Chapter 444. Epidemiology of Childhood Cancer

Childhood cancer is a rare disease diagnosed in around 1 in 600 children under age 15 years. This is in marked contrast to adults, for whom the lifetime risk of cancer is 1 in 3. Nonetheless, cancer is an important cause of death in children. After the first year of life, during which mortality is high largely due to congenital anomalies and complications arising from pregnancy and birth, cancer is the single most common disease-related cause of death in children and accounts for around a quarter of all childhood deaths due to disease. In 2004 in the United States, there were 11,619 deaths in children ages 1 to 14 years; of these, 5365 were due to disease and 26% of these (ie, 1418) were due to cancer (eTable 444.1).1

In adults, the majority of cancers are carcinomas, which arise in the epithelium of the colon, breast, lung, bladder, and skin. In children, carcinomas are rare, and the spectrum of disease is quite different to that in adults. In Canada from 2000 to 2004, leukemias accounted for around 33% of childhood malignancies, brain and other central nervous system tumors for 20%, lymphoma for 12%, neuroblastoma for 7%, soft tissue for 6%, renal tumors for 5%, bone tumors for 4%, and the remaining 13% represented a collection of very rare tumors (Fig. 444-1).2 The distribution is similar in other geographic areas.3,4 Over the course of childhood, the types of cancers change: In infants, the most common form of cancer is neuroblastoma (25% of cancer diagnoses) and for 1- to 14-year-olds, the most common is leukemia (42% of cases, ages 1–4; 34% of cases, ages 5–9; and 22% of cases ages 10–14; eFig. 444.1).2 The outcome for children with cancer varies with the type of disease, as discussed below. Overall, the rate of cancer is about 20% higher in boys than in girls, with the difference being most marked for lymphomas, which are twice as common in boys (eFig. 444.2).2

Rates of childhood cancer have been reported for many countries in national and local registries, and much of these data have been assembled by the International Agency for Research in Cancer (IARC) in Lyon, France (http://www.iarc.fr/).5 In contrast to the United Kingdom and Canada, there is currently no national childhood cancer registration in the United States, but a sample of US cases are reported in the SEER (Surveillance Epidemiology Endpoints Results) data set (http://seer.cancer.gov/), which covers around 26% of the US population.

Across the 15-year age span, infants and 1- to 4-year-old children have the highest rates of malignant disease (226 per million per year and 214 per million per year, respectively, in Canada, 2000–2004). Rates in older children are lower: 115 and 117 per million per year for those ages 5 to 9 and 10 to 14 years, respectively (eFig. 444.3).2

Rates of childhood cancer can vary between and within countries and can even differ between different communities within the same city. For example, the rate of childhood cancer reported for Canada was 158 per million per year for males, with a variation of 108 to 171 between provinces. The equivalent numbers for females were 135 with a range of 95 to 159.6 In the United States, SEER data reports a rate of 163 per million per year for boys, with the within-country rate ranging from 97 in the black community of Los Angeles to 216 in the white community of Atlanta. The SEER rate for girls is 144, with an intercountry range of 90 to 204.6 In Europe, rates range from 114 to 250 for boys and from 89 to 170 for girls.7 Hence, within Europe and North America, the incidence of childhood cancer varies by a factor of around 2 between countries and between communities (eTables 444.2 and 444.3). For childhood leukemia and brain tumors, which together make up more than half of all childhood cancer cases, the between- and within-country variation in rates is greater and nearer to threefold. The reasons for these variations are not well understood and are likely to include differences in genetic susceptibility and environment and lifestyle (see “Causes and Risk Factors for Childhood Cancer,” below).

There have been concerns about whether the incidence rate of childhood cancer is increasing. Certainly the incidence of childhood leukemia increased from the first to the second half of the 20th century, with the peak in incidence occurring at around age 4 to 6 years. The extent to which childhood cancer rates, both overall and by disease group, have increased in more recent decades is unclear.

In the United States, analysis of the SEER data for 1992 to 2004 showed no significant trends. However, there was an incidence of all pediatric tumors of around 0.4% per year (95% CI, –0.1 –0.8%) and of leukemia of 0.7% per year (95% CI, –0.1–1.5%).8 In Canada, the most recent report on national cancer trends concluded that there is no evidence of a change in the rate of cancer in children in Canada between 1995 and 2004.2 In Europe, the Automated Childhood Cancer Information System (ACCIS) group reported increased rates of childhood cancer of around 1% per year using data from 63 European population-based registries.9 In the United Kingdom, there have been reports of increasing rates of solid tumors in the north of England, with rates of increase being different between tumor types and between boys and girls.10

There has been a dramatic decline in the mortality rate from childhood cancer in recent decades. For example, mortality from childhood cancer in Canada declined from around 40 per million per year in 1985 to a little over 20 per million per year in 2005. Similar declines have occurred in the United States and in Europe.2,3,4

For many kinds of childhood cancer, the development of multimodal therapies, including surgery, chemotherapy, radiotherapy, and stem cell transplantation, has led to dramatic changes in outcome over the last 50 years. The organization of the pediatric oncology/hematology clinical research community into a national and multinational cooperative group such as the US Children’s Oncology Group (COG, http://www.childrensoncologygroup.org/) and the UK Children’s Cancer and Leukaemia Group (CCLG, http://www.ukccsg.org/) and their predecessor organizations have played a significant part in this.

