Original Article
Cancer Incidence Patterns Among Children and Adolescents in Taiwan From 1995 to 2009: A Population-Based Study Giun-Yi Hung, MD1,2,3; Jiun-Lin Horng, PhD4; Yu-Sheng Lee, MD2,3,5; Hsiu-Ju Yen, MD1,2,3; Chao-Chun Chen, MD1,2,3; and Chih-Ying Lee, MD1,2,3
BACKGROUND: Currently, little information is available on childhood cancer incidence rates in Eastern Asia. The objective of this study was to report the first population-based cancer surveillance of children and adolescents in Taiwan. METHODS: Data from the Taiwan Cancer Registry were examined for cancer frequencies and incidence rates among individuals ages birth to 19 years from 1995 to 2009. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates were compared by sex and age. For further comparisons with other countries, rates were age standardized to the 2000 world standard population in 5year age groups. Trends in incidence rates also were evaluated. RESULTS: In total, 12,315 individuals were diagnosed with childhood cancers, for an age-standardized incidence rate (ASR) of 132.1 per million person-years from 1995 to 2009. The male-to-female incidence rate ratio was 1.19. Overall, leukemias were the most common cancer (ASR, 39.1 per million person-years), followed by central nervous system neoplasms (15.8 per million person-years), and lymphomas (15.3 per million person-years). During the 15-year study period, the incidence rates increased by 1% annually. Compared with other countries, the rate of hepatic tumors was 2 times greater in Taiwan. The rate of germ cell neoplasms in Taiwan was similar to that in the United States and was 1.3 to 1.9 times greater compared with Canada, Brazil, Israel, and Japan. CONCLUSIONS: Based on the current data, the observed increase in overall incidence rates was attributable only marginally to improvements in case ascertainment and diagnostic procedures. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in the background risk factors. Cancer 2014;120:3545-53. C 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article V under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. KEYWORDS: adolescents, cancer, childhood, epidemiology, incidence, Taiwan.
INTRODUCTION Childhood cancer is rare, comprising approximately 1% of all cancers in the United States and Europe.1-3 Epidemiological surveillance is very difficult because of the diversity and rarity of childhood cancer. Currently, little information is available for approximately 80% of the world’s population living the developing countries.3-5 In Taiwan, children and adolescents (ages birth to 19 years) make up 21.3% of the total population (4,975,411 of 23,344,213 individuals in June 2013).6 In this age group, Taiwan Cancer Registry (TCR) data demonstrate that the average annual numbers of newly diagnosed cancer cases and cancer deaths were 842 and 252, respectively, from 1995 to 2009,7 representing 0.9% of all newly diagnosed cancer cases and 0.49% of cancer deaths in 2009. Childhood cancers are grouped more meaningfully according to histology and primary site based on the standard scheme of the International Childhood Cancer Classification (ICCC).8 In a previous TCR report on childhood cancer incidence, childhood cancers were categorized only according to the 12 main ICCC groups and were not categorized further into the 47 subgroups.9 Thus, by examining the reported data over the 15-year period from 1995 to 2009, the objectives of this study were to fill the data gap in the childhood cancer incidence in Taiwan according to the 47 ICCC subgroups, to contribute to etiologic research, and to highlight the importance of public health. We analyzed the data targeted at the age range from birth to 19 years because most childhood cancers affect children ages birth to 14 years, but
Corresponding author: Giun-Yi Hung, MD, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan, Republic of China; Fax: (011)1886-2-28739019;
[email protected] 1 Division of Pediatric Hematology and Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; 3Department of Pediatrics, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4Department of Anatomy, Taipei Medical University, Taipei, Taiwan; 5Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan
We express our deep gratitude to the Taiwan Cancer Registry staff for their contributions in data collection, validation, and routine analyses. We also are grateful to Dr. Shu-Chiung Chiang (Institute of Hospital and Health Care Administration, National Yang-Ming University) for statistics consulting. We greatly appreciated the valuable comments suggested by anonymous reviewers from the journal Cancer. DOI: 10.1002/cncr.28903, Received: December 28, 2013; Revised: April 13, 2014; Accepted: June 5, 2014, Published online July 16, 2014 in Wiley Online Library (wileyonlinelibrary.com)
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some peak at ages 15 to19 years; thus, we wanted to follow the international standards recommended by the International Agency for Research on Cancer (IARC), in which the suggested age range is from birth to 19 years, whenever possible instead of ages birth to 14 years.10 Furthermore, it is known that ethnic variations exist in the incidence of childhood cancer.4 Because up to 98% of the population of Taiwan is Han Chinese,6 in this study, we also wanted to provide more comprehensive information for comparing data on Han Chinese with data from other ethnic groups.
