td>0.01</td><td>143.9</td><td>0.00</td><td>17.4</td><td>519.7</td><td>0.97</td><td>4.5</td><td>0</td><td>2</td><td>0</td><td>0</td></tr><tr><td>Miscellaneous</td><td>1</td><td>0.09</td><td>11</td><td>0.17</td><td>0.3</td><td>61.1</td><td>0.44</td><td>5.67</td><td>0</td><td>1</td><td>0</td><td>0</td></tr></tbody></table>

511

512

513

514

515

516

517

518

519
520

521

522

523 **Figure legends**

524 **Figure 1.** Age-standardized rates (per 1,000,000 per year) for each included country and pooled across Europe. Age 0-14, period of diagnosis 2000-2013

525

526

527 **Figure 2.** 5-year survival of children aged 0-14 with a diagnosis of retinoblastoma in 2000-2013, by country. Countries are labelled as: National when the registry has a national coverage; Pool when estimates are derived from multiple registries with local coverage; Children when data are collected by specialized child registries.

528

529

530

531