Download Inferior survival among Aboriginal children with cancer in Ontario

Original Article
Inferior Survival Among Aboriginal Children With Cancer in
Ontario
Stacey Marjerrison, MD, MSc, FRCPC2; Jason D. Pole, PhD3; and Lillian Sung, MD, PhD1
BACKGROUND: Pediatric cancer distribution and outcomes have not been examined in Canadian Aboriginal children. The objective of
this study was to describe the distribution, event-free survival, and overall survival of Aboriginal children with malignancies who reside in Ontario compared with non-Aboriginal children. METHODS: This population-based study included 10,520 Ontario children
(aged <18 years) who were diagnosed with cancer between 1985 and 2011. Patients were identified from the Pediatric Oncology
Group of Ontario Networked Information System database. Aboriginal children were identified by self-reported ethnicity or postal
code on a Native reserve at diagnosis. Descriptive statistics of the patients were presented and compared using the Fisher exact test.
Event-free and overall survival probabilities were calculated for Aboriginal and non-Aboriginal children, described using Kaplan-Meier
curves, and compared using log-rank tests. RESULTS: In total, 65 Aboriginal children and 10,364 non-Aboriginal children with malignancy were identified. The distribution of malignancy type was similar between the 2 groups. There were no significant differences in
baseline characteristics, presence of metastatic disease, or treatment approach (clinical trial, standard of care, or individualized protocol) between the groups. The 5e-year event-free survival rate (6 standard error) was 56.3% 6 6.2% among Aboriginal children versus
72.8% 6 0.4% among non-Aboriginal children (P 5.0042), and the 5-year overall survival rate was 64% 6 6.0% versus 79.3 6 0.4%
(P 5.0017), respectively. The cause of death did not vary according to Aboriginal ethnicity. CONCLUSIONS: Survival was significantly
inferior among Aboriginal children who had cancer compared with non-Aboriginal children who had cancer in Ontario. Future studies
are required to define the etiology of this disparity, evaluate the issue nationally, and create interventions to improve outcomes for
C 2014 American Cancer Society.
Aboriginal children. Cancer 2014;000:000-000. V
KEYWORDS: Aboriginal, indigenous, child, pediatric, cancer, malignancy, survival, Canada.
INTRODUCTION
In Canada, Aboriginal peoples comprise those of First Nations, Inuit, or Metis heritage.1 Several studies have described
poor health outcomes among Aboriginal Canadians, and Aboriginal children in particular have higher rates of infant mortality, infections (respiratory tract infections and hepatitis A), chronic illnesses (diabetes), and injuries compared with
non-Aboriginal children.2-9 Although multifactorial, the reasons behind these poorer health outcomes for Aboriginal children are thought to be grounded in higher rates of poverty, household food insecurity, and substandard housing as well as
over-representation in the child welfare and youth criminal justice systems.2,9
In the United States, Native American (American Indian and Alaskan Native) children share many of the same characteristics and challenges as Canadian Aboriginal children. Demographically, these populations have in common similar
ethnic backgrounds,10 a proportion of their population living on self-governed lands (Native reserve/American Indian reservation) and a higher than average percentage of their population living below the poverty line.11 In contrast, Native
Americans make up a smaller proportion of the general population than Aboriginal Canadians (1% vs 4%)12 and have
higher rates of high school graduation (percentage gap compared with the general population, 28% vs 9.5%).13 From a
child health perspective, Native American children, like Canadian Aboriginal children, have higher rates of infant mortality, infections, and injuries than the general population.11 Native American children with cancer from the United States
have generally worse survival compared with non-Native American children.14-21 This association has been observed most
clearly in acute lymphoblastic leukemia (ALL)16,18,19 and neuroblastoma.15 Proposed reasons include advanced
Corresponding author: Stacey Marjerrison, MD, MSc, FRCPC, Division of Hematology/Oncology, McMaster Children’s Hospital, 1200 Main Street W, Hamilton ON,
L8N 3Z5, Canada; Fax: (905) 521-1703; [email protected]
1
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 2Division of Hematology/Oncology, McMaster Children’s Hospital,
Hamilton, Ontario, Canada; 3Pediatric Oncology Group of Ontario, Toronto, Ontario, Canada
We thank Dr. Loraine Marrett and Diane Nishri (Population Studies and Surveillance, Cancer Care Ontario) for methodological assistance and Alethea Kewayosh
and Usman Aslam (Aboriginal Cancer Control Unit, Cancer Care Ontario) for aid with protocol review and knowledge translation.
DOI: 10.1002/cncr.28762, Received: December 5, 2013; Revised: March 17, 2014; Accepted: April 1, 2014, Published online Month 00, 2014 in Wiley Online
Library (wileyonlinelibrary.com)
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Original Article
presentation at diagnosis15,18 and poorer adherence to
therapy.18 Genomic differences in susceptibility and
response to therapy may also play a role, as recently demonstrated in ALL.22-24 However, some studies have
reported the persistence of these survival differences when
adjusting for known risk factors16,19 and have suggested
that the issue may be a combination of biologic factors
and socioeconomic lack of access to care. Isolating these
factors to examine their relative contribution is difficult in
the US health system.
