Cancer mortality in long-term survivors of retinoblastoma

doi:10.1016/j.ejca.2009.05.011

European Journal of Cancer

Volume 45, Issue 18, December 2009, Pages 3245-3253

https://doi.org/10.1016/j.ejca.2009.05.011 Get rights and content

Abstract

This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.

Introduction

Retinoblastoma is a rare childhood cancer of the eye. The disease is caused by a RB1 gene mutation in all patients with bilateral retinoblastoma, as well as in 10% of those with unilateral retinoblastoma.¹ Nowadays children diagnosed with retinoblastoma in the western world have excellent cure rates (up to 99%).² However, hereditary retinoblastoma survivors are at an exceptionally high risk of developing subsequent primary malignancies in childhood and adolescence.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 So far, little information is available on long-term excess mortality among survivors of retinoblastoma.7, 14, 15 Published studies include few patients with more than 50 years of follow-up, implying that mortality risk of retinoblastoma survivors has been hardly examined at ages during which death rates increase in the general population.

The national retinoblastoma registry of the Netherlands includes 1068 retinoblastoma patients diagnosed since 1862. Therefore, the registry offers a unique opportunity to analyse cause-specific mortality after long-term follow-up in a large group of retinoblastoma survivors, according to treatment and heredity.

Section snippets

Study population

The cohort analysed in this study has been described previously.¹³ In brief, the cohort includes 1068 Dutch retinoblastoma patients diagnosed from 1862 to 2005. For each patient data were collected concerning demography, family history of retinoblastoma, tumour laterality, treatment for retinoblastoma (including radiotherapy fields and energy type, and chemotherapeutic agents), second and subsequent cancers and date and (underlying) cause of death. If a cohort member had died, the date, the

Results

Table 1 shows the general characteristics of the study population; retinoblastoma patients diagnosed between 1862 and 2005, who were at risk of death between January 1901 and June 2007. The median follow-up time for hereditary retinoblastoma survivors was 25.8 years (range = 0.13–79.9 years). For non-hereditary retinoblastoma survivors, the median follow-up was 34.2 years (range = 0.01–89.7 years). Most of the hereditary patients (56.2%) were treated with radiotherapy for their retinoblastoma,

Discussion

To our knowledge, this is the first study that evaluates mortality among retinoblastoma patients in a nationwide cohort with very long-term follow-up and near complete cause of death information. Statistically significantly elevated risks of death were only found for second malignancies among hereditary retinoblastoma survivors, with an almost 13-fold increase of second malignancy death compared with general population expectations. During follow-up, the AER increased and amounted to 23.2

Conflict of interest statement

None declared.

Acknowledgements

We are grateful to Drs. Willem J. Klokman, senior statistical analyst, for his statistical support. We thank Prof. Dr. Johan P. Mackenbach for the historical mortality reference rates.

The study was supported by award VU 2004-3046 from the Dutch Cancer Society. The Dutch Cancer Society had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, or in the preparation, review and approval of the manuscript, other than with respect to the

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Cited by (60)