the 12 major ICCC-3 groups as follows: leukemias included leukemias, myeloproliferative diseases, and myelodysplastic diseases; lymphomas included lymphomas and reticuloendothelial neoplasms; central nervous system (CNS) neoplasms included CNS and miscellaneous intracranial and intraspinal neoplasms; neuroblastomas included neuroblastoma and ganglioneuroblastoma; soft tissue sarcomas (STS) included soft tissue and other extraosseous sarcomas; germ cell neoplasms included germ cell tumors (GCTs), trophoblastic tumors, and neoplasms of the gonads; and other epithelial neoplasms included other malignant epithelial neoplasms and malignant melanomas.
MATERIALS AND METHODS Data Collection
Analyses
Incidence data for this study were obtained from the TCR, which is organized and funded by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. The TCR is population-based and began registration of all cancers in 1979. In addition, Taiwan’s National Health Insurance program, a mandatory universal health insurance program with a coverage rate of up to 99%,11 was first launched in 1995, enabling all individuals to easily access medical services and prompt treatment. After the enactment of the Cancer Control Act in 2003, hospitals with a capacity of >50 beds that provided outpatient and hospitalized cancer care were mandated to submit cancer data to the central cancer registry, which enhanced the completeness of registration and case ascertainment and improved the quality of cancer data collection.7,9 In terms of data quality of the TCR according to the quality indicators defined by the IARC, the percentage of death certificate only cases (DCO%) fell from 19.63% in 1995 to 1.15% in 2009. The percentage of microscopically verified cases (MV%) is another indicator of data validity; and, although it varies according to the type of cancer, the MV% was 90.75% in 2009 for all cancers combined. The indicators described above reveal the high quality of the TCR and its remarkable improvement over time. The incidence rates for all cancers in children and adolescents (age range, from birth to 19 years) diagnosed from 1995 to 2009 were analyzed. Diagnoses were categorized into 12 main groups and 47 subgroups according to the ICCC version 3 (ICCC-3).8 Only patients who were diagnosed with malignant tumors were included in the data. Patients who had tumors that were not classified by the ICCC-3 or who had in situ cancers were excluded from the final analysis to enable a comparison of the incidence between different countries. We abbreviated 7 of
Crude rates and age-standardized incidence rates (ASRs) were expressed per million person-years according to sex and are presented in accordance with the ICCC-3 into the main groups and subgroups described above. Rates, cumulative risks, standard errors, and 95% confidence intervals (CIs) were calculated according to previously published methods.12 An ASR is a weighted average of the agespecific (crude) rates, in which the weights are the proportions of individuals in the corresponding age groups of a standard population. The potential confounding effect of age is reduced when comparing ASRs that are computed using the same standard population. In this study, ASRs were calculated by the direct method, using the 2000 world standard population based on 5-year age groups (ages birth to 4 years, 5-9 years, 10-14 years, and 15-19 years),12 and were used to compare the rates with those in other countries. Incidence rates by single-year age were compared for specified disease groups as follows: leukemias, lymphomas, CNS neoplasms, germ cell neoplasms, embryonal tumors (including neuroblastomas, retinoblastoma, nephroblastoma, and hepatoblastoma), and certain adolescent tumors (including hepatic carcinomas, osteosarcomas, other specified STS, thyroid carcinomas, and nasopharyngeal carcinomas). Trends were analyzed using the Joinpoint regression model and permutation tests (Joinpoint Regression Program, version 4.0.4; Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute, Bethesda, Md) to identify significant changes13,14 in which up to 3 joinpoints were produced to express the annual percentage change (APC). This software takes trend data and fits the simplest joinpoint model that the data allow. The program starts with the minimum number of joinpoints and tests whether more joinpoints are statistically significant and must be added to the model. The grid search described by Lerman in 1980 was used to
