Article Text
Abstract
Aim: This paper describes the treatment and survival of 1576 children with retinoblastoma in Great Britain diagnosed 1963–2002.
Methods: Survival rates were analysed according to period of diagnosis and tumour laterality.
Results: Survival was calculated by calendar period of diagnosis, 1963–1982 and 1983–2002. For both unilateral and bilateral retinoblastoma, survival improved between the two periods. The survival curves for the two periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01.
For unilateral cases, the estimated 5-year survival rates rose from 85% for those diagnosed in 1963–1967 to 97% for those diagnosed in 1998–2002. The equivalent rates for bilateral cases were 88% and 100%.
Conclusion: Survival rates were already high at the start of the study period. They increased with changes in treatment regimens.
Statistics from Altmetric.com
Retinoblastoma is a malignant intraocular embryonal tumour of childhood. In Britain, approximately one in 20 000 children is affected; about 40 cases are diagnosed each year.
There are two forms of the disease: “heritable,” that is those that carry a germ-line mutation in the RB1 gene, and “non-heritable.” Bilateral retinoblastoma is invariably heritable, though in most cases there is no preceding family history of the disease. A minority of unilateral cases are also heritable.
The purpose of this study is to describe survival from retinoblastoma in the population of Great Britain and to relate observed changes in survival to developments in treatment.
During the first 20 years of this study, the only treatment offered to children with unilateral retinoblastoma was enucleation, while the mainstay of therapy for children with bilateral retinoblastoma was external beam radiotherapy, often following enucleation of the eye with the more advanced tumour. A few children with relatively small tumours were offered xenon arc photocoagulation, cryotherapy or radiation brachytherapy with cobalt scleral plaques.
In the mid-1980s, in an attempt to reduce deaths from metastatic disease, adjuvant chemotherapy was introduced for children with advanced retinoblastoma undergoing enucleation and found to have unfavourable histological features identified by the pathologist. During the latter part of the 1980s, chemotherapy was added to radiotherapy for children with advanced bilateral retinoblastoma in an attempt to reduce the bilateral enucleation rate.
In the early 1990s, chemotherapy was introduced as primary treatment for all children with familial retinoblastoma in an attempt to avoid the damaging effects of external beam radiotherapy in this very young age group. During the last decade of the study, primary chemotherapy has become the standard care for all children with bilateral disease, in conjunction with cryotherapy for peripheral tumours. External beam and plaque radiotherapy or laser thermotherapy have been reserved for salvage therapy of tumours which relapse or are refractory to chemotherapy. In addition, approximately 15% of patients with unilateral disease presenting with small tumours are now offered primary chemotherapy rather than enucleation.
METHODS
Ascertainment of cases
We ascertained cases of retinoblastoma diagnosed between 1963 and 2002 from the population-based National Registry of Childhood Tumours (NRCT).1 Oxfordshire Research Ethics Committee (Oxfordshire REC C, Ref 07/Q1606/45) approved the use of the data reported in this study in 2007.
Laterality
Cases of bilateral retinoblastoma are usually recognised as such soon after the initial diagnosis of retinoblastoma in one eye. Cases that were originally unilateral were categorised as bilateral if a tumour subsequently developed in the second eye.
There were 1601 cases diagnosed between 1963 and 2002. Of these, 22 were of unknown laterality and were excluded from the survival analyses. A further three were ascertained through death certificates and were also excluded. The remaining 1576 cases are described in the present paper; see table 1, which shows the cases by age and laterality.
Notifications of deaths were received from the Office for National Statistics (ONS, previously the Office of Population Censuses and Surveys) and the Scottish General Register Office. Actuarial survival rates were calculated separately for unilateral and bilateral cases for the 20-year periods 1963–1982 and 1983–2002.
Statistical methods
Statistical analyses were carried out using STATA software.2 We have taken the value p<0.05 as being statistically significant.
RESULTS
Survival rates for unilateral (996) and bilateral (580) cases by calendar period of diagnosis, 1963–1982 and 1983–2002, are shown in figs 1, 2. For both unilateral and bilateral retinoblastoma, the survival rates improved between the two periods. The survival curves for the two time periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01.
For unilateral cases diagnosed in the earlier period, the survival rate was 93% at 1 year from diagnosis and 86% at 20 years from diagnosis. The equivalent survival rates for unilateral cases diagnosed in the later period were 98% and 95% respectively.
For bilateral cases diagnosed in the earlier period, the survival rates were 96% at 1 year from diagnosis and 80% at 20 years from diagnosis. In the later period, only one case out of 285 died in the first year after diagnosis, giving a survival rate of over 99%; the rate was 86% at 20 years from diagnosis.
For the earlier period, we have also calculated the 40-year survival rates. These were 81% and 75% for unilateral and bilateral cases respectively. When examining the survival curves for the longest periods of follow-up, it should be remembered that the estimates of survival at these points are based on a diminishing number of observations and are correspondingly subject to larger statistical error.
For unilateral cases, estimated 5-year survival rose from 85% for those diagnosed in 1963–1967 to 97% for those diagnosed in 1998–2002. The equivalent rates for bilateral cases were 88% and 100% (ie, for this particular 5-year period, no deaths were observed in the 5 years after diagnosis).
DISCUSSION
The results of this study are based on a large population-based series of cases with a very long follow-up. Survival rates for retinoblastoma have been good throughout the period reported here.
It is well known3 4 that there is a high incidence of non-ocular subsequent primary tumours in survivors of heritable retinoblastoma; some of the deaths in bilateral cases particularly those occurring more than 5 years from the diagnosis of retinoblastoma (fig 2) can be attributed to such tumours. Some cases of unilateral retinoblastoma also have the heritable form of the disease and will exhibit this increased mortality from non-ocular subsequent primary tumours.
The improved survival rates for patients diagnosed in the later period can be related to changes in treatment regimens over the four decades covered by the study; in particular, the introduction of adjuvant chemotherapy for children with advanced retinoblastoma undergoing enucleation and found to have adverse histological features has almost eradicated the problem of metastatic disease in children with non-heritable retinoblastoma. A definitive assessment of recent methods of therapy will, of course, require a longer period of follow-up.
Acknowledgments
We are grateful to colleagues at the Childhood Cancer Research Group, in particular J King, for help with this study and to cancer registries and the Children’s Cancer and Leukaemia Group for providing data to the National Registry of Childhood Tumours. JMB is a Cancer Research UK Professorial Fellow at the University of Manchester.
Footnotes
Competing interests: None.
Ethics approval: The Childhood Cancer Research Group receives Core Programme funding from the Department of Health and the Scottish Ministers. The funding agencies had no role in the design, conduct, reporting or decision to publish the study. The views expressed here are those of the authors and not necessarily those of the Department of Health and the Scottish Ministers. We are grateful to the Childhood Eye Cancer Trust for financial support for Childhood Cancer Research Group retinoblastoma studies.
Ethics approval: Ethics approval was provided by the Oxfordshire Research Ethics Committee.
Linked Articles
- At a glance