In contrast to the Native American literature from
the United States, cancer incidence and outcomes have
not been explored in Canadian Aboriginal children. There
are some important systemic differences between Canada
and the United States. All children with cancer in Canada
have universal access to health care. Furthermore, the Pediatric Oncology Group of Ontario (POGO), which was
established in 1983, ensures equitable access to care across
the province and provides standardized guidelines for cancer treatment and management. Care is provided by 5 pediatric oncology centers, 7 satellite centers, and the
Pediatric Interlink Community Cancer Nursing Program,
which provides single point access to care in the community for every child with a malignancy in the province.
Thus, challenges with access to care described in the
United States should not be a major factor in Ontario.
Given the description of generally poor health outcomes for Canadian Aboriginal children, there is an
urgent need for studies of cancer incidence and outcomes
in this group. Conduct of the current study in Ontario
allowed for evaluation within a system in which access to
care and ability to pay for health care costs should not be
issues and allowed us to explore some of the reasons proposed to explain disparity in survival in the US literature.
Our objectives were to describe the distribution, eventfree survival (EFS), and overall survival (OS) of Aboriginal
children with malignancies who reside in Ontario compared with non-Aboriginal children.
population-based, active registry that has been collecting
information prospectively on all cases of pediatric cancer
diagnosed and treated in the province of Ontario since
1985. Children who are diagnosed and treated at 1 of the
5 tertiary pediatric oncology centers located in the province are included in the database. The 5 tertiary centers
are The Children’s Hospital of Western Ontario (London), McMaster Children’s Hospital (Hamilton), The
Hospital for Sick Children (Toronto), The Kingston
General Hospital (Kingston), and The Children’s Hospital of Eastern Ontario (Ottawa). POGONIS captures
from 96% to 98% of children ages birth to 14 years who
are diagnosed with cancer in Ontario compared with the
Ontario Cancer Registry, although the capture rate (46%)
is much poorer for adolescents ages 15 to 17 years, largely
because of referral patterns of adolescent and young
adults, who attend adult treatment centers outside the
POGO network.25 POGONIS contains detailed information on each patient registered, including demographics (including postal code at the time of diagnosis),
timing of the cancer presentation, diagnostic details (such
as staging), treatment information, and outcomes, including relapse and death. Death information contained in
POGONIS is derived from information collected at each
site as well as through a linkage with the Ontario Cancer
Registry maintained by Cancer Care Ontario, which
obtains quarterly death information from the Registrar
General and from the Statistics Canada Vital Statistics
Death Database, ensuring virtually complete death data
collection at the national level and in the Ontario Cancer
Registry-linked data in POGONIS. It is noteworthy that
POGONIS also captures the ethnic background of each
patient as determined by the local data managers based on
self-reported ethnicity documented in the patient’s hospital chart. Research ethics approval for this study was
obtained from The Hospital for Sick Children, Toronto,
Ontario, Canada.
Outcome, Exposure, and Covariate Variables
MATERIALS AND METHODS
Population and Setting
We examined all malignancies among Aboriginal children
in Ontario compared with non-Aboriginal children. We
included children with de novo cancer diagnosed between
January 1, 1985 and January 1, 2011 who were aged <18
years at diagnosis.
Data Source
The data source was the POGO Networked Information
Systems (POGONIS) database. POGONIS is a
2
Our primary outcomes were EFS and OS. EFS was
defined as the time from diagnosis to either the first event
(relapse, second malignancy, or death, whichever occurred
first) or the end of the study period (January 1, 2011). OS
was calculated as the time from diagnosis to either death
or the end of the study period (January 1, 2011).
Aboriginal status was identified using 2 approaches,
namely, by self-reported ethnicity and by postal code of
residence at diagnosis. First, we included any child whose
reported ethnicity was categorized as Aboriginal (First
Nations, Metis, Inuit, or North American Indian) in the
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Inferior Survival in Aboriginal Children/Marjerrison et al
POGONIS database. Second, we used a previously developed approach that used postal code to describe Aboriginal status in adult cancer.26,27 Based on postal code,
patients were classified as Aboriginal if the postal code at
diagnosis was associated with >95% of inhabitants residing on an Aboriginal reserve. Patients were classified as
potentially Aboriginal if the postal code at diagnosis was
associated with 1% to 95% of residents living on an Aboriginal reserve. Patients were classified as not Aboriginal if
the postal code at diagnosis was not associated with inhabitants living on a reserve. The overall Aboriginal classification considered the child Aboriginal if either the ethnicity
or the postal code algorithm classified the child as Aboriginal. Children were classified as not Aboriginal if both
the ethnicity and the postal code information indicated
that the child was not Aboriginal. Children who were considered potentially Aboriginal by postal code and not
Aboriginal by ethnicity were excluded from the primary
analysis but were described.
