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研究生:柯德敏
研究生(外文):Te-MinKe
論文名稱:嗜中性白血球與淋巴球比例和血小板與淋巴球比例預測直腸癌新輔助性同步放化療預後
論文名稱(外文):Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Survival in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy
指導教授:簡玉雯
指導教授(外文):Yu-Wen Chien
學位類別:碩士
校院名稱:國立成功大學
系所名稱:公共衛生研究所碩士在職專班
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:56
中文關鍵詞:新輔助同步放化療嗜中性白血球與淋巴球比例血小板與淋巴細胞比例直腸癌生存率
外文關鍵詞:neoadjuvant concurrent chemoradiotherapyneutrophil-to-lymphocyte ratio (NLR)platelet-to-lymphocyte ratio (PLR)rectal cancersurvival
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研究背景
局部晚期 (Locally advanced) 直腸癌的治療方式,根據2018年美國國家癌症資訊網指引 (NCCN),目前多建議以新輔助性化放療 (Neoadjuvant concurrent chemoradiotherapy) 並且接續全直腸系膜切除 (Total mesorectal excision) 為主。若是能夠在治療之前獲得有用且實用的指標來預測治療後的結果,這樣的指標將會對於考量術後接受輔助治療 (Adjuvant treatment) 的策略至關重要。本研究將探討新輔助性同步化放療前嗜中性白血球與淋巴球比例 (Neutrophil-to-Lymphocyte Ratio) 和血小板與淋巴球比例 (Platelet-to-Lymphocyte Ratio) 值的高低對於直腸癌患者的預後價值。
材料與方法
本研究為單一機構回溯性世代分析,利用奇美醫學中心2006年1月至2016年12月之間,184例新診斷為直腸癌並且接受新輔助化放療的患者進行研究。其中,嗜中性白血球與淋巴球比例和血小板與淋巴球比例由新輔助性化放療前兩週內的全血球細胞數獲得。而嗜中性白血球與淋巴球比例和血小板與淋巴球比例的高低值界定則是通過兩種不同的方法來設置,分別由平均值方法和Youden’s index的最大值方法。統計方法使用Kaplan-Meier方法和Log-rank檢驗,比較患者在高和低的嗜中性白血球與淋巴球比例和血小板與淋巴球比例值之間的總體存活率 (Overal survival) 和無病存活率 (Disease free survival) 的差異。並且使用單變量和多變量Cox比例風險模型,控制其他干擾因子進行分析。此外,也針對不同病理分期進行分層分析。
結果
本研究平均追蹤時間為72.73 ±36.82個月。使用平均值方法,界定高與低的嗜中性白血球與淋巴球比例和血小板與淋巴球比例的臨界值分別為3.5和188;使用Youden’s index方法,界定高與低的嗜中性白血球與淋巴球比例和血小板與淋巴球比例的臨界值分別為2.6和112.2。嗜中性白血球與淋巴球比例 〉3.5和 〉2.6患者的無病存活率 (p=.011; p=.005) 和總體存活率 (p=.016; p=.038) 比起 ≤3.5和 ≤2.6的差。血小板與淋巴球比例 〉188和 〉112.2患者的無病存活率 (p=.011; p=.039) 比 ≤188和 ≤112.2的差,但在總體存活率 (p=.185; p=.281) 則無此差別。多變量分析中,嗜中性白血球與淋巴球比例 〉3.5和 〉2.6患者的無病存活率 (aHR=2.8, 95%CI: 1.473-5.419, p=.002; aHR=1.769, 95%CI: 1.130-2.771, p=.013) 和總體存活率 (aHR=1.871, 95%CI: 1.029-3.4, p=.04; aHR=1.584; 95%CI: 1.035-2.425; p=.034) 皆較差。此外,血小板與淋巴球比例 〉188和 〉112.2患者的無病存活率 (aHR=2.274, 95%CI: 1.473-5.419, p=.038; aHR=1.667, 95%CI: 1.047-4.937, p=.038) 也較差,但在總體存活率則無此發現。分層分析中,只有在病理期別分期為II和III的患者中,其嗜中性白血球與淋巴球比例 〉3.5和 〉2.6的無病存活率 (aHR=2.334, 95% CI: 1.158-4.725, p=.018; aHR=1.719, 95% CI: 1.170–2.526, p=.006) 和總體存活率 (aHR=2.226, 95% CI: 1.165-4.251, p=.015; aHR=1.552, 95%CI: 1.021–2.361, p=.040) 比較差。此外,只有在病理期別分期為II和III的患者中,其血小板與淋巴球比例 〉188和 〉112.2的無病存活率 (aHR=2.012, 95% CI: 1.049-3.861, p=.036; aHR=1.645, 95%CI: 1.019–2.655, p=.042) 較差。
結論
在兩種不同的方法作為高與低的嗜中性白血球與淋巴球比例和血小板與淋巴球比例下,得到一樣的結果:高的新輔助性同步化放療前的嗜中性白血球與淋巴球比例的患者,其無病存活率和總體存活率皆較差,而高的新輔助性同步化放療前的血小板與淋巴球比例患者的無病存活期較差。此外,新輔助性同步化放療前的嗜中性白血球與淋巴球比例對於病理完全緩解 (Pathological complete response) 的預測力優於血小板與淋巴球比例。因此,新輔助性同步化放療前的嗜中性白血球與淋巴球比例更適合作為直腸癌患者不良預後的獨立預後因素,此結果可以協助直腸癌術後接受輔助治療的決策。
