Drug Costs Analysis Among Cancer Inpatients And Evidence-based Medicine About Risk Factors For Gynecological Cancer

Cancer is one of the leading causes of death in both developed and developing countries.In the United States,when deaths are aggregated by age,cancer has surpassed heart disease as the leading cause of death for those younger than age 85.As indicated previously by us,the populations in developing countries adopt Western diets and a high-stress lifestyle,the change of geographic distribution of many chronic diseases incidence has emerged,with a marked elevation in developing countries.According to national health statistics,cancer ranks as the first major cause of death among urban population and third among rural population in China.Cancer is also associated with an immense economic burden on patients,families and society.Estimation of charges and costs for cancer has been performed in many developed countries.However,little has been known about the medical expenditures for cancer in China.Cancer is considered to be a result of gene-environment interactions, which is a complex,multi-step and multi-factorial process.Many epidemiological studies and randomized controlled trials are aimed to assess the potential risk factors of cancer.However,due to the differences in the methodology,the results varied.Meta-analysis is a statistical technique for summarising,and reviewing the finding from independent studies to derive an overall estimate.By using meta-analysis,a wide variety of questions can be investigated.PartⅠ:Social health insurance and drug expenditures among cancer inpatients in ChinaBetween 1950 and 1980,in the urban areas the health care system in China traditionally comprised two major schemes:the government insurance scheme(GIS)covered workers in the public sector and government agencies as well as students in colleges and universities;and the labor insurance scheme(LIS)covered the workers in state-owned and collective-owned enterprises.However,GIS and LIS are third-party insurance,providing comprehensive benefits with minimal cost sharing to constrain beneficiaries,which contributed to China's rapid health care cost inflation.Since 1978 when the economic reform was launched,the planned economy of China has been replaced by the market economy.Meanwhile, China announced series of health insurance system reform to control health care costs without reducing or dropping coverage.In 1998,the government made a major policy decision to establish a social health insurance(SHI)program for urban workers which replaced the existing GIS and LIS.The purposes of the reform were to ensure that the new SHI can be more efficient and more equitable in accessing health care. Furthermore,a new pricing structure was introduced.Most of the established services were priced below cost,while profits can be made from drugs and technology.And to our knowledge,little is known about the association of health insurance coverage with drug expenditures among cancer patients in China.The present study is to assess the differences in drug expenditures among cancer inpatients according to SHI status and to explore the factors that influence drug costs.One thousand six hundred and thirty one cancer inpatients were included in our study.The median drug cost was approximately RMB 8,069 per inpatient.Among these seven cancers,the median of drug cost was highest for esophageal cancer(median=RMB 11,028)and lowest for breast cancer(median=RMB 4,309).The drug cost for SHI inpatients (median=RMB 8,933)was significantly higher(P＜0.001)than that for non-SHI inpatients(median=RMB 7,616).Statistics tests for each type of cancer also showed that the differences were significant as regards breast (P＜0.001),lung(P=0.018),liver(P=0.046),pancreatic(P=0.040), esophageal(P=0.048)and colorectal(P=0.004)cancer,whereas the drug cost for gastric cancer showed no measurable difference(P=0.400).We also performed stratified analyses by the median age of all patients (59 years),LOS,sex,type of admission.In statistical analyses stratified by age,sex and type of admission,the difference between SHI and non-SHI group were significant.When stratified by LOS,the significant differences according to SHI status remained in≤20(P＜0.001)and 20-40 LOS subgroups(P=0.011),but was lost in≥41 LOS subgroup(P=0.568).We compared the drug cost per day between insured and uninsured inpatients.We did not observe a significant difference in drug cost per day between SHI and non-SHI patients(P=0.06).And the drug cost per day for female insured patients was significantly higher than that for female uninsured patients(P=0.016).The