Malignancy of all types were included and were categorized according to the International Classification of
Childhood Cancer, third edition.28 Potential covariates
included sex, age at diagnosis (<10 years vs 10 years),
body mass index (BMI) percentile below or above the fifth
to 95th percentiles for age and sex according to the Centers for Disease Control and Prevention,29 diagnostic era
(1985-1998 or 1999-2011), the presence of metastatic
disease, treatment approach (clinical trial, standard of
care, or individualized plan), and times to diagnosis and
treatment. Times to diagnosis and treatment were calculated from the first encounter with a health care professional and from the first visit to the tertiary care pediatric
oncology center, respectively. Causes of death were categorized as progressive cancer (including unresponsive disease, relapsed disease, second malignancy), treatmentrelated causes (infection, hemorrhage, organ failure),
other causes, and unknown cause of death.
Statistical Analysis
The characteristics of Aboriginal and non-Aboriginal children were presented with descriptive statistics and were
compared using the Fisher exact test. EFS and OS were
calculated for each International Classification of Childhood Cancer disease category, for ALL and acute myeloid
leukemia (AML) subtypes, and for a composite solid tumor group that included all nonleukemia or lymphoma
malignancies. Survival curves were described using the
Kaplan-Meier method, and Aboriginal and nonAboriginal groups were compared using the log-rank test.
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Causes of death were presented with descriptive statistics
and were compared using the Fisher exact test.
Sensitivity analyses were performed on the overall
EFS and OS data. The children who were identified as
potentially Aboriginal by postal code were included with
the Aboriginal children and then subsequently with the
non-Aboriginal children to determine the impact of misidentifying those children who were potentially Aboriginal
on the significance of the survival difference observed. A
second sensitivity analysis restricted the age of the children
included to those aged <15 years to determine the effect
of poorer capture of those ages 15 to 17 years.
All statistical analyses were performed using the SAS
statistical program (SAS-PC, version 9.2; SAS Institute,
Cary, NC). All tests of significance were 2-sided, and statistical significance was defined as P < .05.
RESULTS
During the study timeframe, 10,520 Ontario children
with malignancies were identified. Of these, 65 were
determined to be Aboriginal, 10,364 were determined to
be non-Aboriginal, and 91 were determined to be potentially Aboriginal. Of the 65 children who were identified
as Aboriginal, 63 were identified by self-reported ethnicity, demonstrating a sensitivity of 96.9% (95% confidence interval [CI], 88.4%-99.5%) using the combined
criteria as the gold standard. Postal code data, however,
only identified 19 Aboriginal children, demonstrating a
sensitivity of 29.2% (95% CI, 18.9%-42%). There were
17 children identified by stated ethnicity as Aboriginal
whose postal code was in the 1% to 95% on-reserve
group.
Sex, age distribution, BMI percentile, and diagnostic
era did not differ by Aboriginal ethnicity (Table 1). There
were no significant differences in malignancy distribution,
metastatic disease, or treatment plan between the Aboriginal and non-Aboriginal children. Times to diagnosis and
treatment also were similar between both groups,
although these data were missing for many of the children.
The potentially Aboriginal children were generally no different from the Aboriginal and non-Aboriginal children
with regard to these measures (Supporting Table 1) (see
online supporting information), with the exception that
there were more potentially Aboriginal children diagnosed in the earlier period.
Table 2 illustrates the comparison of EFS and OS by
Aboriginal status. Significantly inferior EFS and OS rates
were observed for Aboriginal children when all cancers
were combined (Figs. 1, 2). More specifically, the 5-year
EFS rate (6 standard error) was 56.3% 6 6.2% among
3
Original Article
TABLE 1. Characteristics of the Study Population of 10,429 Ontario Children With Malignancies by Aboriginal Status, 1985 to 2011
No. of Patients (%)
Characteristic
Males
Age at diagnosis
Median [IQR], years
<10 years
10 years
BMI percentile at diagnosis
<5%
5%-95%
>95%
Missing
Diagnosis era
1985-1998
1999-2011
Diagnosis
Leukemia
Acute lymphoblastic