Five-year survival from childhood cancer was 82% for children in Canada who were diagnosed between 1999 and 20032 and was 75% for those diagnosed in the United Kingdom between 1992 and 1996.2,11 Survival varies by disease. For example, in the Canadian series, 5-year survival from retinoblastoma is approximately 99%. For the majority of childhood cancers, 5-year survival is high (leukemia, 85%; lymphoma, 89%; central nervous system and brain tumors, 75%). For neuroblastoma and bone tumors, survival remains lower, at around 70% (eTable 444.4).2 Survival for childhood cancer altogether and for the individual diseases varies greatly across countries not only between the developed and the developing world, but also within the developed world. For example, there are substantive differences in survival across Europe (eFigs. 444.4 and 444.5).12

The majority of children treated with cancer in the developed world will survive their disease and its treatments. About 1 in 1000 adults in their twenties and thirties are survivors of childhood cancer. However, survivors carry with them a health burden due to the initial disease and to its treatments.13 For example, relapse of the first cancer can occur after more than 20 years, and the risk of a second primary tumor is at least four times greater than the general cancer risk to the population. This risk increases with the intensity, duration, and types of treatment. For instance, radiotherapy to the chest is responsible for the high rate of breast cancer in Hodgkin disease survivors; lymphoma is a particular risk in those treated with bone marrow transplantation.14 Survivorship presents a major challenge for patients, health care professionals, and the health care system.

In adults, the majority of cancers arise from lifelong over- or underexposure to cancer-causing or cancer-protective factors, mostly in the food that we eat, the liquids that we drink, and the air that we breathe. The process of carcinogenesis is complex and multifactorial; seldom is there a single cause, and there is an interaction between the susceptibility of the individual and the plethora of cancer-causing and promoting exposures. By their very nature, children have had little opportunity to accumulate such lengthy and diverse exposures, and, just as the cancers themselves differ between adults and children, the causes also differ. There are a few rare genetic syndromes that result in an increased susceptibility to childhood cancers. These include bone marrow failure syndromes, such as Fanconi anemia, Schwachman-Diamond syndrome, and Diamond-Blackfan syndrome. Li-Fraumeni syndrome and neurofibromatosis represent other major cancer predisposition syndromes. Children with Down syndrome are at increased risk of acute leukemia. Children with congenital anomalies such as urogenital tract anomalies and Wilms tumor also have an increased risk of developing certain cancers. However, these conditions together likely account for less than 5% of all childhood cancers, and, with the exception of bilateral retinoblastoma, there is very little evidence of heritability of childhood cancer.15

Despite a substantial body of epidemiological investigation into the etiology of childhood cancers, especially over the past four decades, the cause or causes of the vast majority of cases remain unknown. There are several possible reasons for this, including the probability of childhood cancer arising from a complex and multifactorial process and the rarity of the disease, which makes it challenging to study.

There have been several reviews of the role etiological factors play in childhood cancer—especially leukemia. However, it is outside the scope of this chapter to review the substantial body of work in this area.16-18

Ionizing Radiation

Ionizing radiation can cause cancer in adults and in children. It was first postulated as a cause of childhood cancer by the pioneering British childhood cancer epidemiologist Alice Stewart. She found in her landmark case-control study of cancer deaths in Britain (the Oxford Survey of Childhood Cancer), that children whose mothers had been given x-rays during pregnancy were around two times more likely to develop leukemia and solid tumors than those whose mothers had not been exposed.19 Her findings were part of the evidence that led to the understanding that there is no threshold below which in utero radiation exposure is safe, hence restriction of using x-rays in pregnant women.20

There is little evidence that exposure to natural radiation (eg, to the radioactive gas radon) causes childhood cancer, though it is considered to be the second major cause of lung cancer after smoking and accounts for some 15% of lung cancer cases worldwide.21-23 However, it is extremely challenging to estimate lifelong radon exposures, even in children, in whom the time scales are necessarily shorter; therefore, reliable estimates of exposure are challenging to assemble.

While radiation can cause both hematologic and solid cancers in children, and while children are certainly more radiosensitive than adults, overall radiation exposure to mothers and their children is too low to account for more than a very small fraction of childhood cancer cases.

Infection

The role of infection and the infective process remains a focus for etiological studies of leukemia and other tumors. For leukemia, there is a sizeable body of evidence to suggest unusual patterns of antigen exposure plays a role,24 and evidence from twins and examination of blood samples taken early in life suggests that leukemia-related genetic changes occur in utero.25

Other Causes

There have been many investigations into the role of many potential carcinogens in the etiology of childhood cancer, and leukemia has been the focus of more studies than other cancers. Many studies have explored the association between cancer risk and exposure to potential carcinogens such as pesticides, herbicides, tobacco, some recreational drugs, and so on. In general, associations have been weak and not consistent between studies, and no single exposure has been indentified as causal in a sizable proportion of childhood cancer cases.26