族群性篩檢及治療幽門螺旋桿菌感染對於胃癌與胃食道逆流症自然病史之影響與其經濟評估

Effect of Population-Based Screening and Treatment of Helicobacter pylori Infection on the Natural Course of Gastric Cancer and Gastroesophageal Reflux Disease and the Economic Evaluation

李宜家(Yi-Chia Lee)

指導教授 ： 陳秀熙

國立臺灣大學/公共衛生學院/流行病學研究所/博士(2010年)

https://doi.org/10.6342/NTU.2010.00426

摘要

幽門螺旋桿菌除菌治療可降低胃黏膜的發炎反應，然而族群性大規模除菌治療對於預防胃癌之效益目前仍然未知，本論文第一章節首先使用干涉時間序列設計量化除菌治療對於對於胃癌自然病史之影響。於1995–1999、2004、以及2008年計劃針對胃癌高風險之馬祖居民施行之大規模內視鏡篩檢及胃黏膜組織切片檢查，並於2004及2008年全面篩檢及治療幽門螺旋桿菌感染，研究目的為量化預防胃癌及癌前病變之效益。結果顯示除菌治療降低細菌盛行率之效益為91.4% (95%信賴區間 [CI]: 89.3–93.4%)，細菌再發率為每人年1% (95%CI: 0.6–1.4%)，在幽門螺旋桿菌除菌治療前，胃萎縮發生率為每人年8.2% (95%CI: 6–10.3%)，治療後發生率下降至每人年3.5% (95%CI: 1–6.1%)，相對風險為 0.434 (95%CI: 0.194–0.951)，預防胃萎縮之效益估計為57% (P=0.02)。而腸組織化生於除菌前發生率為每人年4.7% (95%CI: 3.1–6.2%)，於除菌治療後，其發生率略升為每人年6.1% (95%CI: 5–7.1%)，相對風險估計為1.291 (95%CI: 0.881–1.891)，代表此介入無法預防腸組織化生。針對胃癌，除菌治療之前1999–2003年之五年平均胃癌發生率每十萬人年40.3 (95%CI: 20.6–60.0)，於除菌治療之後，2004–2008年五年平均胃癌發生率為每十萬人年30.4 (95%CI: 15.0-45.7)，相對風險為0.753 (95%CI: 0.372–1.524)，介入之效益為25%，但未達顯著水準 (P=0.21)。
我們接著使用卜瓦松迴歸模型調整歷史效應之影響，模型估計歷史效應約貢獻每年6%之胃萎縮下降趨勢，調整歷史效應後介入預防胃萎縮效果估計為61%，與先前以發生率比較估計之效益相似。對於腸組織化生，歷史效應約可貢獻每年6%之下降趨勢，結果仍顯示介入無法預防腸組織化生。我們再使用卜瓦松迴歸模型分析1995–2008年胃癌發生率之長期趨勢，歷史效應約可貢獻每年10%之下降趨勢，介入後2004–2008年與介入前1995–2003年相較，胃癌發生率下降了41%，然仍未達統計上之顯著水準 (P=0.09)。除菌治療對於逆流性食道炎發生及惡化卻有顯著影響，除菌治療後食道炎發生率每人年為6% (95%CI: 5.1–6.9%)。本研究結果證實介入對於預防胃萎縮之效果卓越，此模型可外推至其他高風險族群。
