Trends in Incidence and Survival of Childhood Cancers in Khon Kaen, Thailand (2000-2019): A Population-Based Khon Kaen Cancer Registry Study

doi:10.21203/rs.3.rs-3867461/v1

Background

In Thailand, the national health care system and nationwide standard treatment protocols have evolved over time, potentially influencing the trends in the incidence and survival rates of childhood cancers. However, further investigations are required to comprehensively study these trends in Khon Kaen, Thailand.

Methods

Childhood cancer patients aged 0–14 years (n = 541) who were diagnosed with one of the five most common cancers between 2000 and 2019 from the population-based Khon Kaen Cancer Registry were enrolled. Descriptive statistics were used to analyse the demographic data, which are presented as numbers, percentages, means, and standard deviations. The trends in incidence between 2000 and 2019, including age-standardized incidence rates (ASRs) and annual percent changes (APCs), were analysed using the Joinpoint regression model. Survival analysis was performed for 5-year relative survival rates (RSRs) according to the Pohar Perme estimator and Kaplan–Meier survival curves.

Results

The ASRs of the overall top 5 childhood cancer groups were 67.96 and 106.12 per million person-years in 2000 and 2019, respectively. Overall, the APC significantly increased by 2.37% each year for both sexes. The overall 5-year RSRs were 60.5% for both sexes, 58.2% for males, and 63.9% for females. The highest 5-year RSR was for germ cell tumours (84.3%), whereas the lowest 5-year RSR was for neuroblastoma (29.1%).

Conclusions

The incidence and survival rates of childhood cancers in Khon Kaen, Thailand, varied according to age and sex. The trend in incidence and survival increased over time. The implementation of national health policies and adherence to national treatment guidelines have improved cancer diagnosis and treatment outcomes.

Trends in incidence

Relative survival

Childhood cancers

Population-based

Although childhood cancers are uncommon, they are considered to be one of the most common causes of mortality among children aged 0–14 years in Thailand (1). The mortality rate ranged from 0.88 to 5.08 deaths per 100,000 population in 2019, emphasizing the considerable impact of this health issue (1). During the period of 1990–2000, the 5-year overall survival rate for childhood cancers in Thailand was only 39.4% (2). Several factors impede the effective treatment of childhood cancer, thereby obstructing the path to achieving desired health outcomes. These include limited health literacy, constrained resources affecting accessibility and diagnostic accuracy, inadequate supportive care, the stigma associated with cancer, and broader social hardships. Together, these challenges contribute to difficulties in accessing health care services and can ultimately lead to patients abandoning therapy (3).

To enhance treatment outcomes, the National Health Security Office (NHSO) implemented the Universal Coverage Scheme (UCS) in 2001, achieving full coverage in 2002, encompassing a majority of Thai people, including children(4, 5). In 2006, the NHSO initiated and supported a nationwide disease management program for childhood leukaemia and lymphoma, subsequently expanding and updating it to include protocols for all types of childhood cancer. These protocols have been implemented nationwide since 2016. As a result, accessibility to health care facilities and advanced treatments for childhood cancer patients substantially improved (6, 7).

Globally, including in Thailand, the incidence of childhood cancer has increased, but mortality has decreased (8). However, the trends in the incidence and survival of childhood cancer in Khon Kaen, Thailand, a city located in an area of high poverty and health care inequality, require comprehensive study (9), particularly following changes in health policy. This study aimed to evaluate the trends in the incidence and survival of childhood cancers in Khon Kaen from 2000 to 2019. Insights from this study could enhance the understanding of the impact of national health policies and treatment guidelines, leading to the development of strategies to improve the health care system in areas with limited resources.

Data quality

The population-based Khon Kaen cancer registry covers 26 districts in Khon Kaen Province, Thailand. Childhood cancer data were collected from 23 community hospitals, 3 private hospitals, Khon Kaen Hospital, and Srinagarind Hospital. The data were reviewed by the Khon Kaen Cancer Unit. The quality of the Khon Kaen cancer registry data consisted of four components according to the National Cancer Institute Thailand: comparability, completeness, validity, and timeliness. The quality of the data was assessed by 4% death certificates only (DCO), and 90% morphological verification (MV) was within the acceptable range. Furthermore, the percentage of MV has increased, while DCO and clinical-based diagnosis have decreased (10).

