Risk Factors Of Cervical Cancer And The Therapeutic Effect And Health Economics Evaluation Of Locally Advanced Cervical Cancer In Yunnan Province

Objectives:1.This study aimed to revealed risk factors associated with cervical cancer,including biological factors(HPV and other microbial infections,etc.)environmental/behavioral factors(gestation,contraceptive methods,smoking,etc.)and host factors(demographic characteristics,familial heredity,etc.),to provide a theoretical basis for the prevention of cervical cancer among different ethnic groups in Yunnan province.2.This study aimed to explore the influence of prognostic factors in patients with locally advanced cervical cancers(IB2 and IIA2 stage),and to evaluate the effects of four treatment methods:concurrent chemoradiotherapy(CCRT),radical surgery(RS),neoadjuvant chemotherapy and radical surgery(NACT+RS),brachy chemoradiotherapy and radical surgery(BCRT+RS).The results of this study provide suggestions for the formulation of treatment plans for locally advanced cervical cancer(LACC)based on the patient’s clinical efficacy,quality of life,and survival time.3.This study also conducted a health economics evaluation of the four clinical treatment methods for locally advanced cervical cancer,including cost-effective analysis(CEA),cost-utility analysis(CUA),and cost-benefit analysis(CBA)for short-term treatment(1 year).The results of this study can serve as a reference for the selection of treatment options for patients with locally advanced cervical cancers by constructing a long-term(30 years)Markov decision-tree model based on the patient’s health outcomes and by comparing the incremental cost-utility ratio(ICUR)between the four treatment methods and screening for more effective protocols from the perspective of health economics.Methods:1.In this study,the patients with cervical cancer residing in Yunnan Province who were first diagnosed at The Third Affiliated Hospital of Kunming Medical University(Yunnan Cancer Hospital/Yunnan Cancer Center)between January 2011 and December 2020 to comprise the case group.A case–control study method was adopted,and according to the principle of 1:1 matching,equal numbers of individuals were selected for the case and control groups.Those who satisfied the following criteria were selected as the control group: were from the same area as the case group;had undergone health check-ups or tumor screening at the same hospital during the same period;were free from cervical cancer;and had an age difference was not more than 3 years.By collecting the demographic characteristics,and data on history of smoking,drinking,family genetics,menstruation,marriage,pregnancy,contraception history,HPV status and genital tract infection in both groups,conditional logistic regression was used to analyze the risk factors of cervical cancer.2.Using a retrospective research design,the following information was collected about the enrolled patients: demographic data,incidence,medical history,clinical characteristics,radiotherapy and chemotherapy,surgery,postoperative pathology,and disease-associated complications of locally advanced(stage IB2 and IIA2)cervical cancer patients who were first diagnosed and treated at The Third Affiliated Hospital of Kunming Medical University(Yunnan Cancer Hospital/Yunnan Cancer Center)from January 2011 to December 2020 were collected.Additionally,the functional assessment of cancer therapy cervix(FACT-Cx),European quality of life-5dimensions with 5 levels(EQ-5D-5L),and a mental health scale(Kessler10)were used to conduct an on-site investigation of eligible patients with locally advanced cervical cancer from 2018 to 2020,and the short-term efficacy of four clinical therapeutic methods(CCRT,RS,NACT+RS,BCRT+RS)was comprehensively evaluated.The Kaplan–Meier method was used to compare the 5-year and 10-year progression-free survival(PFS)and overall survival(OS)rates of