Point Of Care Screening And Management For Cervical Cancer

ObjectivesThis research aims at evaluating and validating a new affordable,time reducing,safe,effective and sustainable screening and treatment model for cervical cancer prevention by combining point-of-care self-sampling HPV DNA testing and thermal ablation,which could achieve the goals of increasing the screening coverage,improving the tests accuracy as well as ensuring robust linkage between screening and treatment.We ultimately hope that the new model could improve the accessibility,availability and affordability of medical and health resources in resource-limited areas,finally promoting the health equity in China and the world,accelerating the global elimination of cervical cancer.Contents1.To evaluate the efficacy of self-sampling HPV DNA testing as the primary screening method for cervical cancer prevention.2.To compare the screening performance of different triage testing for self-sampling HPV DNA-positive women.3.To assess the performance of different management algorithms for self-sampling HPV DNA-positive women.4.To evaluate the safety and acceptability of the thermal ablation treatment method.5.To evaluate the efficacy of thermal ablation in the treatment of cervical precancerous lesions and HPV infection.Materials and MethodsIn 2017 to 2018,a total of 14,466 qualified women aged 25-65 years were recruited from rural and urban areas in China to participate in the new cervical cancer screening and management model(self-sampling HPV DNA testing and thermal ablation treatment),and 2,736 women were recruited from Xiangyuan,Shanxi Province to participate in the traditional cervical cancer screening model(physician sampling HPV DNA testing and LEEP treatment).At baseline,for the new model,participants received care HPV and PCR HPV DNA testing on self-collected samples.Women positive on either HPV testing underwent colposcopy,biopsy and thermal ablation if eligible in one visit.For the traditional model,participants received care HPV and PCR HPV testing on physician-collected samples.Women positive on either HPV testing underwent colposcopy and biopsy if necessary.Subsequent LEEP were provided for women with biopsy-proven CIN2 and 3 in the next clinic visit.During the follow-up,HPV-positive or treated women have been followed up annually.10%of HPV-negative women were selected randomly for rescreening with a 2 and 4-year follow-up and all HPV-negative women were rescreened with a 3 and 5-year follow-up.Socio-demographic information,safety,clinical outcomes,etc.were collected for all the patients to evaluate the safety,feasibility and efficacy of the screening and treatment methods in the two models.Meanwhile,genotyping and cytology were performed on the baseline HPV-positive women to evaluate the suitable management and treatment strategies for the self-sampling HPV-positive women.This research lasts 5 years,and now we have finished the baseline screening,the 2nd and part of the 3rd year follow-up.This paper analyzes the data and summarizes the work accomplished until now.Results1.For self-collected samples,PCR HPV testing positivity was higher than care HPV(rural,18.1%vs.15.0;urban,13.7%vs.9.3%),and detected more CIN2+than care HPV(rural:9.3 vs.7.0;urban:12.1 vs.9.5).Sensitivity of PCR HPV testing to detect CIN2+was superior to that of care HPV testing(rural:96.7%vs.72.5%;urban:94.3%vs.80.7%)with slightly lower specificity(rural:83.3%vs.86.0%;urban:89.5%vs.93.2%).PPV and NPV showed no statistical difference between the two testings.Compared to physician-collected samples,the sensitivity of self-sampling care HPV testing was lower(100.0%vs.72.5%),while PCR HPV testing showed no difference between the two types of the samples(96.7%vs.89.7%).2.For detecting CIN2+or CIN3+,if using the same self-collected specimen,triaging HPV-positive women with HPV 16/18 genotyping considerably improved the specificity(84.4%vs.97.2%for CIN2+and 83.9%vs.96.8%for CIN3+)and positive predictive value(PPV,5.3%vs.20.0%for CIN2+and 2.0%vs.8.4%for CIN3+)with acceptable sensitivities(>77%).Compared with HPV16/18 triaging,adding other HPV genotypes which are especially common in China(HPV31/33/45/52/58)significantly reduced the specificity without significant gain in sensitivity.If