二甲雙胍對口腔癌化學預防的效果—以口腔黏膜下纖維化症患者為例

Chemopreventive Effect of Metformin on Oral Cancer in Patients with Oral Submucous Fibrosis

侯雨辰(Yu-Chen Hou)

指導教授 ： 楊奕馨

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2017年)

摘要

背景：
二甲雙胍(metformin)在過去的體外試驗和動物實驗中已經證實可以抑制口腔鱗狀腫瘤細胞的增生，也可以預防口腔癌前病變進一步發展成為口腔癌。在已發表的流行病學研究中，由於均未校正嚼食檳榔對口腔癌發生的影響，因此二甲雙胍對口腔癌化學預防的效果仍具爭議。由於口腔黏膜下纖維化症(OSF, oral submucous fibrosis)主要發生於檳榔嚼食者，因此針對OSF進行研究，可以排除檳榔嚼食習慣的校正問題，本篇研究之目的為探討二甲雙胍用在口腔黏膜下纖維化症病人對口腔癌發生的影響，並進一步探討是否有累積劑量相關性。
方法：
本研究採回溯性世代研究，以衛生福利部之台灣健保研究資料庫、癌症登記檔及死因統計檔做為研究資料來源。擷取2010-2014年間新診斷之口腔黏膜下纖維化症病人同時有第2型糖尿病史作為研究族群，追蹤期間自診斷有口腔黏膜下纖維化症開始至口腔癌發生或2014年底止。研究組別依口腔黏膜下纖維化症診斷之前後6個月使用二甲雙胍作為分組依據，分別為前後6個月皆有使用、僅前6個月有使用、僅後6個月有使用及前後6個月內均沒使用四組。由於考慮到糖尿病病人在診斷口腔黏膜下纖維化症時有無使用二甲雙胍，會有潛在選樣偏差，因此為增加組間的可比性，先利用傾向分數(propensity score)計算診斷口腔黏膜下纖維化症前接受二甲雙胍的機率，再將前6個月內沒使用二甲雙胍的病人依性別、年齡及傾向分數以1：2配對前6個月內有使用二甲雙胍的病人。統計分析利用Kaplan-Meier estimates分析比較各組口腔癌發生的風險，再利用Cox迴歸分析經調整所有可能影響口腔癌發生的變項後，得到二甲雙胍的使用對目標族群罹患口腔癌的風險比(hazard ratios, HRs)。
結果：
本研究納入1,031位新診斷口腔黏膜下纖維化症合併第2型糖尿病史之病人，在追蹤期間得到口腔癌人數共41位。經由Kaplan-Meier estimates分析發現四組得到口腔癌的風險並無顯著差異(log-rank p=0.2849)。由Cox迴歸分析得出在診斷口腔黏膜下纖維化症後6個月內有使用二甲雙胍的病人，雖有較低的口腔癌風險，但未達統計學上的顯著差異(HR=0.42, 95% CI=0.039-4.569)。當病人使用二甲雙胍的累積劑量高於中位數累積劑量(42 DDD)，相較於沒有使用二甲雙胍有較低的口腔癌風險，不過仍未達統計學顯著性差異(HR=0.28, 95% CI=0.019-4.229, p-value=0.3582)。
結論：
本研究結果顯示，在口腔黏膜下纖維化症併有第2型糖尿病史之病人，二甲雙胍的使用和口腔癌的風險並未有顯著的相關性，也並未有顯著的劑量反應相關性。未來仍需更大樣本數的藥物流行病學研究及臨床試驗來探討二甲雙胍和口腔癌風險的相關性。

關鍵字

口腔癌 ； 口腔黏膜下纖維化 ； 二甲雙胍 ； 化學預防

並列摘要

Background:
The use of metformin is associated with inhibition of oral squamous cell carcinoma proliferation and oral cancer transformation from oral premalignant lesion from reports of preclinical studies. However, due to the limitation of considering betel quid chewing habit as a major confounder, the chemopreventive effect of metformin on oral cancer remains controversial. Since the disorders of oral submucous fibrosis (OSF) are primarily appeared in betel quid chewers, investigation conducted on OSF patients would resolve the adjustment of betel quid chewing habits. The aim of this study is to investigate whether metformin is associated with reduced oral cancer risk in oral submucous fibrosis patients with type 2 diabetes and to further investigate whether there is a dose-response relationship.
Methods:
We conducted a population-based retrospective cohort study using Taiwan Health Insurance Research Database (NHIRD), Taiwan cancer registry and Death registry (DR) databases. The cohort consisted of newly-diagnosed oral submucous fibrosis patients with history of type 2 diabetes during 2010-2014. The 4 study groups were defined based on the usage of metformin within 6 months of before or OSF diagnosis: pre- & post-metformin users, pre-metformin only users, post-metformin only users and non-metformin users. The usage (with or without) of metformin may reflect possible selection bias at the diagnosis of OSF. To achieve better comparative groups, a matched study was conducted based on pre-metformin usage. Propensity scores were first calculated for patients with prior 6-month metformin usage, and then we matched one pre-metformin non-user to two pre-metformin users on the basis of the age, gender and propensity score. Kaplan-Meier estimates were used to compare oral cancer risk between four different groups. Multivariable Cox regression was used to estimate hazard ratios (HRs) of oral cancer between groups and investigate factors that associated with oral cancer risk.
Results:
There were 41 oral caners identified by Taiwan cancer registry from 1,031 OSF patients with type 2 diabetes. The results from Kaplan-Meier estimates showed no significantly difference of oral cancer risk among the four groups (log-rank p=0.2849). Cox regression analysis revealed that metformin used at post-diagnostic of OSF was associated with non-significant 0.42 times reduced oral cancer risk. In addition, OSF patients with type 2 diabetes who had cumulative DDD of metformin more than median cumulative DDD had non-significant 0.28 times (HR=0.28, 95% CI=0.019-4.229, p-value=0.3582) reduced oral cancer risk than patients who did not use metformin.
Conclusion:
Metformin may not have significant chemopreventive effect on oral cancer. In addition, there may not have significant dose-response relationship between metformin and oral cancer risk. Further epidemiological studies with larger sample size and randomized controlled trials are needed to investigate the association between use of metformin and oral cancer risk.

並列關鍵字

Oral cancer ； Oral submucous fibrosis ； Metformin ； Chemoprevention

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