應用糞便免疫潛血法量性數值於正常篩檢大腸鏡後之精準追蹤

Higher Fecal Hb Concentration Predicts Risk of Metachronous Advanced Neoplasia at Surveillance in Subjects With Negative Baseline Colonoscopy

林宣合(Hsuan-Ho Lin)

指導教授 ： 吳明賢

共同指導教授 ： 邱瀚模(Han-Mo Chiu)

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2022年)

https://doi.org/10.6342/NTU202203291

摘要

研究背景論述：
癌症仍為近年來台灣十大死因之首，其中大腸直腸惡性腫瘤之發生率，一直是癌症排行中名列前茅的。糞便免疫潛血法檢測已經是許多國家的標準篩檢工具，台灣也自2004年開始提供檢測，並在2010年擴大到全國篩檢，於2013年將篩檢範圍定在50-75歲之一般民眾。如糞便免疫潛血法檢測出陽性，則建議接受大腸內視鏡檢查。在台灣現行大腸癌篩檢指引中，如果篩檢大腸鏡結果為陰性，則視同其糞便免疫潛血檢測為偽陽性，將與糞便免疫潛血檢測為陰性的民眾一樣，維持兩年後再一次的糞便免疫潛血檢測。
然而，許多實證上的研究顯示，即使在糞便免疫潛血檢測定量上很低的族群，絕對數值越高，仍然可預測後續腺瘤及進行性腺瘤的發生率也顯著地越高。但在國際上現行已發表之研究，僅就免疫法糞便潛血的數值做後續之追蹤分析，並沒有納入任何糞便潛血檢測時基準大腸鏡檢查的資訊。
因此在此前提下，此回溯性研究將收集在本院同時有糞便免疫潛血檢測結果，且當次大腸鏡檢查為陰性的族群，去看糞便免疫潛血檢測的結果，在第一次大腸鏡檢為陰性的狀況下，後續長期追蹤是否會出現進行性腺瘤或大腸癌發生率的差異。希望藉由同時分析多項已知與大腸息肉相關的風險因子，找出是否需針對此兩種族群，來訂定不同的追蹤大腸內視鏡之頻率，以求可以更早發現進行性腺瘤(癌前病變)，更早地在可以痊癒的前提下接受妥善的治療。
研究方法：
本研究為一回溯性研究。收集自2010年到2018年，年齡為45至75歲，同時有接受大腸鏡及糞便潛血免疫法檢驗(檢體需在大腸鏡前兩天內取得)，且該次大腸鏡檢查為陰性之族群。收集基本資料內與後續大腸直腸息肉產生相關的因子，包含年齡、性別、身體質量指數、抽菸及糞便潛血免疫法數值之結果，並追蹤這些族群在日後做追蹤大腸鏡出現大腸息肉之情形，進一步分析可能影響異時性大腸直腸癌和大腸進行性線瘤出現的危險因子。
結果與討論:
在總共4567位收案者中，共有678位在追蹤性大腸鏡中有出現異時性大腸息肉；其中共有592位(87.3%)是非進行性腺瘤、81位(12%)是進行性腺瘤、5位(0.7%)是大腸直腸癌；而糞便免疫潛血陽性的在有息肉的678位裡則有49(7.2%)位。
將有出現異時性大腸進行性腺瘤跟無進行性線瘤的族群進行比較，平均年齡(p=0.05)、糞便免疫潛血數值(p<0.001)、糞便免疫潛血陽性比例(p<0.001)及BMI值(p=0.04)，均有顯著較高。而藉由Cox regression的單變項分析可得知，僅糞便免疫潛血陽性與BMI≥25此兩項，有顯著地產生較高出現異時性大腸進行性腺瘤的風險，風險比(Harzard ratio)分別為4.16(95%信賴區間=2.26-7.66)和1.56(95%信賴區間=1.02-2.39)。然而若是進行多變項分析，則僅有糞便免疫潛血陽性此項目出現顯著較高的校正後風險比(adjusted hazard ratio (aHR)：3.95((95%信賴區間=2.13-7.35)。而將糞便免疫潛血陽性的群體做次族群分析，盡量地依數值高低分成三等份，分別為數值100-199ng/ml(62人)、數值200-399ng/ml(48人)及數值≥400ng/ml(54人)，各別的aHR則為1.5(95%信賴區間=1.02-2.39)、5.90(95%信賴區間=2.13-16.33)和6.02(95%信賴區間=2.59-13.97)。
結論:
在第一次糞便免疫潛血陽性的族群，即使在正常的第一次大腸鏡之後，後續產生異時性大腸進行性腺瘤的風險仍然較潛血陰性的族群高。而風險更是在糞便免疫潛血數值≥200 ng/ml時，更為顯著。然而，能否將此結論於臨床端及篩檢端應用，仍有待後續進一步驗證。