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma
2020, Ophthalmology
Citation Excerpt :
Estimates of standardized mortality ratios ranged from 6.85 (95% CI, 2.75–14.1)47 to 15.2 (95% CI, 4.9–35).76 Unfortunately, many cohort studies lack data on smoking status, which may differ by heritable status.22,47,66,77 In addition, some studies censored patients after the first subsequent malignant neoplasm, thereby reducing the chance of observing lung cancer cases, which are more likely to occur at an older age.22,66
To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma.
We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.
Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center.
Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.
Diagnosis and mortality from subsequent neoplasm.
Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.
This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.
The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma
2020, European Journal of Cancer
Patients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy.
From 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma.
SPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3–11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0–11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5–13.8] vs. IR 3.2 [95% CI: 1.0–7.5]; p < 0.05). In the subgroup without previous radiotherapy SPM were only observed in patients with regular penetrance variants (IR 6.3 [95% CI: 3.0–11.5]). Carriers of incomplete penetrance variants developed similar tumour entities as those with regular penetrance.
Patients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.
Depression, Anxiety, and Stress in Parents of Patients With Retinoblastoma
2019, American Journal of Ophthalmology
To assess depression, anxiety, and stress in parents of patients with retinoblastoma and to evaluate the impact of unifocal vs multifocal retinoblastoma.
A cross-sectional, self-reported psychological assessment of parents of patients with retinoblastoma at a tertiary care ocular oncology center was performed. The Beck Depression Inventory–II (BDI), Beck Anxiety Inventory (BAI), The Parental Stress Index 4–Short Form, and a retinoblastoma Knowledge Assessment questionnaire were administered. Descriptive statistics for outcomes and comparative analyses were made.
There were 138 parents of children with retinoblastoma (unifocal: n = 77, multifocal: n = 61). Overall, parents displayed mild, moderate, or severe depression (BDI) (n = 37, 26.7%); mild, moderate, or severe anxiety (BAI) (n = 49, 35.8%), and stress scores within normal limits (n = 138, 100%). A comparison (unifocal vs multifocal) revealed parents of children with multifocal retinoblastoma with severe depression (1.4% vs 10.2%, P < .02), and no differences in anxiety or stress. Factors associated with moderate or severe parental depression included previous history of depression (30.0% vs 3.9%, P < .001) and factors for moderate or severe anxiety included previous history of depression (33.3% vs 8.6%, P < .001), parent highest level of education at high school or less vs college or beyond (29.2% vs 10.9%, P = .031), and parental report of “child developmental delay” (31.5% vs 11.3%, P = .019).
The majority of parents displayed minimal depression (73.3%), anxiety (64.2%), or stress (100%). However, severe depression is more often found in those whose children have multifocal disease, and previous history of depression and less education can impact psychological function. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”
2019, Progress in Retinal and Eye Research
Citation Excerpt :
Thus, according to a Dutch study, the 40-year absolute excess risk of second primary neoplasms in hereditary retinoblastoma survivors was 261 excess cases per 10,000 survivors per year with a cumulative incidence of 28% (95% confidence interval = CI (21.0–35.0%) (Marees et al., 2008). The cumulative mortality from second primary malignancies 50 years after retinoblastoma diagnosis was 25.5% (95% CI (21–30%)) in hereditary versus 1% (95% CI (0.2–1.8%)) in non-hereditary retinoblastoma survivors (Marees et al., 2009; Yu et al., 2009). Second primary tumors can develop in diverse anatomic locations, including the skull, bones, soft tissues, nasal cavity, skin, orbit, brain, breast, bladder and lung.
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.
Retinoblastoma: The importance of early diagnosis
2018, Archivos de la Sociedad Espanola de Oftalmologia
El retinoblastoma es el tumor intraocular maligno más frecuente en la infancia y tanto su curación como las secuelas derivadas del mismo dependen fundamentalmente de un diagnóstico precoz. En la actualidad, no existe consenso en su manejo diagnóstico y terapéutico.
Estudio descriptivo, retrospectivo, no aleatorizado, de serie de casos (39 pacientes-58 ojos), tratados durante el período 2006-2013 en nuestro servicio, nombrado centro de Referencia Regional de Tumores por la Agencia de Calidad del SNS.
El signo más frecuente de comienzo es la leucocoria (71,8%), seguido de estrabismo (17,9%). Todos los casos de tumoración bilateral presentaban mutación germinal del gen RB1 y un 20% tenían antecedentes familiares. El 55% de los pacientes presentaron estadio E, y el 90% precisó tratamiento quimioterápico. Un 57% de los que presentaban estadios leves, conservaron su ojo respecto al 43% que lo conservó en estadios avanzados.
Este análisis consta de 58 ojos, sin que existan estudios previos en nuestra comunidad y pocas series tan numerosas en todo el país. Basado en tratamiento no estandarizados, eligiendo el más adecuado según las características del tumor. El manejo multidisciplinar, formado por oftalmología, oncología pediátrica, oncología radioterápica y radiofísica, es fundamental para la elección de tratamiento más correcta. La quimiorreducción junto a tratamientos de consolidación ofrece resultados esperanzadores en el control de los mismos, sobre todo en los de menor severidad. La enucleación continúa siendo de elección en las estadificaciones más avanzadas con afectación vítrea, poniendo de manifiesto la importancia de su diagnóstico precoz.
Retinoblastoma is the most frequent malignant intraocular tumour in childhood, and both its cure and the sequelae arising from it, mainly depend on an early diagnosis. There is currently no consensus on its diagnostic and therapeutic management.
A descriptive, retrospective, and non-randomised study was conducted on a series of cases (39 patients -58 eyes), treated during the period 2006-2013, in the Regional Reference Centre for Tumours of the National Health Service Quality Agency.
The most frequent presentation sign is leukocoria (71.8%), followed by strabismus (17.9%). All cases of bilateral tumour had a germline mutation of the RB1 gene, and 20% had a family history. Stage E was observed in 55% of the patients, and 90% required chemotherapy treatment. The eye was maintained in 57% of those who had mild stages, compared to 43% who maintained it in advanced stages.
This analysis included 58 eyes. There are no previous studies in our community and there are few series so numerous throughout the country. Based on non-standardised treatment, the most appropriate is chosen according to the characteristics of the tumour. The multidisciplinary management, formed by ophthalmology, paediatric oncology, radiotherapy, and radiophysical oncology, is fundamental for the selection of the most appropriate treatment. Chemo-reduction, along with consolidation treatments, offers encouraging results in the control of these tumours, especially in those of less severity. Enucleation continues to be the method of choice in the most advanced staging with vitreous involvement, with the importance of early diagnosis being highlighted.
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2018, Pediatric Cancer Genetics
The field of pediatric hereditary cancer syndromes is quickly evolving and has become an area of increased clinical interest. This chapter focuses on 15 different hereditary cancer predisposition syndromes that cause increased risk for benign and malignant tumors in the pediatric patient. The clinical features of each condition are detailed as well as the cancer risks, molecular causes, testing options and surveillance guidelines. While this is not an exhaustive list of all possible syndromes with cancer risks in childhood, the main syndromes which you may come across in your clinical practice are summarized.

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Cancer mortality in long-term survivors of retinoblastoma

Abstract

Introduction

Section snippets

Study population

Results

Discussion

Conflict of interest statement

Acknowledgements

Am J Ophthalmol

Ophthalmology

Eur J Cancer

Oral Oncol

Molecular genetics of RB1 – the retinoblastoma gene

Semin Ophthalmol

Retinoblastoma in the 20th century: past success and future challenges the Weisenfeld lecture

Invest Ophthalmol Vis Sci

Non-ocular cancer in patients with hereditary retinoblastoma and their relatives

Int J Cancer

Et al. Second non-ocular tumours in survivors of bilateral retinoblastoma. A 30-year follow-up

Ophthalmic Paediatr Genet

Second primary neoplasms in patients with retinoblastoma

Br J Cancer

Lifetime risks of common cancers among retinoblastoma survivors

J Natl Cancer Inst

Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma

J Natl Cancer Inst

Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up

J Clin Oncol

Second primary tumors in patients with hereditary retinoblastoma: a register-based follow-up study, 1945–1994

Int J Cancer