Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997: Is there an age effect on radiation-related risk?

doi:10.1016/S0161-6420(01)00562-0

Ophthalmology

Volume 108, Issue 6, June 2001, Pages 1109-1114

https://doi.org/10.1016/S0161-6420(01)00562-0 Get rights and content

Abstract

Objective

The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients.

Design

Cross-sectional study.

Participants

The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997.

Methods

A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves.

Main outcome measures

Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation.

Results

The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%–34%) in the early EBRT group, 3% (0%–14%) in the late EBRT group, and 5% (1%–16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined.

Conclusions

Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT.

Section snippets

Study population and follow-up procedures

A follow-up study was performed on retinoblastoma patients born in The Netherlands between 1945 and 1997. A previous report contains a complete description of the methods used to locate survivors and document deaths.14 In short, the Dutch Retinoblastoma Register was completed with the assistance of all University Eye Clinics and Cancer Registration Centers. Hospital records supplied data about demography, tumor laterality, family history of retinoblastoma, treatment, occurrence of SPT, and date

Results

The Dutch Retinoblastoma Register listed 686 patients born between 1945 and 1997, comprising 267 (38.9%) hereditary and 419 (61.1%) nonhereditary retinoblastoma patients. Four hereditary patients with retinomas (a benign form of retinoblastoma with spontaneous growth arrest) were excluded. They were diagnosed only after their offspring had a retinoblastoma develop (and none developed an SPT). The mean duration of follow-up of the 263 hereditary retinoblastoma patients was 20 years (median, 18

Discussion

This study confirms previous observations of an increased risk of SPT in irradiated hereditary retinoblastoma patients.6, 8, 14, 19, 20, 22, 23, 24 The risk was greater in children diagnosed and irradiated before the age of 1 year. However, the presence of equal numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. Given our irradiation protocol, our restricted but biologically sound definitions of the irradiation field and SPT prevented

References (27)

A.B Reese et al.
Treatment of bilateral retinoblastoma by irradiation and surgeryreport on 15-year results
Am J Ophthalmol
(1949)
D.H Abramson et al.
Second tumors in nonirradiated bilateral retinoblastoma
Am J Ophthalmol
(1979)
S.M Imhof et al.
Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma
Ophthalmology
(1996)
J.D Roarty et al.
Incidence of second neoplasms in patients with bilateral retinoblastoma
Ophthalmology
(1988)
B.G Mohney et al.
Second nonocular tumors in survivors of heritable retinoblastoma and prior radiation therapy
Am J Ophthalmol
(1998)
S.J Kony et al.
Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood
Lancet
(1997)
D.H Abramson et al.
Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced?
Ophthalmology
(1984)
L.E Blach et al.
Trilateral retinoblastoma—incidence and outcomea decade of experience
Int J Radiat Oncol Biol Phys
(1994)
A.W Forrest
Tumors following radiation about the eye
Trans Am Acad Ophthalmol Otolaryngol
(1961)
H.B Soloway
Radiation-induced neoplasms following curative therapy for retinoblastoma
Cancer
(1966)

A.C Moll et al.

Second primary tumors in patients with retinoblastoma. A review of the literature

Ophthalmic Genet

(1997)

G.J Draper et al.

Second primary neoplasms in patients with retinoblastoma

Br J Cancer

(1986)

Survival rate and risk factors for patients with retinoblastoma in Japan. The Committee for the National Registry of...

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¹: None of the authors have commercial interests in this study.

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Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997: Is there an age effect on radiation-related risk?1

Abstract

Objective

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Section snippets

Study population and follow-up procedures

Results

Discussion

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Ophthalmology

Am J Ophthalmol

Lancet

Ophthalmology

Int J Radiat Oncol Biol Phys

Tumors following radiation about the eye

Trans Am Acad Ophthalmol Otolaryngol

Radiation-induced neoplasms following curative therapy for retinoblastoma

Cancer

Second primary tumors in patients with retinoblastoma. A review of the literature

Ophthalmic Genet

Second primary neoplasms in patients with retinoblastoma

Br J Cancer

Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997: Is there an age effect on radiation-related risk?¹