differences were also significant in younger patients(P=0.023)and in patients with 21-40 LOS subgroup(P=0.003).The results of multiple linear regression analysis demonstrated that older age,SHI coverage,longer LOS,higher severity of admission,and female sex were associated positively and independently with higher drug costs.Among these factors,LOS made the largest contribution. Furthermore,the results of multiple linear regression analysis also demonstrated that age made the most effects on higher drug costs for non-SHI patients,while LOS was the most influential factor among SHI patients.PartⅡ:The association of tea consumption with ovarian cancer risk:a meta-analysisTea,derived from the top leaves of the plant Camellia sinensis,is second only to water in terms of worldwide popularity as a beverage. Several laboratory studies found that tea may have anticancer activity. Most of tea researches to date have focused on the effect and mechanism of green tea.The main catechins,effective component in green tea,are epigallocatechin gallate(EGCG)and epicatechin gallate(ECG), epigallocatechin(EGC),and epicatechin(EC)catechins.In these components,EGCG has been the focus of a great deal of attention.It has been found to participate in induction of apoptosis and cell cycle arrest, antioxidation and scavenging the free radicals,inhibition of tumor invasion and metastasis.Extracts of black tea such as theaflavins and thearubigins also have been proved by some in vitro and animal studies to have anticarcinogenic properties,such as modulation protein expression of H-ras,c-Myc,p53,and Bcl-2 genes and induction of apoptosis.Moreover,a number of epidemiologic studies also have been conducted to investigate the association of tea consumption with cancer risk including ovarian cancer risk.However,results of these studies were not entirely consistent.And to our knowledge,there is no meta-analysis concerning association between tea consumption and ovarian cancer risk.Therefore,we undertook this meta-analysis to further clarify the association of tea consumption with ovarian cancer risk.Two cohorts and seven case-control studies were included.The summary RR of all studies,did not show that tea consumption was associated with decreased risk of ovarian cancer(RR=0.84,95% CI=0.66-1.07).We also performed a sensitivity analysis which confirmed the stability of our results.The summary RRs neither from cohort studies(RR=0.69,95%CI=0.45-1.06)nor from all case-control studies(RR=0.87,95%CI=0.67-1.13)showed that tea intake was related to decreased ovarian cancer risk.When we separated the population-based case-control studies from their hospital-based case-control studies,we found no apparent difference between hospital-based case-control studies(RR=0.73,95%CI=0.46-1.15)and population-based case-control studies(RR=1.06,95%CI=0.88-1.27).The summary RR of eight studies in all Western countries(RR=0.98, 95%CI=0.84=1.15)and the summary RR of six case-control studies in Western countries were not substantially altered(RR=1.04,95%CI= 0.93-1.15).The test for difference between study from China and studies from Western countries was statistically significant(P＜0.001).There was statistically significant heterogeneity in results across the nine studies(P＜0.001)and seven case-control studies(P＜0.001). However,results from cohort studies alone did not reject the homogeneity hypothesis(P=0.181).The sensitivity analysis showed that the study in China as contributing most to the results and heterogeneity. When this study was excluded,the test of heterogeneity was not statistically significant in results across remain eight studies(P=0.085) and six case-control studies(P=0.193).In addition,no indication of publication bias was found from both visualization of the funnel plot and the Egger's test(P=0.191).PartⅢ:The association of hormone replacement therapy with ovarian cancer risk:a meta-analysisHormone replacement treatment(HRT)is a form of treatment designed to replace one or more female hormones,commonly estrogen and progesterone.In addition to treating the menopausal symptoms such as hot flashes and sleep disorders,HRT gained popularity because it was thought to help reduce the risk of heart disease and bone fractures caused by osteoporosis.However,a number of studies have reported that HRT could increase the risk of cancer especially cancer of female reproductive organs.The available evidence indicated that the risk of breast or endometrial cancer was increased among HRT users,the risk increasing with increasing duration of use.However,knowledge about the relation between HRT use and ovarian cancer risk is