Study population

The study participants were children under 15 years of age in Khon Kaen, Thailand, diagnosed with leukaemia, lymphoma, central nervous system (CNS) neoplasms, neuroblastoma, or germ cell tumours between January 1st, 2000, and December 31st, 2019. The exclusion criteria included incomplete data, household registrations in provinces other than Khon Kaen and previous cancer treatment at hospitals outside Khon Kaen. The population denominator for age-standardized rates (ASRs) was calculated using the population at risk of children aged 0–14 years in Khon Kaen Province between 2000 and 2019; these patients were classified every 5 years based on age and sex.

Data collection

The data were obtained from the population-based Khon Kaen cancer registry. Newly diagnosed childhood cancer patients aged 0–14 years were identified using the International Classification of Diseases for Oncology, third edition (ICD-O-3) and then categorized into the International Classification of Childhood Cancer, third edition (ICCC-3), which includes the top five childhood cancers. The data collected included age at cancer diagnosis, sex, current status, residential area, health insurance, primary disease, stage, histological grade, and extent of disease.

Statistical analysis

Descriptive statistics were used to analyse the demographic data, which are presented as numbers and percentages for categorical data and as the means and standard deviations (SDs) for continuous data. For trend in incidence analysis, ASRs between 2000 and 2019 were analysed using the Joinpoint regression model and are represented in trend graphs. The annual percent change (APC) was used to describe the trend change between 2000 and 2019. Trend analysis was conducted using the Joinpoint Regression Program version 5.0.2 (11).

Survival analysis was performed for 5-year relative survival rates, median survival times, and Kaplan–Meier survival curves. The data analyses were conducted in Stata version 15 (12).

Demographic data

This study included 541 of 578 patients who were diagnosed with leukaemia, lymphoma, CNS neoplasms, neuroblastoma, or germ cell tumours between 2000 and 2019. Thirty-seven patients (6.4%) were excluded because of missing data. The most common cancers were leukaemia (53.8%), followed by CNS neoplasms (19.0%), lymphoma (10.7%), germ cell tumours (9.2%) and neuroblastoma (7.2%). The majority of these patients were male (58.2%). The mean age at diagnosis was 6.48 years (SD = 4.50), and the median age was 6 years (range 0–14). Approximately 40% were aged 0 to 4 years. Approximately 51% of the patients were diagnosed between 2010 and 2019. Regarding the staging of lymphoma and solid tumours, 77.9% of patients presented with stage III to IV disease, 55.9% had poorly differentiated to undifferentiated histological grading, and 47.6% had regional lymph node to distant metastases of cancer spread. The majority of patients (95.2%) had coverage under the Universal Coverage Scheme (UCS) for health insurance. Almost 69% of the participants resided in areas located more than 79.9 km away from the city centre (Table 1).

The incidence rates and trends of childhood cancer

The ASR of the overall most common childhood cancer was 68.0 per million person-years in 2000 and increased to 106.1 per million person-years in 2019. In 2000, the overall ASRs of leukaemia, lymphoma, CNS neoplasms, neuroblastoma, and germ cell tumours were 38.2, 9.9, 13.2, 7.1, and 6.4 per million person-years, respectively. By 2019, the ASRs had increased to 57.5, 11.4, 22.1, 13.9, and 13.0 per million person-years, respectively (Fig. 1).

The incidence of the 5 most common childhood cancers increased significantly by 2.37% annually between 2000 and 2019 (95% CI: 0.32–4.47%). The APCs in the incidence of leukaemia, lymphoma, CNS neoplasms, neuroblastoma, and germ cell tumours increased annually for both sexes by 2.17% (95% CI: -0.20–4.53%), 0.78% (95% CI: -3.04–4.60%), 2.76% (95% CI: -1.34–7.00%), 3.59% (95% CI: -0.75–8.27%), and 3.82% (95% CI: 0.78–7.20%), respectively (Table 2). When stratified by sex, females had a greater increase in the incidence rate of all cancers except lymphoma. The incidence of neuroblastoma significantly increased by 4.36% (95% CI: 1.37–7.58%) among females, and the incidence of germ cell tumours increased significantly by 3.82% (95% CI: 0.78% to 7.20) among both males and females.

