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研究生:廖朝聖
研究生(外文):Chao-Sheng Liao
論文名稱:小型肝細胞癌經皮酒精注射治療之臨床監視及決策分析
論文名稱(外文):Clinical surveillance and decision-making on small hepatocellular carcinoma (HCC) treated with percutaneous ethanol injection (PEI)
指導教授:陳秀熙陳秀熙引用關係
指導教授(外文):Tony HH Chen
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:流行病學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:135
中文關鍵詞:Small hepatocellular carcinomaPercutaneous ethanol injectionWeibull modelCost effectiveness analysisMarkov Model
外文關鍵詞:小型肝細胞癌經皮酒精注射Weibull模式成本效益分析馬可夫模式
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研究背景:小型肝細胞癌接受經皮酒精注射治療後,死亡危險性是否會隨著時間而增加;這些小腫瘤預後如何被治療前變項及一群隨時間變動之預測因子所影響極少被提及。除了以死亡作為主要研究終點之外,利用經皮酒精注射治療後腫瘤復發作為中介終點,已成小型肝細胞癌接受經皮酒精注射治療後,臨床監測的核心主題。病程中治癒 ─ 復發的發展也提高了小型肝細胞癌接受經皮酒精注射治療的成本,引起對小型肝細胞癌接受經皮酒精注射治療,或手術切除之成本效果分析的注意。
研究目的:本研究目的在發展一個從治療前相關變項,並採用非恆定死亡率與因時變動的預測變項對主要終點 ─ 死亡的完整評估,對基於腫瘤復發的中介終點加以評估,並對小型肝細胞癌接受經皮酒精注射治療與手術療法進行成本效果評估。
研究方法:本研究對108名小型肝細胞癌(小於5公分)患者,接受經皮酒精注射治療或合併動脈血管栓塞的病程發展及預後評估。所有病患之肝功能皆在Child-Pugh A(84人)及Child-Pugh B(24人)。治療後每月死亡危險性亦取對數納入評估,利用Weibull模式闡明治療前臨床病理檢測變項。系列臨床及實驗室檢查監測資料皆由病歷回顧獲得,我們利用時間相關Cox回歸模式建構預測病患死亡風險即時變動評分系統。並利用三階段連續型馬可夫模式估計相關轉移參數
研究結果:
一、病患月死亡率增加為4.7%(百分之九十五信賴區間:3.7%-5.7%),Child-Pugh B病患之死亡相對危險性為2.8倍(百分之九十五信賴區間:1.52-5.16)。AST較高者或酒精性肝硬化者死亡之相對危險性為兩倍(百分之九十五信賴區間:1.14-3.42)。
二、某些預測因子的時間序列變化與累積存活曲線平行,高血清胎兒蛋白為最顯著的時間相關預測因子,其他顯著預測因子包括Asparatate transaminase, Bilirubin, Alkaline phosphotase, Albumin, 及Prothrombin time。即時變動死亡風險評分系統顯示:六個月,一年,及兩年存活預測臨界值各為48,39及36;其對應敏感度為100%,85%,74%;特異度為97%,96%,88%。本預測模式特別是一年內之預測有好的效度。
三、小型肝細胞癌病人約57.19%(95%信賴區間39.82%-74.56%)治療後進入初次治癒階段,年齡和腫瘤大小數目為兩個顯著影響因子。每增加一歲伴隨3%復發風險(OR-1.03; 95%信賴區間:1.00-1.06),也伴隨增加2%再度治癒的機率。大型或多發性腫瘤較單一或小腫瘤有3.7倍的機會(OR-1.03; 95%信賴區間:1.99-6.86)復發;也有2.22倍( 95%信賴區間:1.06-4.64)再治癒機率。其他因時變動的顯著影響因子包括胎兒蛋白,白蛋白,球蛋白,AST大於100 U/L,高膽紅素,高鹼性磷酸脢及凝血脢元時間延長。
四、接受經皮酒精注射治療小型肝細胞癌患者在治療後頭45個月有較佳存活情形;但隨後手術治療組存活情形及超越經皮酒精注射治療組,經皮酒精注射治療及手術治療五年存活率分別為19%及33%,平均成本效果比分別為每增加人月需新台幣19,972.22元及18,748.45元,增加成本效果比為新台幣33,274元。
結論:本論文發展對小型肝細胞癌經皮酒精注射治療的評估系統,對臨床患者接受經皮酒精注射治療提供極大助益。
Background: Rarely has been addressed as to whether risk of death for small hepatocellular carcinoma (HCC) treated by percutaneous ethanol injection increases with time and how prognosis of these small tumours is affected by pretreatment variables and a constellation of time-varying predictors. In addition to using death as primary endpoint, intermediate endpoint based on relapse of tumor after the application of PEI has become the core of subject for clinical surveillance of small HCCs treated by PEI. The disease process in terms of remission-relapse may also increase the cost of PEI, which calls attention to cost-effectiveness analysis for the comparison between PEI and surgery.