Acute myeloid
Lymphoma
Solid tumors
Central nervous system
Neuroblastoma
Retinoblastoma
Renal
Hepatic
Bone
Soft tissue
Germ cell
Epithelial
Other
Metastatic disease
Missing
Time to diagnosis and treatment: Median [IQR], days
HCP to treatment
HCP to TCC
TCC to diagnosis
Diagnosis to treatment
Treatment plan
Clinical trial
Standard of care
Individualized protocol
Otherh
Aboriginal, N 5 65
Non-Aboriginal, N 5 10,365
Pa
38 (58.5)
5691 (54.9)
.62
5.3 [2.8-11.7]
42 (64.6)
23 (35.4)
6.6 [2.8-12.5]
6672 (64.4)
3692 (35.6)
.35b
1.00
2 (9.1)
18 (81.8)
2 (9.1)
43
278 (9.5)
2378 (81.7)
254 (8.7)
7459
1.00
1.00
1.00
31 (47.7)
34 (52.3)
4805 (46.4)
5559 (53.6)
.90
26 (40)
17 (26.2)
6 (9.2)
7 (10.8)
32 (49.2)
11 (16.9)
8 (12.3)
—c
0 (0)
—c
6 (9.23)
—c
0 (0)
0 (0)
0 (0)
8 (15.1)
12
3123 (30.1)
2446 (23.6)
490 (4.7)
1682 (16.2)
5585 (53.6)
2097 (20.2)
634 (6.1)
234 (2.3)
499 (4.8)
143 (1.4)
483 (4.7)
704 (6.8)
361 (3.5)
320 (3.1)
84 (0.8)
1873 (21.1)
1504
.10
.66
.13
.31
.48
.64
.06
.66
.08
.60
.13
1.00
.17
.27
1.00
.40
16 [2-40]
2 [1-15.5]
2 [0-6]
2 [0-19]
17 [5-44]
1.5 [0-12]
2 [1-7]
3 [0-15]
.30b,d
.46b,e
.52b,f
.29b,g
.21
.22
.59
.16
.37
15
23
18
3
(23.1)
(35.4)
(27.7)
(4.6)
3201
3306
2087
872
(30.9)
(31.9)
(20.1)
(8.4)
Abbreviations: BMI, body mass index; IQR, interquartile range; HCP, first seen by any health care professional; IQR, interquartile range; TCC, first seen at a tertiary care center.
a
P values were determined using the Fisher exact test except as indicated otherwise.
b
These P values were determined using the Wilcoxon rank-sum test.
c
The number of incident cases was suppressed because of privacy concerns (n < 5).
d
Data were missing for 53 patients in the Aboriginal group and 7944 patients in the non-Aboriginal group.
e
Data were missing for 53 patients in the Aboriginal group and 7886 patients in the non-Aboriginal group.
f
Data were missing for 0 patients in the Aboriginal group and 222 patients in the non-Aboriginal group.
g
Data were missing for 6 patients in the Aboriginal group and 786 patients in the non-Aboriginal group.
h
These include observation, death before treatment allocation, surgery alone, radiation alone, reduction of immunosuppression, therapy at an outside center,
and missing protocol data.
Aboriginal children versus 72.8% 6 0.4% among nonAboriginal children, whereas the 5-year OS rate was
64% 6 6% versus 79.3% 6 0.4% among Aboriginal and
non-Aboriginal children, respectively. This significant
difference in survival was maintained in the sensitivity
analyses (Supporting Tables 2 and 3) (see online support4
ing information). When considering single diseases,
including ALL and AML separately, there was no single
disease category with a statistically significant reduced
EFS or OS among Aboriginal children. However, for each
disease group in which there were at least 10 Aboriginal
children (ALL, leukemia, solid tumor, central nervous
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Inferior Survival in Aboriginal Children/Marjerrison et al
TABLE 2. Five-Year Event-Free and Overall Survival Probabilities for Ontario Children With Malignancies by
Aboriginal Status, 1985 to 2011
EFS: Mean 6 SE, %
OS: Mean 6 SE, %
Cancer Type
Aboriginal
Non-Aboriginal
Pa
Aboriginal
Non-Aboriginal
Pa
All cancers
Leukemia
ALL
AML
Lymphoma
Solid tumors
CNS
Neuroblastoma
Retinoblastoma
Renal
Hepatic
Bone
Soft tissue
Germ cell
Other epithelial
Other
56.3 66.2
47.3 6 10.2
60.5 6 12.6
16.7 6 15.2b
85.7 6 13.2b
56.3 6 8.8
45.5 6 15
62.5 6 17.1b
100b
NA
100b
50 6 20.4b
50 6 25b
NA
NA
NA
72.8 6 0.4
73.3 6 0.8
79.9 6 0.8
46.2 6 2.3
80 6 1
70.7 6 0.6
67.1 6 1.1
63.8 6 1.9
92.9 6 1.7
81.9 6 1.8
69.2 6 3.9
58.5 6 2.3
67.7 6 1.8
86.2 6 1.9
84.7 6 2.1
65.9 6 5.3
.004
.006
0.16
.15
.88
.097
.09
.93
.70
NA
.54
.77
.35
NA
NA
NA
64.0 6 6.0
54.6 6 10.3
72.8 6 11.7
16.7 6 15.2b
85.7 6 13.2b
65.6 6 8.4
54.5 6 15
75 6 15.3b
100b
NA
100b
50 6 20.4b
75 6 21.7b
NA
NA
NA
79.3 6 0.4
80.8 6 0.7
87.1 6 0.7
57.2 6 2.3
87.1 6 0.8
76.1 6 0.6
72.5 6 0.9
68.6 6 1.9
97 6 1.1
89.8 6 1.4
70.3 6 3.9
63.9 6 2.3
72.6 6 1.7
90.7 6 1.6
91.7 6 1.6
69.6 6 5.1
.002
.004
.32
.05
.38
.14
.13
.97
.80
NA
.54
.51
.90
NA
NA
NA
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; EFS, event-free survival; CNS, central nervous system; NA, not available
(because no Aboriginal children had these diagnoses); OS, overall survival; SE, standard error.
a
P values were determined using the log-rank test. Values in boldface indicate a statistically significant difference.
b
There were fewer than 10 children with this diagnosis.
