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

Primary Prevention for Gastric Cancer with Helicobacter pylori Eradication and the Cost-Effectiveness Analysis

李宜家(Yi-Chia Lee)

指導教授 ： 陳秀熙

共同指導教授 ： 林肇堂(Jaw-Town Lin)

國立臺灣大學/公共衛生學院/預防醫學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.00396

摘要

第一部份

雖然幽門螺旋桿菌的除菌治療可以減少胃癌的發生，然而針對整個社區的一般民眾而言，幽門螺旋桿菌除菌治療之最佳處方目前並不了解，因此，本論文的第一部分，報告一種新型的幽門螺旋桿菌除菌治療流程之效果，此計畫乃基於檢驗、除菌、再檢驗、再除菌(test-treat-retest-retreat initial failures) 的流程。

於2004至2005年，在馬祖地區，我們總共收集2,658位居民接受碳13幽門螺旋桿菌吹氣試驗 (13C urea breath test)，以確定個案與否感染幽門螺旋桿菌，而幽門螺旋桿菌陽性的個案，將接受7天的標準三合一治療，此第一線治療包含: 每天40 mg 之耐適恩 (esomeprazole)，以及早晚各1 g之安莫西林 (amoxicillin)，再加上早晚各500 mg 之開羅里黴素 (clarithromycin)，若是個案第一線治療失敗，會追加10天的再治療，此再治療的處方包含: 每天40 mg的耐適恩 (esomeprazole)，早晚各1 g的安莫西林 (amoxicillin)，以及每天500 mg的可樂必妥 (levofloxacin)，而處方的除菌效果及負作用，我們各於治療後六週整體評估。

基於886位清楚回答之個案，分析結果顯示幽門螺旋桿菌除菌的效果如下: 第一線治療有效之除菌率為86.9% (95% 信賴區間: 84.7% ~ 89.1%)，若針對完全遵守治療流程、完整服用藥物之個案來說，有效之除菌率為88.7% (95% 信賴區間: 86.5% ~ 90.9%)，而就再治療之處方而言，它可以成功治癒91.4% 之第一線藥物除菌失敗者 (總共有105位個案，95% 信賴區間: 86% ~ 96.8%)，有798位個案達到藥物的完整順從率 (90.1%)，而在105位接受再治療的個案，其藥物之完整服用順從率為100%。就藥物負作用來說，有24% 的個案發生了輕微的負作用，但是只有極少數因而中斷治療。就接受本計畫兩階段除菌處方 (幽門螺旋桿菌除菌治療以及再治療) 之個案，其成功除菌治療比率高達97.7% (95% 信賴區間: 96.7% ~ 98.7%)，而若是針對完全順從處方服藥之個案，成功除菌率為98.8% (95% 信賴區間: 98.5% ~ 99.3%)，而影響除菌治療成功與否之最關鍵因子為病患的藥物順應性，若順應性差，其治療失敗之風險比為 3.3 (95% 信賴區間: 1.99 ~ 5.48)。

第一階段總結來說，我們發現以開羅里黴素 (clarithromycin) 為基礎的初段治療，以及可樂必妥 (levofloxacin) 為基礎的再治療，對無症狀之一般族群來說，是一個非常有效的除菌處方，這樣的兩階段除菌治療方針基本上相當安全，病患的順應度亦高，可以有效地清除幽門螺旋桿菌。

第二部份

因為胃癌的初段預方及次段預防之防治方針，都可以有效降低胃癌的死亡率，然而，我們對於其相對之成本效果，目前並沒有結論，因此，論文之第二部分主要探討胃癌初段預防及次段預防的相對成本效果，我們將論文第一部分所執行之研究，與先前1995至1999年之胃癌次段篩檢計畫來做比較。此外，我們也探討胃癌篩檢之最佳起始年齡，以及胃癌篩檢之最佳篩檢間隔。
針對胃癌風險特高之馬祖居民，第一次之胃癌預防介入，為1995至1999年所執行之胃癌次段預防，此次段預防乃以胃蛋白脢原 (pepsinogen) 之血清學測量做為第一階段篩檢之工具，而證實為高風險之民眾將接受第二階段內視鏡之確診。而第二次之胃癌預防介入，乃介於2004及2005年之初段預防 (即本論文的第一部分)，此計畫使用幽門螺旋桿菌之除菌治療，作為胃癌初段預防之工具。 我們根據哥利亞 (Correa) 的胃癌發展模式，以電腦模擬胃癌之自然病史，並使用單方向之敏感度分析 (one-way sensitivity analysis)，及隨機性之敏感度分析 (probabilistic sensitivity analysis)，針對不確定之參數進行不同範圍之檢視。主要之測量指標為多增加一單位之平均餘命所需要之額外花費。我們使用每年3% 的折扣率 (discounted rate) 針對成本與效果做折價。初段預防及次段預防間之相對成本及效果比較，我們使用增量成本效果比(incremental cost-effective ratio: ICER) 來做分析。

研究結果發現，依據我們建構的胃癌自然病史推演，與實際之統計資料相較，並無顯著之差異。若將胃癌初段預防 (於30歲時執行一次幽門螺旋桿菌治療) 與完全沒有篩檢介入相較，每增加一單位之平均餘命將花費美金 $17,044元。而胃癌初段預防，基本上從愈年輕之時候開始篩檢，其成效愈佳，相對地，若由較晚之年紀開始篩檢，或者以週期性篩檢之方式執行，其增量成本效果比將大為上升。若將胃癌之次段預防 (於50歲開始每年執行篩檢) 與完全沒有篩檢相較，每增加加一單位之平均餘命需花費美金 $29,741元，而次段預防在不同之起始年齡或不同之篩檢間隔時間，其增量成本效果比 (ICER) 卻無顯著的差別。 若我們直接比較初段預防及次段預防，不論願意付出之最高金額 (ceiling ratio) 為美金 $15,762元 (台灣合理標準)，或是美金 $50,000元 (美國合理標準)，胃癌之初段預防都比次段預防較符合成本效果，其相對之增量成本效果比 (ICER)主要由兩個因素決定其優勢性: 第一個因素: 幽門螺旋桿菌的感染率，第二個因素: 胃癌次段預防中早期胃癌所佔之比例。

