Risk of subsequent primary cancer and radiation exposure in the British Childhood Cancer Survivor Study

Clare Frobisher, University of Birmingham 
*Michael Magnus Hawkins, University of Birmingham 
Julie Kelly, University of Birmingham 
Raoul Reulen, University of Birmingham 
David Lindsell Winter, University of Birmingham 

Keywords: subsequent primary cancer, childhood cancer, radiation

Background and Methods National large-scale and principally population-based investigations of subsequent primary cancers (SPCs) after childhood cancer were initiated within Britain in the 1980s. Cohort studies have provided absolute risks and nested case-control studies have addressed dose-response relationships between cumulative exposure to radiation and particular cytotoxic drugs and the risk of specific types of SPC. The British Childhood Cancer Survivor Study (BCCSS) comprises 18000 individuals diagnosed with cancer before aged 15 years, in Britain between 1940 and 1991, and who survived at least 5 years from diagnosis. A particular advantage of the BCCSS relates to its relatively long period of follow-up available for analysis. A critically important unanswered question concerning survivors of childhood cancer as increasingly large numbers reach mature adulthood relates to their risks of those diseases which are common among mature adults in the general population including cancer and circulatory diseases. Diseases which are common in the general population pose a particularly serious concern in relation to survivors because even relatively modest multiplicative excess risks may result in substantial additional numbers of survivors being affected. The greater the background risk in the general population the larger the additional number of survivors affected.

Selected recent results Most recent consideration (1) of the Absolute Excess Risk (AER) of deaths from specific causes by duration of follow-up from diagnosis within the BCCSS indicates that between 5 to 14 years from diagnosis the percentage of the total AER attributable to recurrence, SPCs and circulatory cancers were 85%, 7% and 2% respectively. The corresponding percentages beyond 45 years from diagnosis were 7%, 51% and 26%, respectively (1). Consideration of the AERs associated with specific cancers which are common in mature adults in the general population (specifically - digestive, genitourinary, breast and lung cancer) reveals that among survivors aged 5 to 19 years the percentage of the overall AER attributable to these cancers were 8%, 2%, 1% and 2% respectively (2). However, among survivors aged over 40 years the percentage of the overall AER attributable to these cancers were 18%, 18%, 7% and 9% respectively. In aggregate, 52% of the AER is attributable to these four cancers among survivors aged over 40 years (2). The cumulative incidence of colorectal cancer was investigated in relation to attained age among the sub-cohort who had received direct abdominopelvic irradiation and the observed cumulative incidence consistently exceeded that expected among individuals with two first degree relatives diagnosed with colorectal cancer (2). Within a recently published cohort study and nested case-control study including 247 subsequent primary CNS tumours (of which 137 were meningiomas and 73 were gliomas) 3.6% were affected by 40 years of follow-up (2.3% for meningioma and 0.8% for glioma). Among those who had been irradiated for a first primary CNS tumour, 9.1% were affected by 40 years of follow-up (6.3% for meningioma and 2.4% for glioma) (3). Within the nested case-control study the relative risks of meningioma were 1, 1.1, 35.1, 57.8, 69.6 and 94.2 corresponding to meningeal tissue exposed to 0, 0.01 to 9.99, 10.00 to 19.99, 20.00 to 29.99, 30.00 to 39.99 and at least 40 Gy, respectively (3). The corresponding relative risks of glioma were 1, 0.5, 0.5, 2.6, 3.4 and 4.4, respectively, in relation to similar exposure categories for the relevant brain tissue (3). The Excess Relative Risk of meningioma and glioma increased linearly with increased cumulative exposure to radiation in Gy with values of 5.1 (95%CI, 0.7 to 107.7) and 0.079 (95%CI, 0.021 to 0.229) per Gy (3).

Conclusions and future work • The absolute risk of colorectal cancer among those who received direct abdominopelvic irradiation raises the question of extending routine screening to this group. This is under consideration by the National Health Service bowel cancer screening program in Britain. Implications for survivorship guidelines also need careful consideration. • Our finding that the majority (52%) of the total AER, among survivors aged at least 40 years, was attributable to digestive, genitourinary, breast and lung cancers confirms the importance of these cancers which account for 74% of all incident cancers in the general population of the UK. • The risk of meningioma was strongly and linearly related to dose. This raises the question of screening with magnetic resonance imaging or computed tomography and this raises the question of whether neurosurgical intervention at an early stage would be beneficial. • PanCareSurFup, a European Commission funded international collaborative study involving many European countries, has a large cohort within which a nested case-control study of subsequent primary digestive and genitourinary cancers is being undertaken. 1. R.C. Reulen, D.L. Winter, C. Frobisher, E.R. Lancashire, C.A. Stiller, M.E. Jenney, R. Skinner, M.C. Stevens and M.M. Hawkins, Long-term Cause-Specific Mortality Among Survivors of Childhood Cancer. JAMA. 304, 172-179 (2010). 2. R.C. Reulen, C. Frobisher, D.L. Winter, J. Kelly, E.R. Lancashire, C.A. Stiller, K. Pritchard-Jones, H.C. Jenkinson and M.M. Hawkins, Long-term Risks of Subsequent Primary Neoplasms Among Survivors of Childhood Cancer. JAMA. 305, 2311-2319 (2011). 3. A.J. Taylor, M.P. Little, D.L. Winter, E. Sugden, D.W. Ellison, C.A. Stiller, M. Stovall, C. Frobisher, E.R. Lancashire and M.M. Hawkins, Population-based Risks of CNS Tumors in Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 5287-5293 (2010).