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fit the segmented regression function, the P value of each permutation test was estimated using Monte-Carlo methods, and the overall asymptotic significance level was maintained through a Bonferroni adjustment.14 The APC was considered significant if the 95% CI did not include zero. To compare our data with the cancer incidence data for children and adolescents ages birth to 19 years from other countries, we compiled world rates by searching the databases available from the internet (Medline, National Center for Biotechnology Information, PubMed) and the annual reports of national cancer registries. RESULTS In total, 12,315 patients ages birth to 19 years were diagnosed with childhood cancers from 1995 to 2009, for a crude rate of 130.97 and an ASR of 132.08 per million person-years (Table 1). The cumulative risk of developing cancer at an age 2) were observed for Burkitt lymphoma, intracranial and intraspinal GCTs, and nasopharyngeal carcinomas. Gonadal carcinomas occurred almost exclusively in females, with an M/F IRR of only 0.02. Females also predominated in other and unspecified malignant gonadal tumors, thyroid carcinomas, other specified malignant bone tumors, other specified and unspecified CNS neoplasms and malignant melanomas, with M/F IRRs ranging from 0.20 to 0.83. Incidence Rate by Age
The age patterns of certain cancer groups are depicted in Figure 1. For leukemias (Fig. 1a), the most common subgroup was lymphoid leukemias, with a distinct peak observed among children ages 2 to 3 years. No apparent difference was observed in the age patterns of CNS neoplasm subtypes (Fig. 1b), except that intracranial and intraspinal embryonal tumors were more common before age 10 years. For lymphomas (Fig. 1c), the incidence of non-Hodgkin lymphomas gradually increased with age and reached a peak in adolescence. Hodgkin lymphoma was rare before age 11 years; however, there was a gradual increase in the incidence with age. In contrast to nonHodgkin lymphoma and Hodgkin lymphoma, which were reported mainly during the second decade of life, the incidence of miscellaneous lymphoreticular neoplasms peaked in infancy, then declined rapidly during ages 1 to 4 years to a rate that was almost zero thereafter. The patterns of age-specific incidence of principle embryonal tumors and certain adolescent tumors are depicted in Figure 1d,e; note that the former peaked during infancy in contrast to the latter, which peaked during adolescence. In the subgroups of germ cell neoplasms (Fig. 1f), the incidence rates of malignant gonadal GCTs and extracranial and extragonadal GCTs both peaked during the first year of life, and another peak during puberty also was observed. Temporal Trends
Cancer incidence trends varied according to the ICCC groups (Table 2). Overall, the APC for total cancers was 3547
TABLE 1. Annual Cancer Incidence Rates (per Million) Among Children and Adolescents Aged Birth to 19 Years by Sex and International Classification of Childhood Cancer, Version 3 Group and Subgroup: Taiwan, 1995 to 2009a Both Sexes
Males a
Females a
No.
ASRa
M/F IRR
ICCC-3 Group
No.
Crude Rate
ASR
No.
ASR
