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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