關鍵字

大腸直腸腫瘤 ； 異時性大腸進行性腺瘤 ； 糞便潛血免疫法

並列摘要

Background:
Higher fecal hemoglobin concentration (FHbC) is associated with advanced neoplasm at diagnostic colonoscopy but whether baseline FHbC could be a predictor of metachronous advanced neoplasia(AN) after a negative colonoscopy remains unclear. We aim to elucidate the association between baseline FHbC and the subsequent risk of AN, in order to tailor the surveillance after negative colonoscopy.
Method:
Those who received both screening (baseline) and surveillance colonoscopy from 2010 to 2018 in National Taiwan University Hospital with negative baseline colonoscopic findings were enrolled. We analyzed those 4,567 consecutive subjects who had concurrently received fecal immunochemical test(FIT) and with negative baseline colonoscopy. Stool samples were collected within two days prior to the baseline colonoscopy. Demographic and clinical information, including gender, age, FHbC, body mass index, and smoking at the timing of baseline colonoscopy were analyzed. FHbC ≥100 ng/ml was defined as high FHbC and FHbC<100 ng/ml was defined as low FHbC group. Besides, we divided high FHbC groups into subgroups averagely. Comparison of metachronous AN risk between FHbC subgroups was conducted using Kaplan-Meier analysis for univariate analysis and Cox-regression models for multivariable analysis.
Results:
Of those 4,567 subjects, a total of 678 subjects had metachronous colorectal neoplasm at surveillance colonoscopy. among them, 592(87.3%), 81(12.0%), and 5(0.7%) subjects had non-advanced adenoma (non-AA), advanced adenoma (AA), and invasive cancer, respectively. There were 49(7.2%) subjects had FHbC of 100 ng/mL or higher among the metachronous CRN group. Comparing the group of metachronous AN to group of non-AN, the mean age (p=0.05), level of FHbC(<0.001), proportion of high FHbC (p<0.001) and BMI (p=0.04) were significantly higher. The Kaplan-Meier analysis revealed that subjects with high FHbC and BMI≥25 had significantly higher risk of metachronous AN at surveillance colonoscopy with hazard ratio(HR) of 4.16(95%CI=2.26-7.66) and 1.56(95%CI=1.02-2.39) respectively. In the multivariate analysis, only high FHbC was associated with significantly higher risk of metachronous AN, with adjusted hazard ratio (aHR) of 3.95 (95%CI=2.13-7.35). In the subgroup of FHbC(100-199; n=62), FHbC(200-399,n=48) and FHbC(≥400,n=54), the aHR was 1.50(95%CI=0.36-6.15), 5.90(95%CI=2.13-16.33) and 6.02 (95%CI=2.59-13.97) respectively.
Conclusion:
Subjects who had higher baseline FHbC(especially ≥200) had a significantly higher risk for developing metachronous AN at surveillance after negative baseline colonoscopy. Tailored surveillance interval based on FHbC may be beneficial but requires further study.

並列關鍵字

colorectal neoplasm ； metachronous advanced neoplasia ； fecal hemoglobin concentration

參考文獻

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249

2. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687–96.

3. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–81.

4. Lieberma D et al. Progress and challenges in colorectal cancer screening and surveillance. Gastroenterology. 2010 Jun;138(6):2115-26

5. Rex DK et al. Colorectal cancer screening: Recommendations for physicians