Figure 1. Kaplan-Meier event-free survival was estimated for Aboriginal children compared with non-Aboriginal children during
the study period from 1985 to 2011. Event-free survival was inferior for the Aboriginal children (log-rank test at 5 years, P 5.004).
The number of patients still at risk is indicated below the graph.
system tumor), survival was always qualitatively worse for
Aboriginal children (Table 2). There were no patients
with multiple primary diagnoses among the Aboriginal
children, but there were 224 such patients (2.14%) in the
non-Aboriginal population. Qualitatively, the survival
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among the potentially Aboriginal children was generally
between that of the Aboriginal and non-Aboriginal
groups, although the difference rarely reached statistical
significance (Supporting Table 4). The cause of death did
not differ significantly between the Aboriginal and non5
Original Article
Figure 2. Kaplan-Meier overall survival was estimated for Aboriginal children compared with non-Aboriginal children during study
period from 1985 to 2011. Overall survival was inferior for the Aboriginal children (log-rank test at 5 years, P 5.002). The number
of patients still at risk is indicated below the graph.
Aboriginal children (Table 3), with the potentially Aboriginal children qualitatively distributed between these
groups (Supporting Table 5) (see online supporting information). Notably, cause of death was unknown in approximately 33% of Aboriginal children and in just over 20%
of non-Aboriginal children (Table 3).
DISCUSSION
The current results demonstrate that, although the distribution of cancers is similar, survival is significantly inferior among Aboriginal children with malignancies in
Ontario compared with non-Aboriginal children when all
cancers are considered. This finding highlights a major
disparity in outcome for Aboriginal children with cancer
despite universal access to health care and suggests that
these children should be the focus of future study and
intervention to improve their outcomes.
We were not able to identify a clear etiology for the
survival discrepancy. Many potential explanations for
poorer outcomes that could be driven by lower socioeconomic status were not supported by our data. The
observed difference in outcome was not explained by baseline characteristics, nutritional status (BMI at diagnosis),
or type of malignancy. With no significant differences in
the times to diagnosis and treatment or in the presence of
metastatic disease at diagnosis, there was no evidence that
6
TABLE 3. Causes of Death for Ontario Children
With Malignancies by Aboriginal Status, 1985 to
2011
No. of Patients (%)
Cause of Death
Progressive cancer
Treatment-related
Infection
Hemorrhage
Organ failure
Other treatment-related
Other
Unknown cause of death
a
Aboriginal,
N 5 25
Non-Aboriginal,
N 5 2333
Pa
14 (58.3)
2 (8.4)
0 (0)
1 (4.2)
0 (0)
1 (4.2)
0 (0)
8 (33.3)
1495 (64.25)
250 (10.7)
57 (2.5)
32 (1.4)
92 (4)
69 (3)
80 (3.4)
502 (21.6)
.41
1.00
1.00
.30
.62
.53
1.00
.22
P values were determined using the Fisher exact test.
poor outcomes were related to delays in diagnosis or treatment. Furthermore, the local health care system should
reduce the impact of socioeconomic disparities. While on
therapy, the Interlink Program ensures that all children
have equal access to care as well as standardized treatment
approaches and guidelines irrespective of rural or urban
residence. Abandonment of therapy (discontinuing treatment against medical advice), in which a child with cancer
has a reasonable likelihood of long-term cure and cannot
consent to therapy cessation, mandates referral to the legal
system in the Canadian and American contexts. In this
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Inferior Survival in Aboriginal Children/Marjerrison et al
case, the court may apprehend the child and mandate continuation of treatment.30 Thus, abandonment of therapy
cannot explain our findings.
Previous studies have suggested that children from
ethnic minority groups are registered less often on clinical
trials31,32 and thus lack the potential survival advantage of
state-of-the-art therapy. However, there was no significant
difference in clinical trial enrollment, provision of standard of care, or individualized treatment plans by Aboriginal ethnicity in our results. Furthermore, centralized care
in Ontario to 5 pediatric centers makes a differential
approach to treatment less likely.
The survival discrepancy was not limited to a single
disease but, rather, appeared consistently among different
diseases. This observation suggests that adherence to
chemotherapy is unlikely to be a major factor, although
we did not have any specific data on treatment adherence.
If adherence was the primary reason for poor outcomes,
then we should have observed a greater difference in survival for diseases based on at-home, self-administered oral
chemotherapy (such as ALL) compared with inpatient
treatment (such as AML).