I. Leukemias Lymphoid leukemias Acute myeloid leukemias Chronic myeloproliferative diseases Myelodysplastic syndrome and other myeloproliferative diseases Unspecified and other specified leukemias II. Lymphomas Hodgkin lymphomas Non-Hodgkin lymphomas except Burkitt lymphoma Burkitt lymphoma Miscellaneous lymphoreticular neoplasms Unspecified lymphomas III. CNS neoplasms Ependymomas and choroid plexus tumor Astrocytomas Intracranial and intraspinal embryonal tumors Other gliomas Other specified intracranial and intraspinal neoplasms Unspecified intracranial and intraspinal neoplasms IV. Neuroblastomas Neuroblastoma and ganglioneuroblastoma Other peripheral nervous cell tumors V. Retinoblastoma VI. Renal tumors Nephroblastoma and other nonepithelial renal tumors Renal carcinomas Unspecified malignant renal tumors VII. Hepatic tumors Hepatoblastoma Hepatic carcinomas Unspecified malignant hepatic tumors VIII. Malignant bone tumors Osteosarcomas Chondrosarcomas Ewing tumor and related sarcomas of bone Other specified malignant bone tumors Unspecified malignant bone tumors IX. Soft tissue sarcomas Rhabdomyosarcomas Fibrosarcomas, peripheral nerve sheath tumors, and other fibrous neoplasms Kaposi sarcoma Other specified soft tissue sarcomas Unspecified soft tissue sarcomas X. Germ cell neoplasms Intracranial and intraspinal germ cell tumors Malignant extracranial and extragonadal germ cell tumors Malignant gonadal germ cell tumors Gonadal carcinomas Other and unspecified malignant gonadal tumors XI. Other epithelial neoplasms Adrenocortical carcinomas Thyroid carcinomas Nasopharyngeal carcinomas Malignant melanomas Skin carcinomas Other and unspecified carcinomas XII. Other and unspecified malignant neoplasms Other specified malignant tumors Other unspecified malignant tumors Total
3520 2258 888 211 46
37.43 24.01 9.44 2.24 0.49
39.12 25.64 9.55 2.11 0.52
2004 1309 485 123 26
42.70 28.44 10.06 2.35 0.56
1516 949 403 88 20
35.24 22.61 8.99 1.86 0.47
1.21 1.26 1.12 1.26 1.18
117 1470 324 721 168 149 108 1449 148 606 415 206 45 29 587 561 26 228 243 205 37 1 424 145 183 96 705 525 46 79 43 12 933 288 116
1.24 15.63 3.45 7.67 1.79 1.58 1.15 15.41 1.57 6.44 4.41 2.19 0.48 0.31 6.24 5.97 0.28 2.42 2.58 2.18 0.39 —b 4.51 1.54 1.95 1.02 7.50 5.58 0.49 0.84 0.46 0.13 9.92 3.06 1.23
1.30 15.27 3.15 7.38 1.88 1.78 1.09 15.76 1.67 6.45 4.61 2.21 0.50 0.32 7.17 6.90 0.27 2.87 2.88 2.50 0.37 —b 4.61 1.81 1.84 0.97 6.98 5.16 0.44 0.83 0.43 0.12 9.66 3.17 1.18
61 963 207 481 123 85 67 805 85 309 243 133 22 13 346 327 19 129 133 111 22 0 267 87 118 62 414 311 30 48 18 7 511 167 70
1.29 19.29 3.94 9.50 2.63 1.91 1.31 16.85 1.85 6.34 5.19 2.72 0.46 0.28 8.07 7.69 0.38 3.10 3.03 2.61 0.42 —b 5.54 2.08 2.28 1.18 7.88 5.88 0.56 0.95 0.34 —b 10.18 3.52 1.36
56 507 117 240 45 64 41 644 63 297 172 73 23 16 241 234 7 99 110 94 15 1 157 58 65 34 291 214 16 31 25 5 422 121 46
1.32 10.93 2.30 5.08 1.05 1.63 0.85 14.59 1.47 6.58 3.97 1.65 0.55 0.36 6.20 6.05 —b 2.62 2.71 2.38 0.31 —b 3.62 1.52 1.35 0.74 6.02 4.39 0.32 0.69 0.52 —b 9.09 2.80 0.99
0.98 1.76 1.71 1.87 2.49 1.17 1.53 1.15 1.25 0.96 1.31 1.65 0.83 0.78 1.30 1.27 —b 1.18 1.12 1.10 1.35 —b 1.53 1.37 1.68 1.59 1.31 1.34 1.79 1.37 0.65 —b 1.12 1.26 1.38
5 429 95 1267 214 341 605 91 16 1376 12 544 181 63 77 499 113 23 90 12315
—b 4.56 1.01 13.47 2.28 3.63 6.43 0.97 0.17 14.63 0.13 5.79 1.92 0.67 0.82 5.31 1.20 0.24 0.96 130.97
—b 4.29 0.96 13.29 2.17 3.68 6.43 0.85 0.16 13.29 0.14 5.17 1.71 0.65 0.76 4.86 1.17 0.23 0.94 132.08
1 217 56 683 148 228 302 2 3 576 3 106 134 29 41 263 65 11 54 6896
—b 4.20 1.07 14.08 2.87 4.51 6.61 —b —b 10.78 —b 1.97 2.45 0.58 0.77 4.94 1.32 0.22 1.09 142.81
4 212 39 584 66 113 303 89 13 800 9 438 47 34 36 236 48 12 36 5419
—b 4.39 0.83 12.42 1.41 2.79 6.22 1.72 0.27 15.98 —b 8.59 0.91 0.72 0.75 4.77 1.01 0.24 0.78 120.43
—b 0.96 1.29 1.13 2.03 1.62 1.06 0.02 0.20 0.67 —b 0.23 2.68 0.80 1.02 1.03 1.30 0.94 1.41 1.19
Abbreviations: ASR, age-standardized rate; CNS, central nervous system; ICCC-3, International Classification of Childhood Cancer, version 3; M/F IRR, maleto-female incidence rate (age-standardized rate) ratio. Data include malignant tumors only. a ASRs are per 1 million person-years and were age adjusted to the 2000 world standard population. b There were
