以馬可夫決策模式探討子宮頸癌篩檢及疫苗成本效益分析

Abstract

研究背景 從1960年開始，子宮頸抹片就廣泛的用在西方國家的子宮頸癌篩檢以降低子宮頸癌的死亡率，但過去三十年來此種三年一次篩檢之效益呈現瓶頸。因此結合人類乳突病毒去氧核醣核酸檢測及施打人類乳突病毒疫苗也成為子宮頸癌發生及減少死亡之另類預防措施。然而如何結合子宮頸抹片和人類乳突病毒去氧核醣核酸檢測或施打人類乳突病毒疫苗以增加篩檢的效益及其相關的成本效益研究卻較少被提及。 研究目的 在於探討不同篩檢間隔下傳統子宮頸抹片與人類乳突病毒去氧核醣核酸檢測及施打疫苗之各種不同組合之預防措施對子宮頸癌發生及死亡避免之效益及成本效益分析。 研究方法 本研究針對台灣三十歲共十五萬婦女世代進行四十年追蹤，研究設計以馬可夫分析決策模型首先模擬出在無預防政策下，由健康至人類乳突病毒感染、子宮頸上皮細胞病變、子宮頸原位癌、發展至子宮頸侵襲癌再到死亡的疾病進展過程，再探討出16種預防策略 (根據篩檢間隔的不同：每年一次、每三年一次、50歲前三年一次，50歲後五年一次及每五年一次；使用篩檢工具的不同：子宮頸抹片或合併人類乳突病毒去氧核醣核酸檢測；以及是否施打疫苗) 如何改變上述疾病自然病史並和現行三年一次篩檢策略作比較。評估效益終點包括子宮頸癌前病變、子宮頸癌發生及子宮頸癌死亡。有關效益及成本效益分析參數的來源主要來自文獻查證。另外考慮參數的不確定性，我們選用適合的統計分佈，運用蒙地卡羅模擬，進行5000次的電腦模擬。結果的呈現是比較不同篩檢策略之下，平均與增加成本效益比(average and incremental cost-effectiveness ratios(ICERs))以及淨利益增量(incremental net benefit(INB))。 研究結果 本研究在不同策略之效益比較上，主要發現有 (一) 以子宮頸抹片策略為主之效益發現與三年一次抹片相比，每年一次抹片可降低11%癌前病變發生，43%子宮頸癌發生及45%子宮頸癌死亡。 (二) 以人類乳突病毒去氧核醣核酸檢測加子宮頸抹片策略為主之效益發現與三年一次抹片相比，每年一次人類乳突病毒去氧核醣核酸檢測加子宮頸抹片策略可降低17%癌前病變發生，54%子宮頸癌發生及55%子宮頸癌死亡。 (三) 以疫苗施打加子宮頸抹片策略為主之效益發現與三年一次抹片相比，疫苗施打加每年一次子宮頸抹片策略可降低29%癌前病變發生，56%子宮頸癌發生及56%子宮頸癌死亡。 (四) 以疫苗施打加人類乳突病毒去氧核醣核酸檢測加子宮頸抹片策略為主之效益發現與三年一次抹片相比，疫苗施打加每年一次人類乳突病毒去氧核醣核酸檢測加子宮頸抹片策略可降低33%癌前病變發生，59%子宮頸癌發生及60%子宮頸癌死亡。在相同的篩檢策略之下，施打疫苗比沒有施打疫苗可以減少5-24%子宮頸癌的發生以及子宮頸癌死亡率。 成本效益分析的主要結果發現「每年一次子宮頸抹片」和「施打疫苗加上每年一次人類乳突病毒去氧核醣核酸檢測及子宮頸抹片」為較具優勢的預防策略。若將「每年一次子宮頸抹片」和「每三年一次子宮頸抹片」相比，符合成本效益的機率非常高為99.5%，每增加一年平均餘命需多花費美金$23,093元，同樣的每減少一名子宮頸癌的發生需美金 $41,991元，在使用者付費意願為美金$50,000元時，淨利益增量為美金$435.9元。 若比較「施打疫苗加上每年一次人類乳突病毒去氧核醣核酸檢測及子宮頸抹片」和「每三年一次子宮頸抹片」，符合成本效益的機率也非常高為95.5%，每增加一年平均餘命需多花費美金$34,306元，同樣的每減少一名子宮頸癌的發生需美金 $59,375元，在使用者付費意願為美金$50,000元時，淨利益增量為美金$339.0元。 結論 「每年一次子宮頸抹片」或「施打疫苗加上每年一次人類乳突病毒去氧核醣核酸檢測及子宮頸抹片」的策略和三年一次子宮頸抹片相比，比其他策略更符合成本效益。

