Pediatr Blood Cancer 2007;48:453–459 Risk of a Second Malignant Neoplasm Among 5-Year Survivors of Cancer in Childhood and Adolescence in British Columbia, Canada Amy C. MacArthur, MHSc, 1 John J. Spinelli, PhD, 1,2,3 Paul C. Rogers, MBChB, 4 Karen J. Goddard, FRCP, 5 Norm Phillips, MA, MSc, 6 and Mary L. McBride, MSc 1,2 * INTRODUCTION As a result of improvements in therapies for childhood and adolescent cancers in the last several decades, survival rates are increasing. However, those same cancer therapies have been shown to increase risk of a subsequent cancer among survivors [1,2]. Recent published reports suggest that the risk of developing a second malignancy in cohorts of 3- or 5-year survivors is 3 to 15 times greater than the incidence in the general population, and that the cumulative risk varies between 2% and12% at 20 years after the original diagnosis [1–4]. Early studies of small, homogeneous, clinic-based cohorts with short follow-up periods reported somewhat higher incidence ratios, approaching 20-fold excess risks in comparison to the general population [5]. The Childhood Cancer Survivor Study (CCSS), which followed a large multi-center cohort of childhood cancer patients with selected diagnoses in the US and Canada between 1970 and 1986, reported an SIR of observed-to-expected second cancers of 6.4 [6]. Population-based cohorts from the UK and five Nordic countries have reported SIRs of 6.2 and 3.6 respectively [7,8], but these studies did not examine risk among survivors diagnosed during the 1990s. A population- based cohort that followed patients diagnosed with an original cancer before the age of 25 years through the 1990s reported an SIR of 4.4 for second malignancies [9], whereas a small clinic-based study from Slovenia reported an SIR of 8 [10]. Research also indicates that, while the major determinant of a second cancer is treatment (including high-dose radiation therapy and certain chemotherapy agents), risk may vary according to the patient’s gender, age at diagnosis of the original cancer, and genetic predisposition to cancer [2,3,11]. In order to address second cancer risk, more information is needed among the total population of survivors, with extensive follow-up, and on risks to cohorts diagnosed during different treatment eras. For this study, we utilized the population-based cancer registry to investigate the risk of developing a second malignant neoplasm (SMN) among a cohort of 5-year childhood cancer survivors originally diagnosed with a Background. We examined second malignancies, a recognized late effect of therapy among survivors of childhood and adolescent cancer, among a recent, population-based cohort of 2,322 5-year survivors diagnosed before 20 years of age in British Columbia (BC), Canada between 1970 and 1995. Procedure. Survivors and second malignancies were identified from the BC Cancer Registry. Risk of second malignancy was evaluated using standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative risk. The effect of demographic, temporal, and disease-related characteristics on risk was assessed. Results. Fifty-five second malignancies were observed after 26,071 person-years of follow-up. Relative rate of developing a second malignancy among survivors was 5 times higher than expected (SIR ¼ 5.0, 95% CI, 3.8–6.5), and absolute excess risk was 1.7 deaths per 1,000 person-years. Cumulative incidence of a second malignancy was 5.1% at 25 years after diagnosis of the first cancer. SIRs and absolute excess risk of subsequent cancer was higher among females (SIR ¼ 5.9, 95% CI, 4.5–8.3 and AER ¼ 2.66). While relative risk of second cancer was higher for those diagnosed before 10 years of age (SIR ¼ 10.6, 95% CI, 7.1–16.0), absolute excess risk was slightly higher for those diagnosed after 10 years of age. SIRs were significantly elevated for all follow-up periods, but absolute excess risk of a second cancer was highest among patients surviving more than 15 years. Conclusions. Increased risk of a subsequent neoplasm is evident among childhood cancer survivors diagnosed in more recent periods than has been previously reported, continues years after diagnosis, and varies according to several risk factors. Continued surveillance is essential to quantify and characterize long-term and changing risks for appropriate follow-up. Pediatr Blood Cancer 2007;48:453–459. ß 2006 Wiley-Liss, Inc. Key words: childhood and adolescent cancers; late effects; second malignant neoplasm; subsequent cancer; survivorship research ß 2006 Wiley-Liss, Inc. DOI 10.1002/pbc.20921 —————— 1 Cancer Control Research Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 2 Department of Health Care and Epidemiology, University of British Columbia, Vancouver, British Columbia, Canada; 3 Department of Statistics and Actuarial Science, Simon Fraser University, Vancouver, British Columbia, Canada; 4 Division of Oncology, Hematology, and Bone Marrow Transplant, British Columbia Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada; 5 Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 6 Population and Preventive Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada Grant sponsor: Canadian Institute for Health Research; Grant sponsor: The Michael Smith Health Research Foundation. *Correspondence to: Mary L. McBride, Cancer Control Research Program, BC Cancer Research Centre, BC Cancer Agency, 2-107, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3. E-mail: mmcbride@bccrc.ca Received 17 October 2005; Accepted 8 May 2006