臺灣博碩士論文加值系統

研究背景
　　頭頸癌，定義為上消化呼吸道的癌症(如：口腔癌，鼻咽癌…)，主要以鱗狀上皮細胞癌為主。根據國健署101年癌症登記資料顯示，該年新診斷罹患頭頸癌的患者有將近八萬人，而有近三萬人死於頭頸癌，患者以40~60歲中年男性為主，而其中的口腔癌發生率為男性十大癌症排名第四，在女性排名第十五，在台灣的公共議題上儼然成為一個重要的議題(Taiwan health promotion administration ministry of health and welfare, cancer registry annual report, 2012)。頭頸癌的危險因子如抽菸，嚼檳榔與酗酒，其中所含的致癌物質以及自由基，會使得細胞膜遭受破壞及變性，長期反覆暴露下來，細胞產生癌病變的機率增加。因此有人猜想，如果降血脂的藥物可能會藉由降低血脂而使得上述機轉被影響而達到抗癌的效果，於是開始了許多相關的研究。最常見的降血脂藥物為statin，而相對少用的藥物fibrate纖維酸(通常是在使用statin發生副作用或是治療效果不佳時才會使用)，在過去許多年都有做這些藥物與癌症風險的相關性，可是並沒有一致性的結果。有的研究顯示會增加癌症的風險，有的則是降低。
　　基於上述的原因，本研究探討使用降血脂藥纖維酸是否會影響罹患頭頸癌的風險。
研究目標
1.探討服用降血脂藥物纖維酸對於罹患頭頸癌風險的影響
2.對照不同纖維酸藥物對於罹患頭頸癌風險的程度
研究方法
　　本研究採用回溯性世代研究法(retrospective cohort study)，主要利用健保資料庫，追蹤2001年至2008年間新診斷患有高血脂的病患(排除先前有癌症以及小於18歲的病患)，有服用纖維酸藥物(暴露因子)，是否在之後有發生頭頸癌(追蹤到2011年12月底)，接著跟沒有服用纖維酸藥物的族群做比較，來檢測纖維酸是否會降低頭頸癌的風險。頭頸癌的篩選是根據國際疾病分類代碼(ICD-9-CM 140-149)為標準。由於纖維酸藥物濃度會隨時間而更動，本研究把纖維酸當作時間依賴的共變數來處理，藥物濃度則是根據WHO使用每日定義劑量(daily defined dose, D.D.D)來做計算。統計上使用Cox proportional hazard regression models校正性別、年齡、高血壓、糖尿病與冠狀動脈疾病這些干擾因子之後，檢視使用纖維酸和罹患頭頸癌的風險。
研究結果
　　本次研究總共收集了59809位受試者，平均年齡為52歲，男性佔了51.4%，平均追蹤了6.8年，總共有209人發生了頭頸癌，有約3成的人使用纖維酸。經過調整校正干擾因子後，使用纖維酸會稍微的增加罹患頭頸癌的風險，但不具統計上的意義(危險比率1.3, 95%信賴區間0.89~1.92)。但是如果累積劑量達到100DDD，纖維酸會稍微的增加罹患頭頸癌的風險，則具有統計上的意義(危險比率1.06, 95%信賴區間1.01~1.12)。對於不同纖維酸藥物做分組次分析，我們可以看到多利平脂(clofibrate)使罹患頭頸癌的風險上升，特別是口腔癌 (危險比率8.08, 95%信賴區間1.13~57.81)。而弗尼利脂寧(fenofibrate)雖然對頭頸癌的風險沒有影響，但對於像是口咽癌，下咽癌等非口腔癌鼻咽癌的風險則是上升的(危險比率2.84, 95%信賴區間1.17~6.92)。
結論
　　本研究當中發現當藥物濃度累積暴露達100DDD時，會使得罹患頭頸癌的風險上升，而針對不同纖維酸藥物的比較，以多利平脂(clofibrate)和弗尼利脂寧(fenofibrate)有增加罹患頭頸癌的風險。

Background
Head and neck cancer (HNC, for example : oral cancer and nasopharyngeal cancer (NPC)) influence thousands of Taiwanese people every year and has become a great issue on public health in Taiwan. Well-known risk factors like betel nut chewing and smoking lead to carcinogenic process in HNC. Carcinogens among those risk factors like arecoline and tobacco have been thought to produce free radicals, which denature lipid contents of the cell membrane and cause potential cancerous changes. In recent years, several studies demonstrated anti-cancer effects of lipid-lowing drugs such as statins and fibrates, while others showed no evidence of cancer protective effects from those drugs use. Due to conflicting results, we conducted the study to assess the association between fibrate use and potential HNC risk in Taiwanese patients.
Methods
We used data from the National Health Insurance system of Taiwan to answer our question. Study design was set to be a cohort study and we enrolled 59809 participants who were above 18-year-old and had been newly diagnosed with hyperlipidemia between January 1, 2001 and December 31, 2008. Those who were under fibrates therapy were compared with those who were not with matching of sex, age and comorbidities. The fibrate exposure included clofibrate, bezafibrate, fenofibrate and gemfibrozil. Occurrences of HNC were measured by the end of 2011, as well as hazard ratios (HRs) and 95% confidence intervals (CI) of the HNC.
Results
The major outcome was focusing on the developing HNC. Based on the sites of HNC, three cancer types were classified including: 1) oral cancer; 2) nasopharyngeal cancer, and 3) others(ex: hypopharyngeal cancer and oropharyngeal cancer). There was no significant difference of HNC risk for hyperlipidemia patient with and without fibrate exposure (HR = 1.30, 95% CI = 0.89-1.92; Table 2). However, increased risk of HNC were statically significant among people under intensive fibrate treatment (100 defined daily dose, DDD; HR, 1.06; 95% CI, 1.01-1.12), while no risk of NPC was noted (HR, 0.84; 95% CI, 0.59-1.21). Among different fibrates (bezafibrate, clofibrate, fenofibrate, and gemfibrozil), patients who used clofibrate were at higher risk of developing HNC (HR 8.08; 95% CI 1.13-7.81) and oral cancer (HR 13.76; 95% CI 1.91-99.01). Fenofibrate users also potentially had higher risk of developing other types of cancer (ex: hypopharyngeal cancer and oropharyngeal cancer) with HR 2.84; 95% CI 1.17-6.92.
Conclusion
This population-based cohort study showed the increasing incidence of HNC (mainly oral cancer) associated with the use of fibrates, especially the clofibrate and fenofibrate. This is the first study proposing the association. The mechanisms remain unclear. Further studies are necessary and promised.

誌謝 i
中文摘要 iii
Abstract vi
Table of Contents viii
List of Tables ix
List of Figure x
1. Introduction 1
2. Methods 4
2.1 Data source 4
2.2 Study Population 5
2.3 Statistical Analysis 6
3. Results 8
4. Discussion 12
4.1 Carcinogenic effects of fibrates 12
4.2 Anti-cancer effects of fibrates 13
4.3 Neutral effects of fibrates 14
4.4 Association between low levels of lipids caused by fibrates and risk of cancer 14
4.5 Effects of clofibrate on cell growth and cancer progression 15
5. Advantages and limitations 17
6. Conclusion 19
6.1 Further discussion and Study prospects 19
7. 名詞解釋 21
8. Reference 23

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