Background
This study investigated the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT).
Methods
One hundred and eighty-four patients with newly-diagnosed rectal cancer receiving neoadjuvant CCRT were enrolled between January 2006 and December 2016. Pre-CCRT NLR and Pre-CCRT PLR were determined based on complete blood count obtained within two weeks before neoadjuvant CCRT. The cut-off values were set by two different methods: the mean value and the maximum of Youden's index. Overall survival (OS) and disease-free survival (DFS) between patients with high and low NLR and PLR were compared using the Kaplan-Meier method and log-rank tests. We performed univariate and multivariate Cox proportional hazard models controlling for age, gender, grade, perineural invasion (PNI), lymphovascular invasion (LVI), circumferential resection margin (CRM), post-neoadjuvant pathological (yp) stage, and tumor regression grade (TRG). Stratified survival analyses by yp stage were also conducted.
Results
The mean follow-up time was 72.73 ±36.82 months. The cut-off values of pre-CCRT NLR and PLR by using the mean value were 3.5 and 188, respectively.
The cut-off values of pre-CCRT NLR and PLR by using the maximum of Youden's index were 2.6 and 112.2, respectively. Patients with NLR 〉3.5 and 〉2.6 had statistically significantly worse DFS (p=.011; p=.005) and OS (p=.016; p=.038) compared with patients with NLR ≤3.5 and ≤2.6, respectively. PLR 〉188 and 〉112.2 patients possessed statistically significantly inferior DFS (p=.011; p=.039) but not OS (p=.185; p=.281) compared with PLR patients ≤188 and ≤122.2, respectively. Multivariate analyses revealed worse DFS (adjusted HR [aHR]=2.8, 95%CI: 1.473-5.419, p=.002; aHR=1.769, 95%CI: 1.130-2.771, p=.013) and OS (aHR=1.871, 95%CI: 1.029-3.4, p=.04; aHR=1.584; 95%CI: 1.035-2.425; p=.034) in the NLR 〉3.5 and 〉2.6 groups after adjusting for covariates. After adjustments, the PLR 〉188 and 〉112.2 groups had inferior DFS (aHR=2.274, 95%CI: 1.047-4.937, p=.038; aHR=1.667, 95%CI: 1.263-2.014, p=.038) but not OS. Further stratified analysis by yp stage indicated that only yp stage II and III patients with NLR 〉3.5 and 〉2.6 had worse DFS (aHR=2.334, 95% CI: 1.158-4.725, p=.018; aHR=1.719, 95% CI: 1.170–2.526, p=.006) and OS (aHR=2.226, 95% CI: 1.165-4.251, p=.015; aHR=1.552, 95%CI: 1.021–2.361, p=.040). Additionally, only yp stage II and III patients with PLR 〉188 and 〉112.2 had inferior DFS (aHR=2.012, 95% CI: 1.049-3.861, p=.036; aHR=1.645, 95%CI: 1.019–2.655, p=.042).