Survival

The relative survival rates (RSRs) of patients with overall childhood cancer between 2000 and 2019 at 1, 3, 5, and 10 years were 77.0% (95% CI: 73.2–80.4%), 63.0% (95%: 58.7–67.0%), 60.5% (96% CI: 56.2–64.6%), and 57.1% (95% CI: 52.5–61.4%), respectively (Fig. 2).

A comparison of the relative survival of the 5 most common childhood cancers in Khon Kaen by ICCC group between 2000 and 2019 revealed that the most common were germ cell tumours (84.3%; 95% CI: 70.6–92.0%), lymphomas (75.1%; 95% CI: 61.3–84.6%), and leukaemia (63.1%; 95% CI: 57.2–68.4%). The least common 5-year RS was neuroblastoma (29.1%; 95% CI: 15.9–43.8%), followed by CNS neoplasms (44.4%; 95% CI: 34.1–54.1%) (Fig. 3a) (Table 3). Among the leukaemia subgroups, acute lymphoid leukaemia (ALL) patients had a higher 5-year RSR (67.5%; 95% CI: 60.4–73.6%) than acute myeloid leukaemia (AML) patients (41.6%; 95% CI: 28.4–54.3%) (Fig. 3b). For lymphomas, the 5-year RSR was 86.2% (32.3–98.1%) for Hodgkin lymphoma (HL) and 69.2% (51.1–81.7%) for non-Hodgkin lymphoma (NHL) (Fig. 3c).

This population-based study revealed an upward trend in the incidence of the 5 most common childhood cancers overall in Khon Kaen between 2000 and 2019, with an annual increase of 2.37% each year from 2000 to 2019. This trend is consistent with patterns observed in the Thailand database and in many countries worldwide (2, 13). The success of universal health care coverage implementation in reducing socioeconomic inequalities in health care access, particularly in rural Thailand, is demonstrated by this trend (14). Furthermore, advances in diagnostic techniques and cancer registration have contributed to the increasing incidence of cancer.

In our study, leukaemia was the most common cancer diagnosed, and the APC in the incidence of leukaemia increased (2.2% each year) for both sexes. This finding aligns with that from a study from Korea, which observed a significant increase in leukaemia cases between 1999 and 2011, with APCs of 1.9% for males and 2.1% for females(15). A similar trend in leukaemia incidence from 1990 to 2011, with an APC of 1.5%, was also reported in a multicancer registry analysis in Thailand (2). The high ASR and APC of leukaemia in Khon Kaen may indicate improvements in case diagnoses, particularly in the classification of leukaemia cases in the registry, health care accessibility, and the introduction of technologies such as cytochemistry and molecular diagnostics for leukaemia diagnosis. Additionally, environmental factors such as air pollution may contribute to the increased incidence of childhood leukaemia(16). In Khon Kaen, a rapidly urbanizing and industrializing area in Northeast Thailand, increased air pollution has resulted from swift industrial expansion and the emergence of various transport systems. High levels of particulate matter (PM2.5)-bound heavy metals, including manganese, aluminium, lead, copper, cadmium, iron, and zinc, have been found in residential and industrial areas in Khon Kaen, posing potential carcinogenic risks to children (17). A previous study reported that paternal occupational exposure to pesticides, animals, and organic dust is associated with an increased risk of acute myeloid leukaemia (AML)(18). However, the direct association between environmental factor exposure and the incidence of childhood leukaemia requires further investigation.

In addition to leukaemia, we observed upward trends in all cancers, with significant increases in germ cell tumours and neuroblastomas (p < 0.05). Similar trends were found in nationwide studies in Thailand (2), Estonia (19) and Austria (20). These trends may be attributed to enhanced diagnostic methods, leading to earlier investigations of slow-growing tumours. The introduction of noninvasive techniques, such as tumour marker detection, has been beneficial in the diagnostic process. Additionally, the widespread availability and easy accessibility of computed tomography (CT) and magnetic resonance imaging (MRI) have continued to play important roles in the detection and characterization of tumours (21, 22).