Host biology is another plausible explanation for
our findings. Differences in pharmacogenomics are less
likely to be the primary explanation given the wide variety
of chemotherapy regimens for these diverse cancers. However, other host biology features may be important. Despite similar mortality from treatment-related
complications, it is unknown whether Aboriginal children
experience higher rates of treatment-related toxicity,
resulting in chemotherapy dose reduction. Another explanation may be related to the presence of comorbidities
and whether Aboriginal children with cancer are more
likely to have other chronic health conditions compared
with non-Aboriginal children.
Our data build on what is known about Native
American childhood cancer outcomes. We demonstrated
the presence of a survival discrepancy among Canadian
Aboriginal children similar to that observed in the United
States. Our unique contribution, however, is that our
results indicate that this disparity is not because of therapeutic approach, nutritional status (BMI), or metastatic
disease at diagnosis, allowing us to speculate that it is not
driven by differences in adherence or access to care in the
community. Combined, these observations suggest that
there are biologic features that need further delineation
and that the disparity in outcomes in the United States is
unlikely to be explained by access to care alone. Future
studies should be broad in their conceptualization of reasons for inferior cancer outcomes for Aboriginal CanaCancer
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dian/Native American children, including detailed
evaluation of socioeconomic, biologic, treatment selection, and treatment response variables.
We also were interested in comparing our current
results with those in the adult literature. Historically, cancer incidence and mortality rates among Canadian Aboriginal adults have been lower than those among the
general Canadian population.33-36 Recent studies, however, have demonstrated that incidence and mortality rates
in Canadian Aboriginal adults are now equivalent to or
higher than the rates in the general population.27,36-40 It is
believed that the worse outcomes in Aboriginal adults are
caused by a combination of environmental exposures, lifestyle factors, and access to care, although the questions of
genetic predisposition and response to therapy remain
unanswered.27,36-40
According to Ontario census data, Aboriginal children comprise 2.77% (86,665 of 3127,700) of the population aged 19 years.41 However, in our study, the
proportion of children with cancer who were identified as
Aboriginal was only 0.62%. This suggests that our definition of Aboriginal failed to capture all Aboriginal children, and the major question is whether those identified
were somehow systematically different from children who
were not identified as Aboriginal. Alternatively, there may
be a lower incidence of pediatric cancer across diagnoses.
This hypothesis is supported by data from the US
National Cancer Institute’s Surveillance, Epidemiology,
and End Results Program demonstrating a lower incidence of cancers among Native American children compared with other ethnic groups, although only 42% of this
population is captured and, thus, the sample may not be
entirely representative.20,42 Poorer capture of children
ages 15 to 17 years in the POGONIS database also may
have contributed to this finding.25
Our study also highlights a methodological finding.
In defining Canadian Aboriginal pediatric cancer patients
for future studies, postal code information should not be
used alone, because it is not a sensitive method of ascertaining Aboriginal status. Conversely, chart review
appears to be a sensitive approach to patient identification. However, we would recommend the combined
approach for future similar studies.
Our report has several important strengths. To our
knowledge, it is the first to evaluate the cancer outcomes
of Canadian Aboriginal children, a population known to
have generally poor health outcomes. We used a
population-based database that allowed capture of virtually all children ages birth to 14 years with cancer and all
deaths, regardless of location of death or enrolment on a
7
Original Article
clinical trial. This database also allowed us to examine a
breadth of factors implicit in cancer outcomes. We were
able to perform sensitivity analyses that demonstrated the
robustness of our findings to the risk of ethnic misclassification and to poorer capture of those ages 15 to 17 years.
Finally, we used a novel approach to identify Aboriginal
children by combining self-reported ethnicity, as
abstracted by chart review, and postal code as an indication of living on an Aboriginal reserve.
However, our report must be interpreted in light of
its limitations. The number of Aboriginal children with
cancer identified was small; consequently, survival analyses within specific diagnoses were underpowered. Furthermore, given the information available, we had limited
ability to understand the reasons behind worse outcomes
in Aboriginal children. Although there were no differences between Aboriginal and non-Aboriginal children
regarding covariates, our small sample size precluded
adjusting for these potential confounders in the analysis.
Another limitation of our study is that there is an important difference between access to care and utilization of
care. We were not able to disentangle this issue, and previous research has suggested that, even in Ontario, there
may be barriers to utilization of care for Aboriginal
patients.37,43 Future research into utilization of pediatric
oncology care among minority and marginalized populations in Canada is required. Finally, our data set did not
contain information regarding adherence to therapy.
Although we did not observe a difference in outcome
between the inpatient setting and the outpatient setting, it
has been demonstrated that this is an important predictor
of outcome in pediatric cancer and 1 that may vary by ethnicity44; thus, specifically assessing this factor in future
studies will be important.
There are several important avenues for future
research. A Canada-wide analysis would increase the sample size considerably and would indicate whether our findings are limited to Ontario or are generalizable outside the
province. Second and most important, we need to understand the mechanisms behind worse outcomes for Aboriginal children. These studies will be facilitated by the
larger sample size of a pan-Canadian or North Americanwide study. Furthermore, detailed data on genomics, socioeconomic status, treatment trajectories, and decision
making may shed insight into the disparity in outcome.