using physician-collected specimen,triaging HPV-positive women with cytology only or the combination of cytology and genotyping improved specificity and PPV,of which the combination of cytology(LSIL+)and HPV16/18 genotyping could achieve the optimal performance with the sensitivity of 92.8%,specificity of 95.3%,PPV of 14.9%,colposcopy referral rate of 5.5%,AUC of 0.94 and 6.7 colposcopies to yield one CIN2+case.3.Firstly,the overtreatment rate for treating self-sampling HPV-positive women with colposcopy suspected lesions would be 37.6%.Among HPV-positive women without treatment,2.9%would have CIN2+and been missed for treatment.Triaging HPV-positive women with cytology(LSIL+)or HPV16/18 genotyping alone would minimize the overtreatment rates to 14.1%or 17.1%,while the rates for being missed for treatment would increase to 3.7%and 3.3%.Overtreatment rate for treating all HPV-positive women would reach up to 89.3%.Triaging strategies would decrease overtreatment rates,but still more than 65%.If the rate for being missed for treatment is limited to less than 3%or 1%,triaging with the combination of cytology(LSIL+)and HPV16/18 would be the optimal strategy in the 'colposcopy-and-treat' or 'screen-and-treat' approach.Secondly,for HPV-positive women with normal cervix/CINl at baseline,the CIR of CIN2+in two years for women with HPV16/18 infection and ASCUS or worse,or HPV16/18E6 oncoprotein,or CIN1 lesions were more than 10%.4.Among self-sampling HPV-positive women with colposcopy suspected lesions,42.9%were eligible for thermal ablation and all of them accepted the same day treatment.During the treatment,55.8%of the treated women reported pain,and 1.8%had mild bleeding.At four-week follow-up,a few women reported mild bleeding or vaginal discharge in 10-15 days post-treatment.No other side-effects or complications were reported.Additionally,directed biopsy,taken just before thermal ablation,has proved to be safe with no major bleeding from the biopsy site post-treatment.In fact,thermal ablation is efficient in stopping the post-biopsy bleeding from cervix.5.For women with histologically confirmed CIN at baseline,cure rates of CIN were 84.6%for thermal ablation and 86.8%for LEEP treatment.Cure rates following thermal ablation were 90.3%for CIN1 and 76.2%for CIN2+.For HPV-positive women,the HPV clearance rate of thermal ablation and LEEP were 80.4%and 74.4%,respectively.For overtreated women with thermal ablation,the HPV clearance rate was up to 83.0%,which was much higher than that in HPV-positive women with normal colposcopy/pathology and without treatment in the same cohort(39.4%).During the follow-up,HPV testing had the NPV of 98.7%to detect CIN2+and the PPV was 40.4%.Conclusions1.For self-collected samples,the screening performance of PCR HPV testing for CIN2+detection was superior to that of care HPV testing.When used with PCR HPV testing,testing on self-collected samples was similarly accurate as on physician-collected samples.While care HP V testing on physician-collected samples was more accurate.2.HPV 16/18 genotyping was the appropriate testing for triaging self-sampling HPV-positive women with good clinical performance when using self-collected samples.And the combination of HPV 16/18 and cytology(LSIL+)was the good choice for triaging HPV-positive women when using physician-collected samples.3.Colposcopy and triaging can reduce the overtreatment of the 'screen-and-treat'strategy with a few CIN2+lesions being missed for treatment.When translating this scenario into the cervical cancer screening program,the impact of overtreatment and missed treatment on women's health and screening efficiency should be considered.4.Thermal ablation as a POC technique was safe and well-accepted with fewer side effects and complications.It was effective for the treatment of CINs and HPV infection.HPV testing was effective in following women post treatment and the women with persistent HPV infection should be treated,especially if the follow-up is uncertain.5.Self-collection of vaginal samples for a PCR-based high risk HPV testing,triaging of HPV-positive women with HPV 16/18 genotyping,colposcopy of triage positive women followed by immediate treatment could be the appropriate POC screening and treatment cascade for China.