Our study revealed greater survival rates for most cancers, except for neuroblastoma, than did a multicancer registry analysis in Thailand (2). The 5-year RSRs in our study were 67.5% for ALL, 41.6% for acute myeloid leukaemia (AML), 86.2% for Hodgkin lymphoma (HL), 69.2% for non-Hodgkin lymphoma (NHL), 44.4% for CNS neoplasms and 84.3% for germ cell tumours. These rates are higher than those of a previous study (2001–2011), which reported lower RSRs: 52.5% for ALL, 26.5% for AML, 60.6% for HL, 49.1% for NHL, 31.6% for CNS neoplasms and 63.4% for germ cell tumours. Regarding neuroblastoma, both our study and nationwide data (29.1% versus 27.6%) revealed similar poor prognoses, largely because most patients presented with high-risk features. The standard treatment for high-risk neuroblastoma involves multiagent chemotherapy, surgery, autologous haematopoietic stem cell transplantation (HSCT), radiation, and immunotherapy (2). Unfortunately, not all neuroblastoma patients have access to HSCT, and immunotherapy is currently unavailable in our country.

In the context of Khon Kaen, despite high poverty levels, the implementation of universal health care coverage and nationwide guidelines has substantially improved patient access to health care. These upward trends in the incidence and survival rates are indicative of the success of Thailand's national health policy and treatment standards (23–25). Nonetheless, survival rates in Thailand are still lower than those in developed countries (26–28), possibly due to disparities in accessibility to diagnostic and health care services, as well as other resource constraints (29, 30). Furthermore, disparities in childhood cancer infrastructure between nations with developed and developing economies contribute to variations in medical training and expertise, impacting early cancer detection (30–32).

The strength of this study is that all patient data included in this study were from the Khon Kaen Cancer Registry, which was established in 1984 and has been quality controlled for comparability, completeness, validity, and timeliness by the National Cancer Institute Thailand, with DCO and MV percentages falling within the acceptable range. However, this study has several limitations. First, data collection for childhood cancer patients is scarce, especially for early data predating the establishment of the cancer registry. Some older patients were excluded due to incomplete data for analysis. Additionally, extensive staging and histological information were missing. Second, certain risk factors that could impact disease outcomes, such as sociodemographic and environmental factors, were not included in this study. To identify these risk factors and address knowledge gaps for improving childhood cancer outcomes, further research on sociodemographic and other risk factors in childhood cancers is recommended.

The trends in the incidence and survival of childhood cancers in Khon Kaen, Thailand, have increased over time. These rates vary depending on age and sex. The implementation of national health policies and adherence to national treatment guidelines have improved childhood cancer diagnosis and treatment outcomes.

ALL: Acute lymphoblastic leukaemia

AML: Acute myeloid leukaemia

APC: Annual percent change

ASR: Age-standardized rate

CI: Confidence interval

CNS: Central nervous system

CSBMS: Civil Servant Medical Benefit Scheme

CT: Computed tomography

DCO: Death certificate only

HL: Hodgkin lymphoma

HSCT: Haematopoietic stem cell transplantation

ICCC-3: International Classification of Childhood Cancer, third edition

ICD-O-3: International Classification of Diseases for Oncology, third edition

KM: Kilometre

MRI: Magnetic resonance imaging

MV: Morphological verification

NHL: Non-Hodgkin lymphoma

NHSO: National Health Security Office

RSR: Relative survival rate

SD: Standard deviation

UCS: Universal Coverage Scheme

Ethics approval and consent to participate

This study was approved by the Khon Kaen University Ethics Committee for Human Research based on the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines (HE661255). The informed consent was waived by the Khon Kaen University Ethics Committee for Human Research because this is a secondary analysis of population-level data from the Khon Kaen cancer registry and lacks personally identifiable data.

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the Khon Kaen Cancer Registry, but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. However, the data are available from the authors upon reasonable request and with permission of the Khon Kaen Cancer Registry.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

KS and SP conceptualized and designed the study. CP analysed the patient data and was a major contributor to the writing of the manuscript. PS managed the patient data and defined the statistics for analysis. CS collected and generated a dataset from the Khon Kaen Cancer Registry. SC and PK interpreted the patient data regarding haematology-oncology. All the authors reviewed and approved the final manuscript.

Acknowledgements

The authors would like to express their gratitude to the registry staff at the Khon Kaen Cancer Registry for providing data on childhood cancers. In addition, the faculty of Public Health at Khon Kaen University contributed to this research.