Studies within single diseases will likely be more
informative.
In summary, this first study of malignancy outcomes
among Canadian Aboriginal children demonstrated that
they have inferior survival compared with non-Aboriginal
8
children. This difference in survival was not explained by
demographic features, cancer type, metastatic disease at
presentation, or treatment plan. Further studies are necessary to determine the etiology of this difference and to
quantify the issue nationally.
FUNDING SUPPORT
Dr. Sung was supported by a New Investigator Award from the Canadian Institute of Health Research.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
REFERENCES
1. Aboriginal Affairs and Northern Development Canada. Terminology.
Available at: http://www.aadnc-aandc.gc.ca/eng/1100100014642/1100
100014643. Accessed June 12, 2013.
2. Bennett K, ed. Position Paper: Aboriginal Children and Youth in
Canada: Canada Must Do Better. Ottawa, Ontario, Canada: Canadian Council of Provincial Child and Youth Advocates. 2010.
3. Statistics Canada. Aboriginal Peoples Survey 2006. Ontario, Ottawa,
Canada: Public Health Agency of Canada; 2006.
4. Assembly of First Nations. First Nations Regional Longitudinal
Health Survey (RHS) 2002/03 Results for Adults, Youth and Children Living in First Nations Communities. Ontario, Ottawa, Canada: Assembly of First Nations/First Nations Information
Governance Committee; 2007.
5. Jin A, Martin JD. Hepatitis A among residents of First Nations
Reserves in British Columbia, 1991-1996. Can J Public Health.
2003;94:176-179.
6. Bratu I, Lowe D, Phillips L. The impact of fatal pediatric trauma on
aboriginal children. J Pediatr Surg. 2013;48:1065-1070.
7. Luo ZC, Kierans WJ, Wilkins R, Liston RM, Uh SH, Kramer MS.
Infant mortality among First Nations versus non-First Nations in
British Columbia: temporal trends in rural versus urban areas, 19812000. Int J Epidemiol. 2004;33:1252-1259.
8. Dean H. NIDDM-Y in First Nation children in Canada. Clin
Pediatr (Phila). 1998;37:89-96.
9. Smylie J, Adomako P. Indigenous Children’s Health Report: Heath
Assessment in Action. Toronto, Ontario, Canada: Keenan Research
Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Dalla Lana School of Public Health; 2009.
10. He Y, Wang WR, Li R, Wang S, Jin L. Genetic divergence disclosing a rapid prehistorical dispersion of Native Americans in Central
and South America [serial online]. PLoS One. 2012;7:e44788.
11. Sarche M, Spicer P. Poverty and health disparities for American Indian and Alaska Native children: current knowledge and future prospects. Ann N Y Acad Sci. 2008;1136:126-236.
12. Cornell SE; Native Nations Institute for Leadership Management
and Policy; The Harvard Project on American Indian Economic Development (Malcolm Wiener Center for Social Policy). Indigenous
Peoples, Poverty and Self-Determination in Australia, New Zealand,
Canada and the United States. Joint Occasional Papers on Native
Affairs No. 2006-02. Cambridge, MA: The Harvard Project on
American Indian Economic Development; Tucson, AZ: The University of Arizona Native Nations Institute for Leadership, Management, and Policy; 2006.
13. United Nations. Department of Economic and Social Affairs. State
of the World’s Indigenous Peoples. New York: United Nations;
2009.
14. Lanier AP, Holck P, Ehrsam Day G, Key C. Childhood cancer
among Alaska Natives [serial online]. Pediatrics. 2003;112:e396.
15. Henderson TO, Bhatia S, Pinto N, et al. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children’s Oncology Group study. J Clin Oncol. 2011;29:76-82.
Cancer
Month 00, 2014
Inferior Survival in Aboriginal Children/Marjerrison et al
16. Goggins WB, Lo FF. Racial and ethnic disparities in survival of US
children with acute lymphoblastic leukemia: evidence from the
SEER database 1988-2008. Cancer Causes Control. 2012;23:737-743.
17. Johnson KA, Aplenc R, Bagatell R. Survival by race among children
with extracranial solid tumors in the United States between 1985
and 2005. Pediatr Blood Cancer. 2011;56:425-431.
18. Foucar K, Duncan MH, Stidley CA, Wiggins CL, Hunt WC, Key
CR. Survival of children and adolescents with acute lymphoid leukemia. A study of American Indians and Hispanic and non-Hispanic
whites treated in New Mexico (1969 to 1986). Cancer. 1991;67:
2125-2130.
19. Kadan-Lottick NS, Ness KK, Bhatia S, Gurney JG. Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia.
JAMA. 2003;290:2008-2014.