Aims: We aimed to develop a comprehensive clinical surveillance system for evaluation of primary endpoint in mortality in association with pre-treatment variables allowing for non-constant hazard rate and dynamic change of time-varying predictors, for evaluation of intermediate endpoint based on relapse of tumour, and for cost-effectiveness analysis of comparing two treatment modalities.
Methods: A total of 108 patients with hepatocellular carcinoma smaller than five cm in diameter treated by percutaneous ethanol injection with or without transcatheter arterial chemo/embolization were recruited. All patients’ liver function reserve were classified as Child-Pugh A (n=84) or B (n=24) at diagnosis. Pre-treatment variables and series of laboratory data and clinical assessments were retrieved from medical records of surveillance and treatments. Logarithm of hazard rate (per month) with time since therapy was assessed. The Weibull model was used to elucidate the effect of pre-treatment clinico-pathological variables on prognosis.The time-dependent scoring system for the prediction of risk for death was developed on the basis of time-dependent Cox regression model. A three-state continuous Markov model was constructed to estimate the transition parameters.
Results:
Part I: The rate of death increased by 4.7% (95% CI: 3.7-5.7%) per month since treatment. Child-Pugh B status was associated with a 2.8-fold risk (95% CI: 1.52-5.16) of death. Those with a high level of AST or alcoholic cirrhotics had a two-fold risk (95% CI: 1.14-3.42) for death from HCC.
Part II: The time trends of some predictors parallels cumulative survival of small hepatocellular carcinoma cases. Higher serum alpha-fetoprotein level was identified the most significant time-dependent predictor. Other significant predictors included asparatate transminase, bilirubin, alkaline phosphatase, albumin, and prothrombin time. Time-dependent surveillance scoring system shows the cutoff points of scores for 6-month, 1-year, and 2-year survival were 48, 39, and 36, respectively; with the corresponding estimates of sensitivity, 100%, 85%, 74%, and estimates of specificity, 97%, 96%, 88%, respectively.
Part III: Prompt initial remission after curative treatment was achieved in 57.19% (95% CI: 39.82%-74.56%), treatment modality was significant associated with initial remission. Age and tumour morphology were two significant predictors. An increased one unit of age (in year) led to 3% extra risk for relapse (OR=1.03, 95% CI:1.00-1.06), which was slightly larger than 2% additional chance of returning to remission. Multiple nodules or large tumour had 3.7-fold (95% CI: 1.99-6.86) risk for relapse, which was also greater than 2.22-fold (95% CI: 1.06-4.64) chance of remission as compared with solitary nodule or small tumour. Significant time-varying factors included level of AFP, level of albumin, level of globulin, level of AST greater than 100 U/L, high level of bilirubin, high level of ALKP, and longer prothrombin time.
Part IV: Patients treated by PEI have better survival than those treated with surgery before 45 months post treatment. Cumulative survival of PEI treated patients become worse later with 5-year survival of 19% in comparison with 33% in surgical treated patients. Average cost-effectiveness ratios for surgery and non-surgery were 18,748.45 NTD and 19,972.22 NTD per life-month saved. The incremental cost-effectiveness ratio was 33,274 NTD.
Conclusion: Systematic evaluation of clinical surveillance of small HCCs treated by percutaneous ethanl injection was developed in this thesis. This system is very useful for clinical management of patients treated by percutaneous ethanl injection.

中文摘要…………………………………………… 1-3
Abstract……………………..……………………… 4-7
Introduction……………………..……..…………… 8-12
Literature Review……………………..……………
Overall Survival…………………………….….…………………. 13
Cumulative Survival by different staging systems…....…………... 14
Predictors for the prognosis of HCC……………………...………. 15
Tumour Size………………………………………………………. 15
Other Tumours-related Factors……………………………………. 16
Liver Cirrhosis……………………………………………………. 17-18
Alpha-fetoprotein (AFP)………………………………………….. 19-20
Scoring System…………………………………………………… 21-24
Treatment of Hepatocellular Carcinoma…………………………. 25-26
Surgical resection………………………………………………… 26-27
Percutaneous Ethanol Injection (PEI)……………………………. 28-29
Liver transplantation……………………………………………... 29-31
Summary and comparison of hazard rate between surgery and non-surgery….. 31-34
Proposal Subjects 34-36
Table 2-1. Estimated hazard rates of death for patients with HCC treated by PEI, from the literature between 1995 and 2000. 37-38
Table 2-2. Estimated hazard rates of death for patients treated with hepatic resection 39
Part 1
Patients………………………………………………………........ 40-42
Prognostic factors………………………………………………… 43
Statistical Methods………………………………………………..