patients in the four treatment groups,to comprehensively evaluate the long-term effects of the treatment scheme.Cox regression analysis was used to analyze the factors affecting survival and prognosis of patients with locally advanced cervical cancer.3.Through the hospital’s information system,details of all medical expenses of locally advanced(IB2 and IIA2 stage)cervical cancer patients who were first diagnosed and treated at The Third Affiliated Hospital of Kunming Medical University(Yunnan Cancer Hospital/Yunnan Cancer Center)from January 2018 to December 2020,as well as the non-medical expenses and indirect expenses caused by illness,were collected,and the total economic cost was calculated.From the perspective of short-term treatment,the health-related quality of life scale(EQ-5D)was used to measure the patient’s utility value,and the quality-adjusted life-year(QALY)was calculated by weighting in the patient’s survival year for 1 year post-treatment.Incremental cost-effectiveness,incremental cost-utility,and incremental cost-benefit analyses were used to evaluate the short-term economic benefits of the four treatment methods(CCRT,RS,NACT+RS,and BCRT+RS).From the perspective of long-term treatment,based on the probability of metastasis between the three health states(progression-free survival,progressive disease,and death)of patients with locally advanced cervical cancer,and the economic cost parameters of each treatment group,Tree Age Pro 2019 software was used to construct the decision analysis Markov model of the outcomes of the four treatment methods.The long-term(30-years)treatment outcomes of patients with locally advanced cervical cancer were simulated,and the cost-utility of long-term treatment with the four therapeutic methods was evaluated using the regression analysis,Markov cohort simulation,single factor,and probability sensitivity analysis,and a scheme with better economic benefits was determined according to the evaluation results.Results:1.The average age of patients with cervical cancer in Yunnan Province was 47.6years,and the average age of patients of ethnic minorities was younger than that of patients of Han ethnicity.More than 73.0% of the patients were farmers,who were educated to the primary school level or lower.Among patients with cervical cancer and a history of smoking,those of Han and ethnic minorities accounted for 1.0% and1.3%(P <0.01),whereas those with a history of drinking accounted for 0.40% and1.4%(P<0.05),respectively;both of these were higher in ethnic minorities.However,the proportions of passive smoking were 93.9% and 64.2%(P<0.01),whereas those of intense passive smoking were 84.9% and 66.3%(P <0.01),respectively,in the patients of Han and ethnic minorities;both of these were higher in the Han population.Taking effective contraceptive measures was a protective factor in preventing cervical cancer(OR=0.26,P <0.001),and this was more prominent among ethnic minorities(OR=0.01,P<0.001)than in the Han population(OR=0.29,P<0.001).2.Compared with the control group,a younger age at the last pregnancy(25.32 ±10.73 and 26.67 ± 9.49 years,P < 0.01),and higher number of pregnancies(≥3times: 66.3% and 58.4%,P<0.01)and childbirth(≥2 times: 67.7% and 55.8%,P<0.01)were observed in those of Han ethnicity,and were associated with a higher risk of cervical cancer.In contrast,an older age at menarche(14.58 ± 1.88 and 14.18 ±1.84 years,P < 0.01),younger age at first marriage(21.38 ± 3.25 and 22.21 ±3.68 years,P<0.01),younger age at first pregnancy(21.91 ± 3.02 and 22.57 ± 3.48 years,P<0.01),and greater number of deliveries(≥2 times: 68.8% and 62.9%,P<0.05)were associated with a higher risk of cervical cancer in ethnic minorities.3.The proportions of people with HPV infection in the cervical cancer case and control groups of the Han and ethnic minorities were 88.5% and 10.2%,83.8% and14.2%,respectively(P<0.01).Patients with cervical