Childhood Cancer Survival in Brunei Darussalam

Background: This study aims to determine the survival rates for children and adolescents aged 0-19 years diagnosed with childhood cancer and to evaluate the associated factors for childhood cancer survival in Brunei Darussalam. Methods: The analysis was based on de-identified data of 263 childhood cancer for the period 2002 to 2017 retrieved from a population-based cancer registry. Overall survival was estimated using the Kaplan-Meier method. Univariate analysis, using the log-rank test, was used to examine the differences in survival between groups. Multivariate analysis, using the Cox Proportional Hazard (PH) regression model, was used to estimate the hazard ratios (HRs) and select the significant associated factors for childhood cancer patients’ survival. Results: The overall 1-, 5- and 10-year survival rates for all childhood cancers combined were 79.4%, 70.0% and 68.8% respectively. The most common types of cancer were leukemias, malignant epithelial neoplasms, lymphomas and tumours of the central nervous system (CNS). The 5-year survival estimates were highest for malignant epithelial neoplasms (84.2%) while the lowest was tumours of the CNS (44.1%). Log rank tests showed significant differences in childhood cancer patients’ survival between tumour types and period of diagnosis. In the Cox PH analysis, the presence of lymphomas, gonodal and germ cell neoplasms, and malignant epithelial neoplasms compared to leukemia; children aged 1-4 and 5-9 years compared to adolescents aged 15-19 years; and periods of diagnosis in 2002-2006 and 2007-2011 compared to 2012-2017 were significantly associated with lower hazard of death in this study. Conclusion: This study provides a baseline measurement of childhood cancer survival for monitoring and evaluation of cancer control programmes, to allow planning of cancer control program strategies such as surveillance, screening, and treatment to improve childhood survival rates in Brunei Darussalam.


Introduction
Cancer in children and adolescents aged 0-19 years was the sixth leading cause of total cancer burden globally and the ninth leading cause of childhood disease burden globally (Force et al., 2019). Although childhood cancer is rare compared to adult cancers, it has a tremendous impact on the health of children and their families, and is an important concern for public health, medical care, psychology and society (Steliarova-Foucher et al., 2017). Childhood cancer can also lead to a high burden of serious and chronic disability caused by cancer treatments (Mitra et al., 2017). It is estimated that more than 60% of childhood cancer survivors suffer from at least one chronic condition and almost 30% have severe or life-threatening conditions (Oeffinger et al., 2006).
More than 80% of children with cancer in high-income countries survive 5-years after diagnosis, but in many low-and middle-income countries, survival rates remain significantly lower due to the need for specialized care centers, shortages of essential chemotherapy, treatment

Childhood Cancer Survival in Brunei Darussalam
abandonment, late diagnosis and financial burden (Gupta et al., 2015). In countries with high economic status, children are more likely to have access to high quality treatment and supportive care, health insurance, receive a timely diagnosis and parents are more likely to have high level of knowledge and adherence to therapy, all of which contribute to improved childhood cancer survival rates (Park et al., 2016). In 2018, the World Health Organization (WHO) established the Global Initiative for Childhood Cancer, which aims to achieve a global survival rate of at least 60% for all children diagnosed with cancer by 2030 (World Health Organization, 2018). Increasing survival will require considerable planning by policy makers to ensure adequate resource allocation and health system function.
The leading cause of deaths in Brunei Darussalam is from cancer, which accounts for about 19% of the total mortalities in the country (DPP, 2019). In 2019, children and adolescents made up 25.7% of the total population in Brunei Darussalam. Brunei Darussalam is a country in South East Asia with an estimated population of 459,500 where the major ethnic groups are Malay (65.8%), Chinese (10.2%) and other ethnicities (24.0%) (DEPS, 2019).
This paper aims to determine the survival rates for children and adolescents aged 0-19 years diagnosed with childhood cancer, and evaluate the associated factors for childhood cancer survival in Brunei Darussalam, enabling for comparability with population-based estimates from other countries.
Cancer in children and adolescents aged 0-19 years is referred to as childhood cancer in this article. An age range of 0-19 years was also chosen in WHO and previous US and European studies of childhood cancer incidence and survival (Pritchard-Jones, 2006;Ward et al., 2014). However, the 0-14 year age range was also used to define pediatrics in some countries and international health organizations (Force et al., 2019). The tumour types were grouped according to the third edition of the International Childhood Cancer Classification, ICCC-3 (Steliarova-Foucher et al., 2005). The sixteen years study period was divided into three periods (2002-2006; 2007-2011; 2012-2017) to compare survival over time.
The analyses were performed using R statistical software. Descriptive analyses, which include number of cases and its percentage, were conducted to evaluate the distribution of each variable. Survival time was defined as the period of time from diagnosis to death or end of follow-up. Patients who were still alive or lost to followup at the end of the study period were right-censored.
Overall survival rates, defined as the period of time from diagnosis to death or end of follow-up due to any cause, were calculated using the Kaplan-Meier method. Univariate analysis, using the log-rank test, was used to examine the differences in survival between groups. Multivariate analysis, using the Cox Proportional Hazard (PH) regression model, was used to estimate the hazard ratios (HR) of associated factors on survival and to select the significant predictors for childhood cancer patients' survival. Reference categories were selected logically as the first category (Male and Malay) or as the modal category (15-19 year age group and period 2012-2017). We examined the PH assumption and measured the goodness of fit for model adequacy. For all analyses, the level of statistical significance was set at 5%. Confidence intervals (C.I.) of 95% were reported where appropriate.