less unequivocal and results of previous meta-analyses varied.There was either no suggestion of or a weak if any association between HRT and ovarian cancer and results were mainly restricted to finding of case-control studies.Several prospective cohort studies with large sample sizes and long term follow-up were published recently, providing evidence for an increased risk of ovarian cancer in HRT user. Therefore,we undertook this meta-analysis to further clarify the association of hormone replacement therapy with ovarian cancer risk.Eight prospective studies met the inclusion criteria.The ever use of HRT was associated with a statistically significant 24%increased risk of ovarian cancer(95%CI=1.15-1.34);there was no significant heterogeneity among studies.In addition,no evidence of publication bias was observed with a nonsignificant Egger test(P=0.496).Compared with individuals who had never used HRT,those with current hormone use had a significant higher risk of ovarian cancer(RR=1.28,95% CI=1.15-1.42).Furthermore,Risk was higher among current users of more than 5 years(RR=1.47,95%CI=1.12-1.92)than among those of less than 5 years(RR=1.04,95%CI=0.91-1.20).However,for those with former HRT use,the association was not statistically significant (RR=1.03,95%CI=0.95-1.13).And we also did not find risk estimates significantly related to the duration of use for women who had former HRT use for less than 5 years(RR=1.00,95%CI=0.88-1.13),and for duration of 5 years or more(RR=1.10,95%CI=0.76-1.61).Four cohort studies addressed the association of ERT and EPRT with ovarian cancer, respectively.And a stronger association of ovarian cancer risk was noted in ERT users(RR=1.51,95%CI=1.21-1.88)than in EPRT users (RR=1.24,95%CI=1.00-1.54). Nineteen case-control studies were included.Compared with women who had never used HRT,the pooled estimate of ovarian cancer was 1.19 (95%CI=1.02-1.40)for those who ever used HRT;but there was some indication of heterogeneity among studies.By using a stepwise process, we determined that most of the heterogeneity in the ever-use summary RR was accounted for two studies by Hartge et al.and by Tavani et al. When these two studies were excluded,the remaining studies were homogenous(P=0.120),and the summary estimate for ever use of HRT and ovarian cancer incidence was 1.19(95%CI=1.07-1.32).In additional, we did obtain evidence of publication bias as shown by a statistically significant P value of 0.064 from the Egger's test.The summary estimate was 1.17(95%CI=1.01-1.35)when we pooled eight case-control studies with population-based controls.When we combined 11 case-control studies with hospital-based controls,the association was not statistically significant(RR=1.21,95%CI=0.92-1.60).Summary RRs for the development of ovarian cancer with different type of hormone use were based on data abstract from six studies.And a stronger association of ovarian cancer risk was still noted in ERT users(RR=1.19,95%CI 1.01-1.40)than in EPRT users(RR=1.01,95%CI 0.83-1.22).PartⅣ:The association of cigarette smoking with endometrial cancer risk:a meta-analysisEndometrial cancer originates in the endometrial lining of the uterus. The major etiologic hypothesis for the development of endometrial cancer is exposure to high levels of estrogen in conjunction with inadequate progesterone.Several laboratory studies found that smoking could decrease the risk of endometrial cancer through its anti-estrogenic effect.The antiestrogenic effects of cigarette smoking might through increased level of 2-hydroxylation of estradiol which could decrease cellular proliferation and endometrial cancer risk.In addition,cigarette smoking could increase circulating androgens which might decrease estrogen-induced cellular proliferation in endometrial glands and protect against the development of endometrial cancer.During last three decades, many epidemiological studies have evaluated the association between cigarette smoking and endometrial cancer risk,and results of these studies have not yet been summarized.Ten prospective and 24 case-control studies were included.We found that ever smoking was statistically significantly associated with reduced risk of endometrial cancer among prospective(RR=0.81,95% CI=0.74-0.88)and among case-control studies(RR=0.72,95% CI=0.66-0.79);there was statistically significant heterogeneity among case-control(P=0.021)but not among prospective studies(P=0.338).By using a stepwise process,we determined that most of the heterogeneity was accounted for two studies by Shields et al.and by Weiss et al.When these two studies were excluded,the summary estimate was unchanged (RR=0.73,95%CI=0.67-0.81),but a concomitant shift in heterogeneity was measured(from P=0.02 to P=0.180).Egger's test suggested no statistically significant asymmetry of the funnel plot for prospective (P=0.460)or cancer-control(P=0.892)studies.The RR for current smoking were 0.74(95%CI=0.64-0.84)for prospective studies and 0.63(95%CI=0.55-0.72)for case-control studies. The RR for former smoking were 0.88(95%CI=0.78-0.99)for prospective studies and 0.80(95%CI=0.72-0.88)for case-control studies.Six prospective and six case-control studies were included in this quantitative analysis.Overall,we found that an increment of 20 cigarettes per day was significantly inversely associated with endometrial cancer risk in prospective studies(RR=0.84,95%CI=0.71-0.99)or in case-control studies(RR=0.73,95%CI=0.60-0.89).Several studies have examined this association according to menopausal status.Pooled results found that there was a statistically significant reduction in endometrial cancer risk for cigarette smoking among postmenopausal women(RR=0.71,95%CI=0.65-0.78)but not among premenopausal women(RR=1.06,95%CI=0.88-1.28).The difference between two estimates was statistically significant(P＜0.01). One prospective study and five case-control studies have examined this association according to HRT status.The risk reduction appeared to be stronger among HRT users(RR=0.45,95%CI=0.29-0.70)than among none users(RR=0.65,95%CI=0.51-0.84).PartⅤ:The association of tamoxifen with endometrial cancer risk:a meta-analysisTamoxifen is a nonsteroidal triphenylethylene derivative that has been widely used to treat breast cancer since the early 1970s and that also reduces the risk of a contralateral malignancy in patients with unilateral breast cancer.Tamoxifen is being investigated in trials as a possible prophylactic agent in women at high risk of breast cancer.The most serious adverse effect of tamoxifen is its potential tumor-promoting activity.Treatment with tamoxifen has found to be associated with an increased risk of endometrial cancer,in accord with the selective uptake of tamoxifen by endometrial tissue,with its agonist effects on the endometrium,and with laboratory results.However,the magnitude of the increased risk varies substantially between studies.In these studies,the effect of tamoxifen on endometrial cancer has been reported to increase the incidence rate from two-fold to seven-fold.And to our knowledge, there is no meta-analysis concerning this association.Therefore,we undertook this meta-analysis.Fourteen randomized controlled trials(RCTs)were included. Tamoxifen use was found to be statistically significantly associated with higher risk of endometrial cancer(RR=3.0,95%CI 2.30-3.91).The Cochran's Q test resulted in a P=0.74,indicating that the results of the RCT studies were homogeneous.The funnel plot had the expected funnel shape.The P values for the Egger test were P=0.21,suggesting a low probability of publication bias.When women who were postmenopausal or in treatment trials were considered separately,risk increases were greater(RR=5.19,95%CI 2.58-10.47).When women in risk reduction trials were considered separately,their risk increase was still statistically significant(RR=2.61,95%CI=1.89-3.60).Nine case-control studies and five cohort studies were included. Tamoxifen use was modestly significantly related to the risk of endometrial cancer among observational studies(RR=1.90,95%CI 1.40-2.47).The Cochran's Q test resulted in a p＜0.01,indicating that the heterogeneity among the studies were high.The funnel plot also had the expected funnel shape and the P values for the Egger test were p=0.88. We found that the modest increase of endometrial cancer risk was statistically significant among the case-control studies(RR=2.18,95% CI=1.48-3.21)or among the cohort studies(RR=1.36,95% CI=1.10-1.67).We also conducted analysis based on data abstracted from seven studies to evaluate the association of endometrial cancer risk with different durations of tamoxifen use.The summary risk estimate for less than five years and were 1.75(95%CI=1.29-2.37).More than five years use of tamoxifen was found to be strongly associated with increased risk of endometrial cancer(RR=5.86,95%CI=3.79-9.06). And the difference between these two estimates was statistically significant(P＜0.01).We compared the pooled RR estimates derived from the two separate analyses.The difference between estimates was statistically significant (P=0.02).In addition,we performed a combined analysis of RCTs and observational studies.Tamoxifen use was significantly related to the risk of endometrial cancer(RR=2.02,95%CI 1.82-2.25).