Background Population-based screening for cervical cancer with Pap smear has been widely used worldwide since 1960s and demonstrated to lead to a remarkable reduction of mortality. However, as the reduction of mortality after Pap smear screening has shown a plateau, we still need a breakthrough for cervical cancer prevention. Therefore, screening policy with HPV DNA testing and HPV vaccination are considered as alternative preventive strategies. The additional effectiveness on the basis of economic evaluation from these two related preventive strategies combined with different scheduled Pap smear screening programs has been rarely addressed. Compared with triennial screening program, studies on cost-effectiveness analysis on various combinations of preventive strategies are also limited. Purpose We aimed to elucidate the efficacy and cost-effectiveness of different preventive strategies for cervical cancer screening. Methods The probabilistic cost-effectiveness analysis of various preventive strategies in reduction of cervical cancer mortality and life cost was elucidated by using a population-based study targeted to 150,000 women in Taiwan. A Markov cycle process was defined as a series of multi-state outcome including healthy, HPV infection, CIN1, CIN2+, carcinoma in situ, invasive cancer, and death. Total of 16 preventive strategies considering screening intervals (annually, triennially, 3 yearly for age under 50 and 5 yearly for age over 50, and 5 yearly), screening modalities (HPV DNA testing, Pap smear), and HPV vaccination are further developed to compare with triennial Pap smear screening strategy used in current clinical practice. The parameters for analysis were derived from literatures. By assigning the specific statistical distribution to each parameter, Monte Carlo simulation with 5000 microsimulation trials was therefore applied to capture the parameter uncertainty. We then present the outcome in terms of incremental cost-effectiveness ratios (ICERs) per life-year gained and incremental net benefit (INB) under varying prevention strategies compared with triennial Pap smear screening program. Result In terms of elucidating the effectiveness of different strategies in our study, we have the following main finding, 1. Compared with triennial Pap smear, annual Pap smear reduced the 11% of pre-cancer lesions, 43% of invasive cervical cancer, and 45% of cervical cancer death. 2. Compared with triennial Pap smear, annual HPV DNA testing and Pap smear reduced the 17% of pre-cancer lesions, 54% of invasive cervical cancer, and 55% of cervical cancer death. 3. Compared with triennial Pap smear, vaccination and annual Pap smear reduced the 29% of pre-cancer lesions, 56% of invasive cervical cancer, and 56% of cervical cancer death. 4. Compared with triennial Pap smear, vaccination together with annual HPV DNA testing and Pap smear reduced the 33% of pre-cancer lesions, 59% of invasive cervical cancer, and 60% of cervical cancer death. The marginal effect of vaccination therefore might be reckoned around 5-24% under different prevention strategies. The incremental cost-effectiveness ratios for annual Pap smear against the triennial Pap smear were calculated as $41,991 and $23,093 for per cervical cancer prevented and per life-year gained, respectively. The corresponding figures for vaccination program with annual HPV DNA testing followed by Pap smear against the triennial Pap smear were calculated as $59,375 and $34,306 for per cervical cancer prevented women and per life-year gained, respectively given the threshold of $50,000 of willingness to pay. Compared with triennial Pap smear, the probability of being cost-effective by the acceptability curve were 99.5% for annual Pap smear and 95.5% for vaccination program with annual HPV DNA testing followed by Pap smear, respectively. The corresponding INBs given the threshold of $50,000 of WTP for annual Pap smear and vaccination program with annual HPV DNA testing followed by Pap smear were calculated as $ 435.9 and $339.0. Conclusion Compared with current practice (triennial Pap smear screening program), annual Pap smear or vaccination program with annual HPV DNA testing followed by Pap smear is the more cost-effectiveness strategies among all various preventive strategies.