Results
A total of 263 cases of childhood cancer registered during January 2002 to December 2017 were included in the analysis. The highest number of cases was recorded in year 2015 (n=28 cases) while the lowest was in year 2002 (n=8 cases), with an average of 16 cases per year. Of these 263 children and adolescents, 20.2% (n=53) had died within 1 year, and 28.1% (n=74) within 5 years of diagnosis. The mean and median ages at diagnosis were 9.4 years (standard deviation=6.8) and 9.0 (0-19) years, respectively.
This study found majority of the cases were in the period 2012-2017 for all childhood cancers except for gonadal and germ cell neoplasms, neuroblastoma, renal tumours, malignant bone tumours and an equal number of cases for CNS tumours with period 2007-2011. For those diagnosed with leukemia, malignant epithelial neoplasms, and gonadal and germ cell neoplasms, the lowest 5-year survival rates was in period 2012-2017. For lymphomas, we found an improvement in survival from childhood cancers by age group and period of diagnosis. For children between 0-14 years of age, the three leading cancers were leukemia (n=71), CNS tumours (n=24) and lymphoma (n=17) while for adolescents aged 15-19 years, the three most common cancers were malignant epithelial neoplasms (n=28), lymphomas (n=16) and leukemias (n=15).
Approximately 82.6% of those diagnosed with leukemia were children aged 0-14 with 5-year survival rate of 80.1%. Most of the children diagnosed with leukemia were in the 1-4 age group (38.4%) but they also had the highest 5-year survival rate of 90.9% compared to the other age groups with leukemia. The same trend could be seen for children diagnosed with CNS tumours where most were diagnosed in the 1-4 age group (  Cox PH regression analyses found that tumour types, age at diagnosis and period of diagnosis were significant factors for childhood cancer patients' survival (p<0.05), shown in Table 3. No violations of PH assumptions were observed. For tumour types, as compared to a patient diagnosed with leukemia, the hazard ratios (HRs) for those diagnosed with lymphomas, gonodal and germ neoplasms, and malignant epithelial neoplasms were 0.34 (95% C.I.