1. Time trend equations………………………………………… 43-44
2. The Weibull model…………………………………………... 45-46
Part 2
Patients…………………………………………………………… 47
Clinical surveillance of HCC patients……………………………. 48
Statistical Analysis……………………………………………….. 48-50
Part 3
Data Source………………………………………………………. 51
Remission and Relapse…………………………………………... 52
Types and Definition of Predictors………………………………. 53
Model Specification ……………………………………………... 53
Statistical Analysis……………………………………………….. 54-56
Part 4
Decision Framework…………………………………………….. 57
Data Sources……………………………………………………... 57
Surveillance strategy……………………………………………... 59
Base-case Estimates……………………………………………… 60
Monte Carlo Computer Simulation……………………………… 60
Table 3-1. Cumulative survival of small HCC cases by demographic and clinico-pathologicalal variables 61
Table 3-2. Strategy of clinical surveillance……………………...……....... 62
Figure3-1: Framework of Clinical Surveillance For Small Hepatocelluar Carcinoma 63
Figure 3-2: Markov decision analysis on cost-effectiveness analysis using tree-age 64
Overall Remission-Relapse-Death 74
Part 1
1. Cumulative survival and hazard rate………………………….…….. 66-68
2. Multiple Regression using the Weibull model…..…………….……. 68
3. The Weibull model for prediction of survival for HCC cases treated with PEI 69
Part 2 70-72
Part 3
Overall Remission-Relapse-Death………………………………….. 73-74
Remission-Relapse-Death by Predictors…………………………… 74-77
Goodness of fit ………………………………………………………. 77
Part 4
Base-case estimates…………………………………………………. 78
Average and incremental cost-effectiveness ratios…….………….. 78-79
Sensitivity analysis………………………………………………….. 79
Table 4-1. Cumulative survival of small HCC cases by demographic and clinico-pathologicalal variables 80-81
Table 4-2 Hazard ratios from the Weibull regression model……………. 82
Table 4-3 Univariate analysis for time-dependent predictors…………... 83
Table 4-4 Multivariate analysis for time-dependent predictors……........ 84
Table 4-5 Time-dependent surveillance score and cumulative survival after diagnosis by 3-month interval 85-86
Table 4-6 The types of transition, transition probabilities, and observed number of transition for the overall three-state continuous Markov model 87
Table 4-7 Univariate analysis of the effects of baseline characteristic on initial remission 88
Table 4-8 Univariate analysis of the effects of baseline characteristics on remission-relapse-death transition 89
Table 4-9 Univariate analysis of the effects of time-varying predictors associated with remission-relapse-death 90
Table 4-10 Multivariate analysis for the effect of baseline characteristics and time-varying factors on remission-relapse-death model 91-92
Table 4-11 Model validation of the three-state Markov model taking probability of initial remission into account 93
Table 4-12 Relevant parameters for treatment modalities for small hepatocellular carcinoma 94
Table 4-13 Relevant costs for treatment modalities for small Hepatocelluar carcinoma 95
Table 4-14 The result of cost-effectiveness analysis for small Hepatocelluar carcinoma treatment 96
Table 4-15 The results of sensitivity analysis by changing value of relevant parameters or costs 97
Figure 4-1 .The hazard rate of death for small HCC cases treated by PEI with or without TAE 98
Figure. 4-2. 98-99
Figure 4-3 100
Figure 4-4 101
Figure 4-5 Cumulative probabilities of returning to remission, having relapse, and deteriorating into metastases or death 102
Figure 4-6 Cumulative rate of remission, relapse, and metastases or death by baseline clinical characteristics 105
Figure 4-7 Five-year survival rate of surgery and non-surgery 104
Discussion
Part 1
1.Implication for the surveillance of small HCC cases treated by PEI…… 105
2.Comparisons between current study and earlier findings 105
3.Prognostic factors 106-107
4.Methodological consideration 107-109
Part 2 110-115
Part 3
Overall Remission-Relapse-Death 116
Significant Predictors 116-117
Usefulness of Model 117-118
Conclusion 118
Part 4 119-120
Conclusion 121
Table 5-1 The hypothetical cases for low, median, and high risk, respectively 122
References 123-135

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