Our study shows that the overall national 5-year survival rate in Brunei is 74.1% from 2002-2017. This indicates that survival of cervical cancer patients in Brunei is at par with survival in high-resource nations (in 2010-2014, the highest 5-year survival in women with cervical cancer in Europe was in Iceland (80%), Norway (73%) and Switzerland (71%) [8]). Meanwhile, the highest 5-year survival rates among Organisation for Economic Co-operation and Development (OECD) countries have previously been reported in Korea (76.8%), Norway (71.4%) and Israel (71.4%), with the average from 19 OECD countries (OECD19) at 66% for the period 2006-2011 [9]. The high 5-year survival rate of cervical cancer patients in Brunei may be accounted for by the two-pronged preventive approach including Pap cytology screening and HPV prophylactic vaccine, as well as a universal healthcare system, with highly accessible diagnosis and treatment facilities which are available at no cost to all citizens. The heterogeneity in the 5-year survival rates of cervical cancer patients globally may be due to inequality or inequity to healthcare access and resources. A global estimation of the incidence and mortality of cervical cancer in 2018 showed that cervical cancer was the main cause of cancer-related death in women in Eastern, Western, Middle, and Southern Africa, correlating with a lack of preventive approaches including screening and HPV immunisation vaccine, or inadequate healthcare in these regions [4]. Therefore, cautious consideration should be made when comparing the survival rate of cervical cancer patients between countries due to variation in healthcare infrastructure, study design, study time frames, statistical analysis, population size, sociodemographic features, cultural and/or social factors.
There is a 39.2% increase in the number of cervical cancer patients diagnosed in 2010-2017 compared to 2002-2009. There is also a shift in the demographics of patients with cervical cancer in Brunei where the proportion of younger patients (<40 years) as well as in situ and distant stage diagnoses increased in the later period (2010-2017). Although more patients are being diagnosed at an early (in situ) stage, it has been shown that there is a 57% significantly higher risk of mortality in the later (2010-2017) period (p<0.05) suggesting that recently-diagnosed patients have poorer survival outcomes. However, this may not reflect clinical reality due to several reasons. Implementation of the Bru-HIMS system (since September 2012) may have led to improved surveillance in recording of vital statistics including cervical cancer patients’ death certification (i.e. The lack of surveillance infrastructure and harmonised coding system may not have captured all cervical-cancer related deaths pre-Bru-HIMS, leading to an overestimation of patients’ survival in the earlier period (2002-2009)). The increased risk of mortality in 2010-2017 may also be attributed to other factors (such as the presence of co-morbidities including diabetes and obesity) that are not included and/or analysed in this study. Therefore, prognostic factors behind the increased mortality in 2010-2017 remain to be determined. Increased uptake of Pap smear cytology upon implementation of the national screening programme in 2011 may also account for the increasing incidence in 2010-2017, increased proportion of younger patients (<40 years) diagnosed (38% in 2010-2017 compared with 21.5% in 2002-2009) as well as the increase (14.5-fold) in in situ cases (10.9% in 2010-2017 compared with 1.0% in 2002-2009). As cancers have a long latency period [10], increased distant stage cases may be due to improved surveillance and or management following the introduction of the national screening programme in 2011. An analysis of national data (1982–2006) has revealed increasing rates of cervical cancer in young women between 20 to 29-year-olds across most regions in England from 1996 onwards, whereas incidence rates in women aged 30–39 years have mainly stabilised [11]. HPV infection solely is not sufficient (although necessary) to promote cervical cancer, and other factors affect the risk of HPV infections progressing to cervical intraepithelial neoplasia (CIN). As HPV is sexually transmitted, aspects of sexual behaviour and multiple reproductive factors influence the risk of CIN and invasive cancer (including number of sexual partners, age at first intercourse, early age at first full-term pregnancy, smoking and passive smoking [12] and increasing duration of oral contraceptive use (reviewed in [11]). The association between these risk factors and the increasing proportion of cervical cancer diagnosis in women <40 years in our study remains to be determined. Evaluating cervical screening intervals between age groups and lifestyle/social factors is essential to facilitate informed decisions pertaining to changes in recommendations for screening guidelines and vaccination against HPV infections [13]. In 2022, the inaugural birth cohorts of women offered HPV vaccination as girls (under the national vaccination programme in 2012) will enter cervical screening. These women are better safeguarded against cervical cancer and could therefore receive recommendations for less intensive screening [14]. Therefore, it is timely for an update of the screening guidelines in terms of the initiation and interval of screening for HPV-vaccinated women.