Discussion
This is the first study in Brunei Darussalam looking at the survival rates and the associated factors for childhood cancer patients' survival aged between 0-19 years of age. For all cancers combined, the overall survival rates of childhood cancer patients aged 0-19 years during 2002-2017 at 1-, 5-and 10-year were 79.4%, 70.0% and 68.8% respectively.
Although Brunei Darussalam has achieved the WHO's target of 60% overall survival rate of childhood cancer, our overall 5-year survival for childhood cancer patients aged 0-19 years (70.0%) for 2002-2017 were found to be lower than that reported by published literatures from the United States at 83.0% (Ward et al., 2014) and Canada at 82.0% (Ellison et al., 2007) but comparable to Turkey at 67.8% (Kutluk and Yesilipek, 2018) and Singapore at 75% (Tan and Ha, n.d.). The 5-year survival rate for children aged 0-14 years for all cancers combined in this study was 74.4%, higher than developing countries in Asia such as Thailand (47.2%) (Bidwell et al., 2019) and    (Zheng et al., 2015), but lower than other developed countries such as South Korea (78.2%) (Park et al, 2016) and Australia (79.5%) (Baade et al., 2010). These disparities may be caused by multiple factors, with a country's economic status being one contributor (Park, 2016). It is important to note that direct comparison with published survival rates internationally should be made with caution because of the different methodologies used, such as the age groups and time periods considered in the analyses.
Overall, among children and adolescents aged 0-19 years in Brunei Darussalam, the most common types of cancer were leukemias, malignant epithelial neoplasms, lymphomas and tumours of the CNS. However, the most common childhood cancers globally vary by age. Globally, cancers that were most common in children aged 0-14 years were leukemia, tumours of the CNS and lymphomas (Steliarova-Foucher et al., 2017), similar to our study. For adolescents aged 15-19 years, we found that the most common cancers were malignant epithelial neoplasms, followed by lymphomas and leukemia. Although globally, lymphomas were the most common cancer, followed by epithelial tumours and leukemia for adolescents aged 15-19 years, the most common cancer for adolescents in Oceania, east Asia, central America and the Caribbean and in white non-Hispanic children in the USA, was epithelial tumours and melanoma (Steliarova-Foucher et al., 2017), consistent with our study.
Leukemia contributed to roughly one-third of the childhood cancer cases in Brunei Darussalam, similar to that reported elsewhere (Bidwell et al., 2019;Park et al., 2016). Children aged 0-14 years diagnosed with leukemia had 5-year survival rate of 80.1% in this study. Japan reported 5-year survival rate of 83% (Nakata et al., 2018) while South Korea recorded 5-year survival rate of 75.4% (Park et al., 2016) for this age group. We found huge differences in survival among age groups for childhood leukemia, with highest survival for children aged 1-4 years while lowest survival for adolescents aged 15-19, similar to a study in the United States which reported the age group 15-19 continued to show the lowest survival for longer time, while the age group 1-4 showed a persistent highest survival (Holmes et al., 2012). Improvements in childhood leukemia survival over time have been reported internationally and have been suggested to be most likely due to advances in treatment, standardization of treatment protocols and improvements in diagnosis of leukemia (Bonaventure et al., 2017) Among the childhood cancers, for children and adolescents aged 0-19, the highest 5-year survival rate was observed in malignant epithelial neoplasms (84.2%) while the lowest survival was for CNS tumours (44.1%). Adolescents aged 15-19 years diagnosed with CNS tumours observed 5-year survival rate of 16.7%, much lower than studies reported internationally with estimates that range from 39.4% to 54.8% (Bidwell et al., 2019;Ballantine et al., 2017). The low survival rate observed in this study indicates a need for future follow-up studies focusing on the specific group of cancer, age groups and the associated risk factors. However, children aged 0-14 diagnosed with CNS tumours had survival rate of 52.5%, which is comparable to studies from Korea at 59.0% (Park et al., 2018), and Estonia at 49.5% (Paapsi et al., 2020) but lower than Australia at 71.0% (Baade et al., 2010). The survival estimates for CNS tumours may be somewhat affected by the use of different diagnostic methods and the classification of tumour behaviour (Peris-Bonet et al., 2006). When compared to children aged 0-14, adolescents observed higher survival rate when diagnosed with lymphomas but lower when diagnosed with malignant epithelial neoplasms. In general, these survival rates are higher than developing countries in Asia (Wiangnon et al., 2011, NCR, 2018 but they are still below those of the international progress (Desandes et al., 2014;Park et al. 2016).
Majority of the childhood cancer cases were in the recent period (2012)(2013)(2014)(2015)(2016)(2017). The increase in the number of childhood cancer cases could be due to the improvement in pediatric cancer registration, detection and reporting in that period. In 2013, Brunei Darussalam healthcare services adopted an electronic medical record system to enhance the accuracy, timeliness and completeness of the country's cancer registry (Leong et al., 2019). The 5-year survival rate for all cancer sites combined improved slightly from 76.5% in period 2002-2006 to 79.5% in 2007-2011 but declined to 64.2% in the period 2012-2017. The lower overall survival rate for period 2012-2017 is contributed by the low survival rates for some cancers, especially leukemia and CNS tumours, as their 5-and 1-year survival rates were found to be 59.1% and 42.4%, respectively in that period.
The following factors were significantly associated with lower hazard of death in this study: the presence of lymphomas, gonodal and germ cell neoplasms, and malignant epithelial neoplasms compared to leukemia; children aged 1-4 and 5-9 years compared to adolescents aged 15-19 years; and periods of diagnosis in 2002-2011compared to 2012. Similar to our study, Zouain-Figuerido et al (2013 reported higher age compared with the 1-4 age group was risk factor for lower survival rates in their study, in which their HR of mortality for adolescents aged 15-19 was 1.64 compared to children aged 1-4. This study has several limitations. Factors such as treatment, information on family history of cancer and cancer stage were associated with childhood cancer patients' survival (Baade et al., 2010;Keramatinia et al., 2018;Kollerud et al., 2018). Information on these factors was not included in this study and should be explored in future studies. In addition, due to the rarity and small number of some cancers, five-year survival rate was not available from the statistical analysis. There was also presence of missing data, commonly seen in all retrospective studies. Despite these limitations, the findings of the present study provide important baseline measurements of childhood cancer survival in Brunei Darussalam.
In conclusion, overall survival rates of childhood cancer and breakdown by types of cancers, age groups and time period found in this analysis provide baseline monitoring and evaluation of cancer control programmes, and the findings will be helpful for planning cancer control program strategies such as surveillance, screening, and treatment to improve childhood survival rates in Brunei Darussalam. Efforts to improve survival should be continued, especially for cancers with low survival rates such as CNS tumours. Effective health campaigns should be implemented to raise awareness on childhood cancers and health education programs emphasizing the importance of early diagnosis, infection control, and education of parents or primary caregivers.