20. Howlader N, Noone AM, Krapcho M, et al. eds. Figure 29.2. SEER
Cancer Statistics Review, 1975-2010 Based on the November 2012
SEER data submission, posted to the SEER web site, April 2013.Bethesda, MD: National Cancer Institute; 2013. Available at: http://
seer.cancer.gov/csr/1975_2010/. Accessed June 7, 2013.
21. Chow EJ, Puumala SE, Mueller BA, et al. Childhood cancer in relation to parental race and ethnicity: a 5-state pooled analysis. Cancer.
2010;116:3045-3053.
22. Xu H, Cheng C, Devidas M, et al. ARID5B genetic polymorphisms
contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol.
2012;30:751-757.
23. Yang JJ, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet. 2011;43:
237-241.
24. Lim JY, Bhatia S, Robison LL, Yang JJ. Genomics of racial and ethnic disparities in childhood acute lymphoblastic leukemia. Cancer.
2014;120:955-962.
25. Greenberg ML, Barr RD, DiMonte B, McLaughlin E, Greenberg C.
Childhood cancer registries in Ontario, Canada: lessons learned from
a comparison of 2 registries. Int J Cancer. 2003;105:88-91.
26. Colquhoun A, Jiang Z, Maiangowi G, et al. An investigation of cancer incidence in a First Nations community in Alberta, Canada,
1995-2006. Chronic Dis Can. 2010;30:135-140.
27. Marrett LD, Jones CR, Wishart K. First Nations Cancer Research
and Surveillance Priorities for Canada. Workshop Report; September
23-24, 2003. Ottawa, Ontario: Cancer Care Ontario; 2004.
28. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International
Classification of Childhood Cancer, third edition. Cancer. 2005;103:
1457-1467.
29. Centers for Disease Control. An SAS Program for the CDC Growth
Charts. Available at: http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. Accessed June 10, 2013.
Cancer
Month 00, 2014
30. Hord JD, Rehman W, Hannon P, Anderson-Shaw L, Schmidt ML.
Do parents have the right to refuse standard treatment for their child
with favorable-prognosis cancer? Ethical and legal concerns. J Clin
Oncol. 2006;24:5454-5456.
31. Howell DL, Ward KC, Austin HD, Young JL, Woods WG. Access
to pediatric cancer care by age, race, and diagnosis, and outcomes of
cancer treatment in pediatric and adolescent patients in the state of
Georgia. J Clin Oncol. 2007;25:4610-4615.
32. Lund MJ, Eliason MT, Haight AE, Ward KC, Young JL, Pentz
RD. Racial/ethnic diversity in children’s oncology clinical trials:ten
years later. Cancer. 2009;115:3808-3816.
33. Gillis DC, Irvine J, Tan L, Chiu S, Liu L, Robson D. Cancer incidence and survival of Saskatchewan northerners and registered Indians, 1967-1986. Arctic Med Res. 1991;Suppl:447-451.
34. Young TK, Choi NW. Cancer risks among residents of Manitoba
Indian reserves, 1970-79. Can Med Assoc J. 1985;132:1269-1272.
35. Young TK, Frank JW. Cancer surveillance in a remote Indian population in northwestern Ontario. Am J Public Health. 1983;73:515-520.
36. Marrett LD, Chaudhry M. Cancer incidence and mortality in Ontario First Nations, 1968-1991 (Canada). Cancer Causes Control.
2003;14:259-268.
37. Sheppard AJ, Chiarelli AM, Marrett LD, Mirea L, Nishri ED,
Trudeau ME. Detection of later stage breast cancer in First Nations
women in Ontario, Canada Can J Public Health. 2010;101:101-105.
38. Sheppard AJ, Chiarelli AM, Marrett LD, Nishri ED, Trudeau ME.
Stage at diagnosis and comorbidity influence breast cancer survival
in First Nations women in Ontario, Canada Cancer Epidemiol Biomarkers Prev. 2011;20:2160-2167.
39. Tjepkema M, Wilkins R, Senecal S, Guimond E, Penney C. Mortality of Metis and registered Indian adults in Canada: an 11-year follow-up study. Health Rep. 2009;20:31-51.
40. Bartlett JG, Sanguins J, Carter S, et al. Cancer and Related Health
Care Utilization in the Manitoba Metis Population. Winnipeg,
Manitoba: Manitoba Metis Federation; 2011.
41. Statistics Canada. 2006 Profile of Aboriginal Children, Youth and
Adults, 2011. Ontario, Ottawa, Canada: Public Health Agency of
Canada; 2011.
42. Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics
Review, 1975-2000 2003. Available at: http://seer.cancer.gov/csr/
1975_2000/. Accessed June 25, 2013.
43. Stewart M, King M, Blood R, et al. Health inequities experienced
by Aboriginal children with respiratory conditions and their parents.
Can J Nurs Res. 2013;45:6-27.
44. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral
mercaptopurine and risk of relapse in Hispanic and non-Hispanic
white children with acute lymphoblastic leukemia: a report from the
Children’s Oncology Group. J Clin Oncol. 2012;30:2094-2101.
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