cancer in Yunnan Province were mainly infected with HPV genotypes 16,18,and 58,and the proportion of high-risk genotypes was 97.7%.HPV infection was the main risk factor for cervical cancer(OR=69.9,P <0.001),and the risk in ethnic minorities(OR=77.54,P <0.001)was higher than that in individuals of Han ethnicity(OR=64.77,P < 0.001).Mycoplasma/Chlamydia infection(OR=17.91,P < 0.001)and pelvic infection(OR=2.92,P=0.001)were risk factors for cervical cancer in the Han population,while urinary tract infection(OR=2.44,P < 0.05),genital tract bacterial infection(OR=3.32,P<0.01),and trichomonas vaginalis infection(OR=3.10,P<0.05)were risk factors for cervical cancer in the ethnic minorities.4.The average diameter of the tumor in patients with locally advanced cervical cancers was 5.27 ± 1.18 cm.Based on the short-term treatment effect,the maximum tumor remission rate was most marked in the CCRT group(effective rate: 55.4%),and the effective tumor remission rate in the NACT+RS group was higher than that in the BCRT+RS group(26.8% and 18.7%,P<0.01).Compared with RS,preoperative adjuvant therapy(neoadjuvant chemotherapy and brachy chemoradiotherapy)had no significant effect on reducing intraoperative hemorrhage and postoperative hospital stay,however,it could reduce the incidence of postoperative complications(vaginal stump infection and lymphedema).The proportions of postoperative complications in the three surgical treatment groups(RS,NACT+RS,and BCRT+RS)were 18.8%,11.1%,and 13.1%(P<0.05),respectively.Compared to the RS group,preoperative adjuvant therapy(neoadjuvant chemotherapy and brachy chemoradiotherapy)improved the local tumor pathological remission rate and controlled micro-metastases,and the postoperative pathological results revealed that the lymph node metastasis rate(19.0%,14.3%,and 32.6%,P < 0.01),deep stromal invasion(31.4%,15.4%,and39.1%,P <0.01),myometrial invasion of the uterine body(12.4%,8.8%,and 18.5%,P <0.05),lymphovascular invasion(12.4%,2.2%,and 18.5%,P <0.01),and high invasion(34.0%,20.3%,and 39.4%,P < 0.01)reflected the advantages of preoperative adjuvant therapy.5.Using the FACT-Cx scale to evaluate the quality of life of patients with locally advanced cervical cancer,the physical well-being score of the patients in the RS group was 23.93 ± 4.197,the social/family well-being score was 25.73 ± 3.602,the functional well-being score was 18.67 ± 4.97,cervix subscale score was 46.78 ±4.562,and the total score on the FACT scale was 135.04 ± 14.336,which were the highest scores among the four treatment groups.However,the PWB score,emotional well-being(EWB)score,and total score on the FACT scale for the BCRT+RS group were 17.20 ± 4.78,16.80 ± 4.59,and 119.20 ± 15.46,respectively,which were the lowest scores among the four treatment groups(P<0.01).The utility index(UI)and visual analogue scale(VAS)scores on the EQ-5D scale were the highest in the RS group,which were 0.95 ± 0.10 and 81.68 ± 13.81(P<0.01),respectively.The lowest scores were in the BCRT+RS group at 0.81 ± 0.18 and 65.00 ± 14.34(P <0.01),respectively.In the evaluation of the mental health status(Kessler10)of the four treatment groups,the highest and lowest scores were observed in the RS(44.32 ± 5.89)and CCRT(40.45 ± 6.472)groups,respectively,with a statistically significant difference(P<0.01).6.The 10-year PFS probabilities of patients in the preoperative adjuvant therapy group(NACT+RS and BCRT+RS)were 76.0% and 70.8%,respectively,which were higher than those seen in patients of the CCRT(70.4%)and RS group(59.5%)(P<0.001).Among the four treatment groups,the 10-year OS probability of the RS group was the lowest at 61.5%,while those of the CCRT,NACT+RS,and BCRT+RS groups were 73.3%,76.4%,and 70.4%,respectively(P>0.05).Postoperative lymph node positivity(hazard ratio[HR]=4.212,P < 0.001),deep stromal invasion of the tumor(HR=2.367,P < 0.001),lymphovascular invasion(HR=2.123,P < 