Currently, screening for cervical cancer in Brunei Darussalam is based on Pap cytology. HPV testing and Pap smear cytology (co-testing) could potentially result in earlier identification of women at high risk of cervical cancer, especially those with adenocarcinoma [15]. While there is no published data on the coverage rate of cervical cancer screening in Brunei Darussalam, WHO has proposed a global target of screening coverage (at ages 35 years and 45 years) of at least 70% by 2030 in order to achieve cervical cancer elimination [16]. National organised screening and treatment programmes in many countries has contributed to significant reduction of the incidence and mortality of cervical cancer over the past 30 years and regular screening has been estimated to prevent up to 83% of cervical cancer deaths [17]. Early detection and treatment of pre-cancerous lesions remain the optimal option for millions of women already infected with cancer-causing HPV as the HPV prophylactic vaccine is ineffective if infection is already present [18]. Public health initiatives to uncover the screening coverage rate and if necessary, propel culturally-appropriate education and raise knowledge regarding the benefits of early diagnosis, improving perceptions or attitudes towards screening, as well as implementing self-sampling HPV test [19] and patient-friendly care may be beneficial to reduce barriers or improve screening compliance and reduce risks of mortality and incidence of cervical cancer.
Majority of the women in this study (52.7%) were diagnosed between the age group 40-59 years, which is concordant with findings from other studies [20][21]. A significantly lower survival as well as a higher mortality risk for age group ≥60 years was observed compared with the other two younger age groups (<40 and 40-59 years) (p<0.001). Differences in treatment regime has been reported where elderly patients are less likely to receive treatment or not receive treatment at all, compared to the younger age groups as they may not tolerate the aggressiveness of the standard treatment regime and also because they are perceived to have reduced life years compared to younger patients [22]. It remains to be determined whether differences in treatment among the different age groups influence survival rates of cervical cancer patients in Brunei. The poor prognosis in patients ≥60 years may also be attributed to the presence of comorbidities. Therefore adaptation of comorbidity management strategies for elderly adults with cancer is necessary to optimize care [23].
SEER staging was used to categorize cervical cancer patients in this study and is comparable to FIGO (International Federation of Gynaecology and Obstetrics) staging where in situ, localized, regionalized and distant SEER stages corresponds to FIGO stage 0, FIGO stage I, FIGO stage II-IV respectively [24]. This study shows that advanced SEER staging is significantly associated with poor 1-,3- and 5-year survival rates (p<0.001), consistent with previous reports [17,20]; underscoring the importance of early diagnosis.
The difference in survival experience among the different ethnicities (Malay, Chinese, Others) was not significant (p=0.300). However, there was a slight difference in 5-year survival rate where Chinese patients (82.7%) have a slightly higher survival rate compared to Malay patients (71.6%). A study reported a significant difference in survival between different ethnic groups (Malays, Chinese and Indians). The lowered survival in the Malays was attributed to their unconventional way of seeking good health, with the belief that traditional medicine is more effective than modern medication. The Malays also tend to present to the clinic at later stages of cancer with large tumors, which may account for the lower survival rate compared with other ethnicities [25].
In this study, the predominant histology at diagnosis is squamous cell carcinoma (54.0%) compared to 68% and 83% by two other studies [20,26]. Meanwhile, 16.2% of patients in this study presented with adenocarcinoma. Although there is no significant difference (p=0.091) in terms of cancer histology and survival rate, the risk of death for cervical cancer patients with adenocarcinoma was 53% higher than patients with squamous cell carcinoma indicating that patients with adenocarcinoma have worse prognosis than those with squamous cell carcinoma in this study. This finding is similar to another study where the relative risk of death was 60% higher for patients with adenocarcinomas than for patients with squamous cell carcinoma [27]. As adenocarcinoma is associated with a poorer prognosis and a greater probability of distant recurrence compared with squamous cell carcinoma, novel or alternative therapeutic strategies for adenocarcinoma patients may be required [28].
Some study limitations include the low population size of this study (457 patients), relative to other studies (a reflection of the small population of Brunei (459,500)). Ethnic ambiguity in medical records may also affect our results. In addition, since Brunei does not currently offer HPV-testing, the distribution of HPV subtypes in our population and the efficacy of the national HPV vaccination programme remains to be evaluated. Future studies on potential prognostic variables (such as presence of comorbidities, cervical screening uptake rate, HPV subtypes, sites of metastasis or treatment received), social history (socioeconomic status, education level, and age at first sexual intercourse) and family health history may better inform predictors of cervical cancer in Brunei, to enable targeted intervention. Current European Guidelines recommend organized population-based screening with primary HPV testing [29]. National health policy makers may wish to review the recommendations for cervical cancer screening as relevant data emerges, in terms of implementing HPV testing concurrently with Pap smear cytology, as well as the flexibility of service options including provision of HPV self-sampling kits to identify high-risk virus subtypes, with close follow-up and monitoring of high-risk patients. Assessing the effectiveness of the national HPV vaccination and screening in Brunei Darussalam will also allow for evaluation of policy and strategy to reduce cervical cancer burden.