Cervical Cancer Screen And Treat Strategy Suitable For Low And Middle Resource Countries And Implementation Research

ObjectivesThis study was conducted from three dimensions,firstly,to investigate the effectiveness of "screen,triage-and-treat" strategy compared to traditional screening strategy in the three-year follow-up and the feasibility of applying the "screen-and-treat"strategy in China;secondly,to model and assess the cost-effectiveness of a series of"screen(triage)-and-treat" strategies in comparison with currently used strategies in China,providing scientific evidence for its introduction in the global screening strategy for cervical cancer elimination;thirdly,to explore disease burden of cervical cancer,health system capacity,progress till date to implement screening and corresponding challenges in ASEAN.Using Burmese and Laotian women as a starting point,the study investigated the current status of knowledge,attitudes and behaviours related to cervical cancer and implemented HPV tests to Burmese and Laotian women,which lay the foundation for the implementation of HPV based "screen(triage)-and-treat" strategies.Materials and methods1.Long-term results of the"screen(triage)-and-treat" strategies for cervical cancer prevention and feasibility of application:A cohort of 4001 women from the novel screening model(self-collected HPV tests and thermal ablation)and 2736 women from the traditional screening model(clinician-collected HPV tests and LEEP treatment)were recruited from Xiangyuan County,Shanxi Province,China.Kaplan-Meier survival curves were plotted and log-rank test was used to compare the cumulative incidence risk of CIN2+and CIN3+between the two model cohorts in three-year follow-up.On this basis,simple random sampling was used to choose participants from the two-model cohort population.Ultimately,470 women were included to evaluate the performance of pointof-care testing(POCT)under different sampling methods.Using histopathological diagnosis as the gold standard,the area under the ROC curve(AUC)was used to compare the accuracy of POCT with careHPV and conventional PCR test for cervical cancer and precancerous lesions screening.In addition,the feasibility of combining POCT-based screening with thermal ablation treatment as a one-visit screen-and-treat strategy was explored for application in low-resource areas of China.2.Cost-effectiveness analysis of the "screen(triage)-and-treat" strategies for cervical cancer prevention in China:A model-based economic evaluation was conducted to assess the cost-effectiveness of "screen(triage)-and-treat" strategies in comparison with currently used screening strategies in China,from a societal perspective.For these strategies,we simulated a single cohort of 100000 females born in 2015 from birth to death(life expectancy 85 years),as the specified screen and treatment pathways,to obtain the estimates of costs and health outcomes.The target population for cervical cancer screening was women aged 30-65 years in urban and rural China,with a 5-year screening interval.Both costs and health outcomes were discounted at an annual rate of 3%.We calculated the incremental cost-effectiveness ratio(ICER),defined as the incremental cost per QALY gained for each strategy compared with the currently used screening strategy,to identify the cost-effective strategy.Here,we applied the Chinese gross domestic product(GDP)per capita($10350 in 2020)as the cost-effectiveness frontier(highly cost-effective,cost-effective,or not cost-effective with an ICER<1,1-3,or>3-times the per-capita GDP).We also evaluated the harm-and-benefit tradeoff of each screening strategy(presented by the numbers of over-treatment vs.the numbers of CIN1+,CIN2+ or CIN3+detected).3.Status of cervical cancer screening and implementation of HPV test based screening strategy in ASEAN countries:Cervical cancer disease burden data in ASEAN was extracted from the Global Cancer Observatory(GLOBOCAN)and analyzed.Implementation status and challenges of cervical cancer screening in each country were summarized from World Health Organization Cancer Country Profile and supplemented with national plan and strategy for cervical cancer control or non-communicable diseases of each country,and related literature.Literature was searched in mainstream database including PubMed,EMBASE,and CNKI for papers published from 2000 to 2021 by using both MeSH and free text terms.And experts from key academic or government institutions in ASEAN countries were consulted for the detailed information on implementation status and challenges of cervical cancer screening in ASEAN.On this basis,a population-based cross-sectional survey was conducted in Oudomxay,Bokeo province of Laos and ChinaMyanmar border areas to investigate the current knowledge,attitudes and behaviours of Laotian and Burmese women regarding cervical cancer through questionnaires and to explore the associated socio-demographic factors using univariate and multi-factor logistic regression models.Cervical cancer screening was conducted in eligible areas to explore the characteristic of HPV infection among Laotian and Burmese women.Results1.Long-term results of the "screen(triage)-and-treat" strategies for cervical cancer prevention and feasibility of application:Based on the traditional model cohort,the cumulative incidence risk of CIN2+in women with normal/CIN1 pathological findings at baseline were 0.37%,0.50%and 10.33%at 12,24 and 36 months