根據論文第一章節大規模除菌治療伴隨逆流性食道炎之增加，本論文第二部份使用2003–2006年台大醫院健康管理中心內視鏡長期追蹤資料，使用含有隨機效應之馬可夫多階段模型來量化胃食道逆流症自然病史，評估代謝性風險因子對於其自然病程之影響，立意對此新興疾病設計預防策略。於2003–2006年之期間內我們共收集了3,669位重複接受上消化道內視鏡篩檢之民眾，我們使用均質性時間連續性之三階段馬可夫模型分析此長期追蹤資料，結果顯示連續三次之篩檢間隔中分別有12.2%、14.9%及17.9%之受檢者由正常食道黏膜進展為糜爛性食道炎，而有42.5%、37.3%及34.6%由輕度食道炎回復正常，模型推估轉移速率為：正常者每年有0.151人次 (95%CI: 0.136–0.165) 於次年產生輕度食道炎，而輕度食道炎患者每年有0.079人次 (95%CI: 0.063–0.094) 於次年進展至重度食道炎，而輕度食道炎患者每年也有0.481人次 (95%CI: 0.425–0.536) 回復正常；然而，重度食道炎患者若無接受妥善藥物治療，將無回復機會；多變數迴歸模型顯示男性 (相對危險性：4.31)、抽菸 (1.2)、以及代謝症候群 (1.75)，會增加罹患食道炎之風險，而短期之組織胺第二型受器拮抗劑或氫離子幫浦抑制劑治療可增加食道炎回復正常之機會 (0.54)，而有助於食道炎回復正常之歸因比可量化為：27%歸因於短期之藥物治療，而73%歸因於生活型態之調整，如戒菸、減重等作為。研究顯示胃食道逆流症與一般常見疾病相似，可表現出慢性進展及回復之自然病史，於群體中有一連串不同嚴重程度之臨床症狀，其異質性可由個體間風險因子多寡之不同，導致快慢不同之病程速率來解釋；了解代謝性風險因子之不良影響，對於此病症之預防及內視鏡資源妥善運用具有重要意義。
經由本論文第一部份，我們證實幽門桿菌除菌治療可預防胃萎縮之發生，進而加速胃癌風險之下降，然而有些民眾之胃炎變化卻已無法藉由除菌而改善，因此於論文之第三章節，我們將基於第一章節馬祖地區胃癌防治計畫之實際資料，使用第二章節之馬可夫多階段複迴歸比例風險模型訂定風險分數，建構於本人碩士論文模擬胃癌自然病史發展之馬可夫循環決策樹上，並模擬胃癌新興指標之效應用以克服族群異質性之問題。研究之防治策略包括：(1) 除菌治療作為胃癌初段預防工具、(2) 除菌治療後輔助一次內視鏡篩檢、(3) 除菌治療後視個體之風險分數及其接受篩檢之起始年齡訂定後續內視鏡定期篩檢。成本效益測量指標為多增加一單位之調整品質後存活人年所需要之額外花費，對於不同防治策略之間的相對成本效益比較，我們使用增量成本效果比來定量，我們也針對模型參數之不確定性進行進行單方向及機率性敏感度分析，每年的折扣率設定為3%。本研究總共模擬了60種情境，以進行各種策略之間比較，針對 30–50歲之中低風險族群，單一次之除菌治療無論是在台灣或是西方國家對於單位效益願意付出之最高費用之上限內，都佔有絕對優勢，而加上單一次內視鏡篩檢對此年輕族群並無好處。在於30–50歲高風險族群，除菌治療後定期內視鏡篩檢在上限為美金 $ 18,414元時，約有70–80%之機率可以符合成本效益。而於50–60歲之間，單一次的除菌治療效益逐漸下降，而相對地內視鏡檢查的效益開始提升。若是60–70歲才開始篩檢之年邁族群，因為此時無症狀之早期胃癌已開始出現，除菌治療後加上單一次的內視鏡篩檢早期胃癌，對於各種風險族群都轉變為最佳預防策略，而對於年邁的高風險族群，定期內視鏡篩檢符合成本效益之機率隨年齡逐漸下降，於70歲後才接受篩檢者，因為競爭死因之干擾，後續的定期內視鏡追蹤符合成本效益之機率下降至9%，而除菌治療加上單一次內視鏡篩檢則提高至90%。本研究結果可用以發展個人化健康經濟學模型，制定不同風險族群在不同篩檢年齡層之間的最佳胃癌防治策略，並可作為日後基礎科學與統計學上連結之橋樑。

