Discussion
SEER 9 registries database used in this study allows us to study infant cancer incidence and survival over 40 years from 1975 to 2014. The SEER 11 and SEER 18 registries database have more geographic coverage, but only cover 23 years and 15 years respectively. This study assessed the incidence, temporal trends, and survival of cancer among infants (age younger than 1 year) and found the important secular trends in infant cancer incidence and survival over a 40-year period of observation in the U.S., using the International Classification of Childhood Cancer (ICCC-3)(11) – the standard classification of child tumors.
In this study, we found a 30% increase in incidence rates of cancer among infants from 20.5/100,000 in 1975-1984 to 26.5/100,000 in 2005-2014. The 40 years of data from 9 SEER registries support the increasing incidence trend and geographic variation in infant cancer incidence rates by sex, type, and race/ethnicity consistent with earlier reports.(5, 6, 13)   Although the reason for infant cancer incidence increase is largely unknown, but some believe that genetic, environmental factors and infectious agents play a significant role in cancer development(14). A study spearheaded by the Environmental Working Group (EWG) found an average of 200 industrial chemicals and pollutants in umbilical cord blood from babies. Tests found as many as 287 chemicals in umbilical cord blood, 180 of which are known to cause cancer in human or aminals.(15) Infectious agents are associated with cancer development and it is reported that about 20% of the world’s cancer burden is attributed to infectious agents(16).New Mexico had the lowest incidence rate compared with other registries, but experienced the largest temporal increase in four decades. New Mexico’s population is 46.4% Hispanic and 41.4% white in 2014 compared with 12.9% Hispanic and 63.9% white nationally(17). New Mexico has the largest Hispanic statewide population share nationally(18). The racial/ethnic composition might play a role. Since SEER9 does not have ethnicity data, further study are needed.
Significant increase trends were found for germ cell, sarcomas, and leukemia over the 40-year period.. It was reported that exposure to post-natal diagnostic x-rays is associated with the risk of childhood acute lymphoid leukemia (ALL), especially B-cell ALL.(19) For sarcomas, although the etiology remains unknown in most cases, environmental factors that increase sarcomas risk include exposure to radiation, chemical carcinogens, and viruses.(20) The heritable aspects of sarcoma have not extensively been studied, but genetic predisposition to sarcoma has been well characterized in some familial cancer syndromes.(21) Germ cell tumors are rare tumors contributing 2.9% to the cancer registry(22) and infancy is one of two peaks in age distribution for germ cell tumors, the other occurring during puberty. The potential influence of in utero exposure to maternal endogenous hormones, parental environmental exposures, and maternal disease during pregnancy relative to the development of childhood germ cell tumors has also been reported.(23) However, the mechanism of how these risk factors have contributed to the increasing trends for these cancers is not clear. For example, a recent study found that exposure to an intrauterine hyperglycemic environment due to maternal gestational diabetes does not increase the risk for pediatric cancer.(24)
The top three infant cancer incidence rates in the U.S., neuroblastomas, leukemia and CNS neoplasms, have also been reported by other countries including France(25) (16.7/100,000 in 2000-2004) and England(26) (16.7/100,000 in 1968-1995). On the contrary, the incidence rate of hepatic tumors was 2 to 5 times higher in China (Beijing and Taiwan) than other countries, which might be strongly related to the high infection rate of Hepatitis B and C among mothers(27) and suggests that genetic variations be considered as a risk factor for infant cancer in China.(28)
Previous epidemiological data reported the impact of cancer genetics and its implication for treatment, prognosis, and improving overall survival rates.(10, 29) However, only few causal factors have been identified for childhood cancer.(30, 31) Given the current surge of molecular biologic technology and DNA sequencing, the study of inherited factors, environmental and epigenetics have become fields of interest to identify predisposing factors for pediatric cancers(31). Although leukemia, sarcomas, and germ cell malignancies have experienced significant incidence increases in the past four decades, the risk factors associated with these changes are unknown.
Enhanced early detection likely contributed to the increased infant cancer incidence in the past four decades, but cannot fully explain the increasing incidence only for leukemia and sarcomas in males while not in females in some registries (such as New Mexico, Detroit and Utah). This suggests that a true increase exists, but it is possible that this difference could be explained by confounding factors such as poorer access and utilization of care by some populations.(32) Efforts should be made to identify the causes of these differences.
Several hypotheses, including maternal and early infancy dietary factors (i.e., determinants of high birth weight), paternal pre-conception occupational exposures and smoking, pre-natal and post-natal exposure to pesticides, and the interplay of maternal or early postnatal immune system response to common infections have been formulated.(33-35) However, causation warrants investigation not only with epidemiologic data but with prospective pregnancy - birth cohorts to minimize potential temporal-relationship or recall bias.(36)
Although survival rates for most infant cancers have improved in past four decades, the improvement has been especially dramatic for only a few cancers. The 5-year relative survival for hepatic tumors, lymphoma and leukemia have greatly improved. The advent of successful transplants using umbilical cord blood since in 1989 and Arsenic trioxide and Imatinib approved by FDA in 2000 and 2001 might have contributed to the dramatic survival improvement for leukemia.(37) Nearly all lymphoma diagnoses among infants younger than 1 year of age are miscellaneous lymphoreticular neoplasms.(38) Treatment advances and effective management of toxicities of treatment over time might have resulted in a significantly longer survival rate for lymphoma patients.(39, 40) Improved survival in brain and CNS tumors might be due to advanced imaging technology, enhanced surgical procedures and better postoperative surveillance with early diagnosis of recurrence and routine use of more effective chemotherapy.(41) The treatment changes of hepatic cancer over the past few decades with curative options such as liver transplantation, hepatic resection and radiofrequency ablation can explain the survival improvement for hepatic cancer.(42, 43)
This study has several strengths. The SEER 9 registries represent approximately 10% of the US population and contain data on more than 3 million cases of cancer.(44) Furthermore, SEER data are well validated, including consistency of histologic diagnosis.(45) This study also has several limitations. First, the change in morphology classification and diagnostic technology over time might have affected the tumor detection and incidence reporting, so that comparisons in this study with previous studies require caution. Second, because the rarity of infant cancers, small numbers of patients in some types were more likely to fluctuate yearly and lead to unstable statistics. Third, it should be recognized that the SEER only collects data about malignant neoplasms, so that the total frequency of tumors in infants in our study is likely underestimated. This limitation is particularly important for brain tumors. Finally SEER 9 does not have ethnicity variable which prevented us from investigating ethnic differences in cancer.
Conclusions : Our analysis suggests that cancer incidence among infants increased over time in U.S. The increasing trends were largely driven by three cancers - leukemia, germ cell and sarcoma and were present mainly among male infants. The overall survival for infant cancer has improved over the years especially since 1990 for hepatic tumors, lymphoma and leukemia. Further research is needed to explore the potential impacts of genetic, environmental, and perinatal factors for possible explanations for these increased cancer incidence trends.
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