Authors' information

¹Doctor of Public Health Program, Faculty of Public Health, Khon Kaen University, Thailand

²Khon Kaen Cancer Registry, Cancer Unit, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand

³Department of Pediatrics, Khon Kaen Hospital, Khon Kaen, Thailand

⁴Division of Hematology-Oncology, Department of Pediatrics, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

⁵Department of Epidemiology and Biostatistics, Faculty of Public Health, Khon Kaen University, Thailand

⁶Department of Public Health Administration, Faculty of Public Health, Khon Kaen University, Thailand

^*Contributed equally

Corresponding authors: Kunanya Suwannaying, Email: [email protected]

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Table 1 Patient demographic data (n=541)

Variable	Number	Percentage
Sex
Male	315	58.23
Female	226	41.77
Age at diagnosis (years)
0-4	220	40.67
5-9	156	28.83
10-14	165	30.50
Mean (SD)	6.48 (4.50)
Median (Min: Max)	6 (0: 14)
Period of diagnosis (10 years)
2000-2009	263	48.61
2010-2019	278	51.39
Childhood cancer group
Leukaemia	291	53.79
CNS neoplasms	103	19.04
Lymphoma	58	10.72
Germ cell tumours	50	9.24
Neuroblastoma	39	7.21
Health insurance (n=497)
Universal Coverage Scheme (UCS)	473	95.17
Civil Servant Medical Benefit Scheme (CSBMS)	24	4.83
Residential area (distance from the city centre)
Short and intermediate distance (<20 km to 79.9 km)	372	68.76
Long distance (≥80 km)	169	31.24
Stage of disease (except leukaemia) (n=77)
Stage I – II	17	22.08
Stage III – IV	60	77.92
Histological grading (except leukaemia) (n=34)
Well - moderately differentiated	15	44.12
Poorly differentiated - undifferentiated	19	55.88
Extent of cancer spread (except leukaemia) (n=21)
Localized - direct extension	11	52.38
Regional lymph nodes - distant metastasis	10	47.62

Abbreviations: km, kilometre; Min, minimum; Max, maximum; SD, standard deviation

Table 2 Annual percent change (APC) in the incidence of childhood cancer by ICCC group and sex from 2000 to 2019

ICCC group

Overall

Sex

Male

Female

Overall top 5 childhood cancer groups

2.37*

(0.32 to 4.47)

1.80

(-1.19 to 4.80)

3.26

(-0.36 to 7.07)

I. Leukaemia

2.17

(-0.20 to 4.53)

1.90

( -1.26 to 5.07)

2.50

( -0.88 to 5.87)

II. Lymphoma

0.78

(-3.04 to 4.60)

1.56

(-1.72 to 4.79)

1.41

(-1.58 to 4.32)

III. Central nervous system neoplasms

2.76

(-1.34 to 7.00)

2.43

(-0.31 to 5.18)

3.71

(-0.63 to 8.24)

IV. Neuroblastoma

3.59

(-0.75 to 8.27)

2.35

(-1.80 to 6.48)

4.36*

(1.37 to 7.58)

X. Germ cell tumours

3.82*

(0.78 to 7.20)

2.61*

( 0.28 to 4.95)

3.82*

(1.37 to 6.49)

*Statistically significant at the level of 0.05

Abbreviations: ICCC, International Classification of Childhood Cancer

Table 3 Overall 5-year relative survival rates by ICCC group

ICCC group	Overall 5-year RSR (%) (95% CI)
ICCC group	Overall 5-year RSR (%) (95% CI)
Overall top 5 childhood cancers	60.5 (56.2 to 64.6)
I. Leukaemia	63.1 (57.2 to 68.4)
II. Lymphoma	75.1 (61.3 to 84.6)
III. Central nervous system neoplasms	44.4 (34.1 to 54.1)
IV. Neuroblastoma	29.1 (15.9 to 43.8)
X. Germ cell tumours	84.3 (70.6 to 92.0)

Abbreviations: CI, confidence interval; ICCC, International Classification of Childhood Cancer; RSR, relative survival rate

No competing interests reported.

Trends in Incidence and Survival of Childhood Cancers in Khon Kaen, Thailand (2000-2019): A Population-Based Khon Kaen Cancer Registry Study

Status:

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Data quality

Study population

Data collection

Statistical analysis

Results

Demographic data

The incidence rates and trends of childhood cancer

Survival

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Journal Publication

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