關鍵字

胃癌防治 ； 幽門螺旋桿菌 ； 干涉時間序列實驗設計 ； 胃食道逆流症 ； 馬可夫多階段模型 ； 成本效益分析

並列摘要

Although screening and treatment for Helicobacter pylori infection is considered a plausible approach for prevention of gastric cancer, few long-term population-based cohort studies have substantiated its efficacy. Gastric cancer prevention programs were implemented for Taiwanese adults residing on Matsu Island including endoscopic screening in 1996, 1998, 2004, and 2008 and treatment of Helicobacter pylori in 2004 and 2008. Main outcome measures were rates of occurrence of premalignant gastric lesions and gastric cancer. The results showed that the annual incidence rate of re-infection/recrudescence was estimated to be 1% (95%CI: 0.6–1.4%) per person-year following treatment. The prevalence of gastric atrophy declined from 60.8% in 2004 to 13.7% in 2008, and the annual incidence declined from 8.2% per person-year between 1996 and 2004 to 3.5% between 2004 and 2008, resulting in an overall efficacy of 57% (95%CI: 5%–81%; P=0.02). In contrast, during the same time study period, the prevalence of intestinal metaplasia was 31.3% and 38.9% with incidence rate of 4.7% and 6.1% per person-year, indicating the lack of intervention effectiveness. The average five-year incidence of gastric cancer declined from 40.3 to 30.4 per 100,000 person-years, resulting in an overall efficacy of 25% but not statistically significant (P=0.21).
Then, we applied Poisson regression models to estimate the treatment efficacy, making allowance of history effect. The results showed that an annual 6.2% decline was attributed to the history effect for both gastric atrophy and intestinal metaplasia. The efficacy in preventing gastric atrophy was estimated to be 61%, which was consistent with previous estimation based on the incidence rate ratio, while the intervention still failed to prevent intestinal metaplasia. Over the whole study period of 1995–2008, the natural decline of gastric cancer incidence was estimated to be 10% per year. Before and after intervention, the decline of gastric cancer incidence was 41% but not statistically significant (P=0.09). The incidence rate of esophagitis was however 6% (95%CI: 5.1–6.9%) following treatment. In conclusion, population-based screening and treatment for Helicobacter pylori infection is associated with successful prevention of gastric atrophy at the expense of increased esophagitis. Furthermore, it appears promising for prevention of gastric cancer especially in high-risk populations.
Following the fact that that gastroesophageal reflux disease increased following Helicobacter pylori eradication, the second part of the dissertation aimed to quantify the natural course of gastroesophageal reflux disease and identify the risk factors associated with disease emergence and progression, in order to design the individual-tailored preventive strategies for this modern disease. A hospital database of 3,669 subjects undergoing repeated upper endoscopy was used. The presence and severity of endoscopic esophagitis have been diagnosed according to the Los Angeles classification. Data were analyzed using a three-state continuous time Markov model to estimate transition rates regarding the natural course of the disease. Individual risk score together with the kinetic curve was derived by identifying significant factors responsible for the net force between progression and regression. The results showed that during three consecutive study periods, 12.2%, 14.9%, and 17.9% of subjects, respectively, progressed from non-erosive to erosive disease, whereas 42.5%, 37.3%, and 34.6%, respectively, regressed to the non-erosive stage. The annual transition rate from non-erosive to class A-B disease was 0.151 per person year (95%CI: 0.136–0.165) and from class A-B to C-D was 0.079 per person year (95%CI: 0.063–0.094). The regression rate from class A-B to non-erosive disease was 0.481 per person year (95%CI: 0.425–0.536). Class C-D, however, appeared to be an absorbing state when not properly treated. Being male (relative risk [RR]: 4.31; 95%CI: 3.22–5.75), smoking (RR: 1.20; 95%CI: 1.03–1.39), or metabolic syndrome (RR: 1.75; 95%CI: 1.29–2.38) independently increased the likelihood of progressing from non-erosive to an erosive stage of disease and/or lowered the likelihood of disease regression. The short-term use of acid suppressants (RR: 0.54; 95% CI: 0.39–0.75) raised the likelihood of regression from erosive to non-erosive disease. Short-term treatment effect accounted for 27% disease regression and lifestyle modification was responsible for 73%. We concluded that the intraesophageal damage is a dynamic and migratory process in which the metabolic syndrome is associated with accelerated progression to or attenuated regression from erosive states. The derived risk score can be generalized to the population residing on the Matsu Island for the design of effective prevention and screening strategies for the gastroesophageal reflux disease.
As the first part of dissertation showed that the benefit of screening and treatment for Helicobacter pylori infection varied from person to person, we designed individualized prevention strategies and evaluated their cost-effectiveness. Base-case estimates, including parameters of natural history, efficacy of intervention, and relevant cost, were derived from the Matsu Gastric-Cancer Chemoprevention Study. Cost-effectiveness was compared between chemoprevention with and without the adjunct of one-time endoscopic screening or periodic endoscopic surveillance. Population was stratified by the demographic data, molecular markers, and initial screening age. The main outcome measure was cost per quality-adjusted life-year gained with a 3% annual discount rate. A total of 60 scenarios were evaluated. Regarding the low- and average-risk groups, one-time chemoprevention was the strategy of choice for the adults aged 30–50 years over conventional levels of willingness to pay. During 50–60 years of age, the benefit of chemoprevention declined but the value of additional endoscopy increased. Above 60 years of age, chemoprevention followed by one-time endoscopy became the strategy of choice. Regarding the high-risk group, chemoprevention followed by periodic endoscopic surveillance had the highest probability of being cost-effective; however, the value of surveillance decreased from the age of 70 years due to competing risks. The above findings were robust to the sensitivity analyses. In conclusion, an individual-tailored strategy is cost-effective providing that the endoscopic resource can be properly allocated through risk assessment. Future inputs of basic research are therefore anticipated.

並列關鍵字

gastric cancer prevention ； Helicobacter pylori ； interrupted time-series design ； gastroesophageal reflux disease ； Markov multistate model ； cost-effectiveness analysis

參考文獻

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135.以幽門桿菌除菌治療為基礎之胃癌初段預防及其成本效果分析。國立臺灣大學預防醫學研究所民國94年碩士論文。研究生：李宜家，指導教授：陳秀熙教授；林肇堂教授。

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