本研究顯示，胃癌之初段預防，並且是於群眾年輕時給予一次之幽門螺旋桿菌除菌治療，為一最佳之防治方案。然而，胃癌初段預防及次段預防之間的選擇，仍可能受到幽門螺旋桿菌的感染風險，以及早期胃癌偵測率之不同所影響，因而結果可能因地而異。

關鍵字

胃癌 ； 幽門桿菌 ； 疾病自然史 ； 成本效果分析 ； 敏感度分析

並列摘要

Part I

Although eradication of Helicobacter pylori (H. pylori) infection can decrease the risk of gastric cancer, the optimal regimen for treating the general population remains unclear. In the first part of thesis, we reported the eradication rate (intention-to-treat and per protocol) of a community-based H. pylori therapy using the strategy of test, treat, retest, and retreat initial treatment failures.

In 2004, a total of 2,658 residents were recruited for 13C urea breath testing. Participants with positive results for infection received a standard 7-day triple therapy (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily), and a 10-day re-treatment (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) if the follow-up tests remained positive. Both H. pylori status and side-effects were assessed 6 weeks after treatment. Among 886 valid reporters, eradication rates with initial therapy were 86.9% (95% confidence interval [CI]: 84.7-89.1%) and 88.7% (95%CI: 86.5-90.9%) by intention-to-treat and per protocol analysis, respectively. Re-treatment eradicated infection in 91.4% (95%CI: 86-96.8%) of 105 non-responders. Adequate compliance was achieved in 798 (90.1%) of 886 subjects receiving the initial treatment and in all 105 re-treated subjects. Mild side effects occurred in 24% of subjects. Overall intention-to-treat and per protocol eradication rates were 97.7% (95%CI: 96.7-98.7%) and 98.8% (95%CI: 98.5-99.3%), respectively, which were only affected by poor compliance (odds ratio [OR], 3.3; 95%CI, 1.99–5.48; P<0.0001).

The results first confirmed that clarithromycin-based initial therapy and levofloxacin-based re-treatment is efficacious on a population basis. This approach is safe, well-tolerated, and achieves high eradication rates. Second, a comprehensive plan using drugs in which the resistance rate is low in a population combined with the strategy of test, treat, retest, and retreat of needed can result in virtual eradication of H. pylori from a population. This provides a model for planning country or region wide eradication programs.

Part II

Though both primary prevention and secondary prevention strategies can reduce the mortality rate of non-cardiac gastric cancer, little is known about their long-term relative cost and benefit. The second part of thesis was to assess the relative cost and effectiveness, optimal initial age and inter-screening interval in a high-risk area regarding primary and secondary preventive strategy.

The base-case estimates, including parameters of natural history of gastric cancer, efficacy of intervention and relevant cost, were derived from two empirical data on two interventions targeting at a high-risk population in two periods, 1995-1999 and 2004-2005. Cost and effectiveness was compared between chemoprevention with 13C urea breath testing followed by H pylori eradication and surveillance strategy for high-risk group based on serum pepsinogen (PG) measurements and confirmed by endoscopy. One-way and probabilistic sensitivity analyses were performed to assess the influences of uncertainty of certain parameters. Our main outcome measure was the cost per life-year gained with 3% annual discounted rate.

The result showed that the incremental cost-effectiveness ratio (ICER) for one-shot chemoprevention at age 30 y versus no screening was US $17,044 per life-year gained. Eradication of H pylori at later age or with a periodic scheme yielded a less favorable result. Annual high-risk screening at age of 50 y versus no screening resulted in an ICER of US $29,741 per life-year gained. ICERs do not substantially vary with surveillance at various initial ages or with different inter-screening intervals. The chemoprevention was more cost-effective than high-risk surveillance, either at ceiling ratios of US $15,762 or up to US $50,000. The results of cost-effectiveness are most sensitive to the infection rate of H pylori and proportion of early gastric cancer in all detectable cases.

In conclusion, we found that early H pylori eradication once in lifetime seems cost-effective than surveillance strategy for high-risk group. However, the choice of population-based preventive strategy is still subject to risk of infection and the detectability of early gastric cancer.

並列關鍵字

gastric cancer ； Helicobacter pylori ； natural history ； cost-effectiveness analysis ； sensitivity analysis

參考文獻

Chapter 1.

1.Chen H, Ward M H, Graubard B I, Heineman E F, Markin R M, Potischman N A, Russell R M, Weisenburger D D, Tucker Katherine. Dietary patterns and adenocarcinoma of the esophagus and distal stomach. Am J Clin Nutr 2002; 75: 137-144.

2.Correa P: Diet modification and gastric cancer prevention. J Natl Cancer Inst 1992;12: 75-8.

3.Forman D, Newell DG, Fullreton F, Yarnell JWG, Stacey AR, Wald N, Sitas F. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ 1991;302: 1302-5.

4.Ito LS, Inoue M, Tajima K, Yamamura Y, Kodera Y, Hirose K, Takezaki T, Hamajima N, Kuroishi T, Tominaga S. Dietary factors and the risk of gastric cancer among Japanese women: a comparison between the differentiated and non-differentiated subtypes. Annals of Epidemiology 2003;13:24-31.