follow-up,respectively.For the novel model cohort,the cumulative incidence risk of CIN2+for women with normal/CIN1 at baseline were 0.06%,1.22%and 2.05%,respectively.The difference in the cumulative incidence risk of CIN2+between the two groups was not statistically significant(P=0.304);for the traditional model cohort,the cumulative incidence risk of CIN3+in women with normal/CIN1 at baseline were 0.16%,0.25%and 2.38%at 12,24 and 36 months follow-up,respectively;the cumulative incidence risk of CIN3+were 0.06%,0.73%and 1.21%for women with normal/CIN1 at baseline in the novel model cohort,respectively.The cumulative incidence risk of CIN3+was also not statistically different between the two groups(P=0.076).Compared to traditional testing methods(careHPV and conventional PCR),POCT had better clinical performance for CIN2+detection.The AUC of POCT HPV test based on self-collected and clinician-collected samples were 0.742 and 0.779,respectively.POCT provided the feasibility for the implementation of HPV test-based "screen-and-treat" strategies in low-resource areas.2.Cost-effectiveness analysis of the "screen(triage)-and-treat" strategies for cervical cancer prevention in China:Compared with current strategies in China(physician-sampling for HPV tests with genotype triage and cytology triage),all "screen(triage)-and-treat" strategies were cost-effective and self-HPV without triage was optimal with the most incremental quality-adjusted life-years(QALYs)gained(220 to 440)in rural and urban China.Each strategy with self-collected samples was cost-saving compared with current strategies($-818430 to $-3540)whereas more costs were incurred using physiciancollected samples compared with current physician-sampling for HPV tests with genotype($20840 to $182840).In utilizing "screen-and-treat" strategies,proportion of costs on cancer treatment would be reduced by 4.38%-12.80%accompanied with more investments towards screening and precancerous treatment.Notably,more than 81.59%of HPVpositive women would be overtreated,that could be reduced by triage with HPV 7 types(2.00%to 2.47%)or HPV 16/1 8(10.34%to 14.38%)with a few cancer cases missing.3.Status of cervical cancer screening and implementation of HPV test based screening strategy in ASEAN countries:Approximately 68558 new cervical cancer cases and 38491 deaths occurred in ASEAN countries in 2020,accounting for 11.3%new cases and 11.3%deaths from cervical cancer worldwide.More than 44%and 63%increases on new cases and deaths are expected in 2040.Only four countries have initiated population-based cervical cancer screening programs,but the participation rate is less than 50%in some countries and even lower than 10%in Myanmar and Indonesia.Laotian women and Burmese women showed lower awareness and knowledge about cervical cancer and prevention.18.0%of Laotian women and 80.2%of Burmese women were unaware of any risk factors for cervical cancer.Only 52.3%of Laotian women and 23.2%of Burmese women believed that cervical cancer is preventable.Female with lower education showed lower awareness and knowledge.In terms of HPV prevalence,the prevalence of HR-HPV infection was 8.71%among Laotian women on self-collected samples and 11.55%among those sampled by physicians,with no statistically significant difference between the two sampling methods(P=0.214);the prevalence of HR-HPV infection was 14.97%among Burmese women on self-collected samples and 14.11%among those sampled by physicians,with no statistically significant difference between the two sampling methods(P=0.505).ConclusionsA three-year follow-up study based on the traditional model and novel model screening cohorts showed no statistical difference in the risk of developing CIN2+and CIN3+between the two populations.The application of POCT for cervical cancer screening had high accuracy and lower detection time,allowing the primary screening with self-collected HPV tests,colposcopy and treatment to be completed in the same visit("screen-and-treat" strategy).On this basis,we found that compared with the currently used strategies,all "screen(triage)-and-treat" strategies were cost-effective whereas selfHPV without triage,i.e.,primary HPV test with self-collected samples followed by the immediate thermal ablation treatment for the HPV-positive women,was the optimal strategy with the most QALYs gained and the most costs saved in China.Further,the costs for cervical cancer treatment among the whole population could be significantly reduced by the screen-and-treat strategies without triage or with HPV 16/18/31/33/45/52/58 triage and the resources may be better utilized towards implementing screening and precancer treatment.From the perspective of implementation of cervical cancer screening strategies appropriate for low and middle resource countries(LMRC),inequity and unavailability in service delivery,lack of knowledge and awareness,limited follow-up and treatment capacity,and funding sustainability affect successful scale-up of cervical cancer screening most in ASEAN.Implementing HPV detection-based primary screening,appropriate management of screen-positives,enhancing health education,integrating health services can accelerate reduction of cervical cancer burden in ASEAN.The study provides evidence for cervical cancer screening strategies in LMRC,which will help improve the accessibility of cervical cancer screening in China and other LMRC and accelerate the global process of cervical cancer elimination.