0.01),myometrial infiltration of the uterine body(HR=2.181,P < 0.01),metastasis(HR=8.110,P < 0.001),and recrudescence(HR=5.093,P < 0.001)were the main factors affecting the long-term survival of patients with locally advanced cervical cancer.7.Among the four treatment groups,the fee for comprehensive medical service,diagnosis,and treatment,and the total fee(direct medical cost)were the highest for the NACT+RS group at 11,032.53 ± 5,344.11 yuan(RMB),18,891.14 ± 8,059.53yuan(RMB),16,358.85 ± 8,968.08 yuan(RMB),and 90.941.16 ± 42,512.30 yuan(RMB),respectively(P < 0.01).The direct non-medical,direct economic,indirect economic,and total economic costs of patients were the highest for the BCRT+RS group at 15,375.69 ± 8,843.23 yuan(RMB),104,565.11 ± 51,597.60 yuan(RMB),8,671.35 ± 4,379.81 yuan(RMB),and 113,236.47 ± 55,492.08 yuan(RMB),respectively(P< 0.05).8.Within one year of comprehensive treatment for patients with locally advanced cervical cancer,the incremental cost-effectiveness ratios(ICER)of the CCRT,NACT+RS,and BCRT+RS groups,compared with the RS group,were: 78,391.48yuan(RMB)/year,73,449.17 yuan(RMB)/year,and 80,910.55 yuan(RMB)/year;the incremental cost-utility ratios(ICUR)were 81,269.35 yuan(RMB)/QALY,76,474.64yuan(RMB)/QALY,and 84,009.58 yuan(RMB)/QALY;and the incremental cost-benefit ratios(ICBR)were: –1.24,–1.07,and –1.41.Thus,the NACT+RS treatment was more cost-effective,cost-effective,and cost-effective.9.Based on the health and economic analysis of long-term treatment,the Markov model simulating 30 years of treatment for locally advanced cervical cancer,demonstrated that the cost-utility ratios(CUR)of the four treatment groups(CCRT,RS,NACT+RS,and BCRT+RS)were 61,253.12 yuan(RMB)/QALY,60,613.38yuan(RMB)/QALY,58,132.55 yuan(RMB)/QALY,and 64,878.63 yuan(RMB)/QALY,respectively.Compared with the RS treatment,the incremental cost-utility ratios(ICUR)of the CCRT,NACT+RS,and BCRT+RS treatments were71,715.51 yuan(RMB)/QALY,47,214.37 yuan(RMB)/QALY,and 569,072.18 yuan(RMB)/QALY,respectively.The threshold of willingness to pay(WTP)was 150,897yuan(RMB)/QALY,and the ICUR of CCRT and NACT+RS were lower than the WTP,indicating that both groups had cost utility.The scheme with the lowest CUR and ICUR was NACT+RS;therefore,NACT+RS has more cost-utility advantages.Conclusions:1.Infection with high-risk HPV genotypes(types 16,18,and 58)is the most important risk factor for cervical cancer in Yunnan Province.Passive smoking and lack of effective contraceptive measures increase the risk of cervical cancer.A younger age at the last pregnancy,and greater number of pregnancies and childbirths among the Han population,as compared with the older the age at menarche,younger age of first marriage,younger age of first pregnancy,and greater number of childbirths in the minorities,increased the risk of cervical cancer.Mycoplasma/chlamydia infection and pelvic infection in the Han population,urinary tract infection,germ tract bacterial infection and trichomonas vaginalis infection in the ethnic minorities were closely related to the incidence of cervical cancer.2.In this study,most patients with locally advanced cervical cancer underwent direct radical surgery.However,research results indicate that preoperative adjuvant therapy reduces surgical complications,improves the pathological remission rate of tumors,and locally controlls micro-metastases and recurrence,thus rendering it essential.It also has the same performance in terms of the 10-year PFS and OS probabilities of patients.3.Through health and economic analysis of short-term treatment of patients with locally advanced cervical cancers,the NACT+RS had better cost-effectiveness,cost-effectiveness,and cost-effectiveness.According to the decision analysis and health economic evaluation of patients’ long-term treatment outcomes,both CCRT and NACT+RS had better cost utility than RS,while NACT+RS had more cost utility advantages.