Conclusions
Elevated pre-CCRT NLR patients had inferior DFS and OS, and high pre-CCRT PLR patients had worse DFS but not OS; the results were similar under two methods of cut-off values. Pre-CCRT NLR seemed to be better than PLR as the predictors for pathological complete response (pCR). Therefore, the study suggested that elevated pre-CCRT NLR might be better than PLR as an independent prognostic factor for poor survival outcome in rectal cancer patients and could be used to identify high-risk patients for more intense treatment and care.
中文摘要 I
Abstract IV
誌謝 VII
List of Tables X
List of Figures XI
Abbreviations XII
Chapter 1. Introduction 1
Chapter 2. Literature Review 3
1. Biomarkers of the systemic inflammatory response 3
2. Application of NLR and PLR in different cancers 4
3. NLR and PLR applied in locally advanced and metastatic CRC 4
4. Different cut-off values of NLR and PLR in previous studies 5
5. Limitation of the previous studies 7
Chapter 3. Study Aims 8
1. The prognostic value of pre-CCRT NLR and PLR in patients with rectal cancer post neoadjuvant CCRT 8
Chapter 4. Materials and Methods 9
1. Data sources 9
2. Study design 9
3. Study materials and measurements 12
4. Data analysis 15
Chapter 5. Results 17
1. Clinico-pathological characteristics of all patients 17
2. Kaplan-Meier plot of DFS and OS between NLR ≤3.5 & 〉3.5 and PLR 〉188 & ≤188, respectively 19
3. Kaplan-Meier plot of DFS and OS between NLR ≤2.6 & 〉2.6 and PLR 〉112.2 & ≤112.2, respectively 19
4. Univariate and multivariate analyses of Pre-CCRT NLR ≤3.5 & 〉3.5 and PLR 〉188 & ≤188 for DFS 20
5. Univariate and multivariate analyses of Pre-CCRT NLR ≤3.5 & 〉3.5 and PLR 〉188 & ≤188 for OS 21
6. Univariate and multivariate analyses of Pre-CCRT NLR ≤2.6 & 〉2.6 and PLR 〉112.2 & ≤112.2 for DFS 21
7. Univariate and multivariate analyses of Pre-CCRT NLR ≤2.6 & 〉2.6 and PLR 〉112.2 & ≤112.2 for OS 22
8. Stratified analyses of Pre-CCRT NLR ≤3.5 & 〉3.5 and PLR 〉188 & ≤188 for DFS and OS by yp stage 22
9. Stratified analyses of Pre-CCRT NLR ≤2.6 & 〉2.6 and PLR 〉112.2 & ≤112.2 for DFS and OS by yp stage 23
Chapter 6. Discussions 24
1. The mechanisms of NLR and PLR 24
2. NLR is superior to PLR in predicting OS 25
3. Different cut-off values 27
4. The potential role of pre-CCRT NLR 29
5. Limitations and strengths 30
Chapter 7. Conclusions 32
References 33
Appendix 39
List of Tables
Table 1. Clinico-pathological characteristics of the patients (n=184) 39
Table 2. Univariate and multivariate analyses of Pre-CCRT NLR and PLR for disease free survival (DFS) 41
Table 3. Univariate and multivariate analyses of Pre-CCRT NLR and PLR for overall survival (OS) 42
Table 4. Univariate and multivariate analyses of Pre-CCRT NLR and PLR for disease free survival (DFS) by different cut-off value 43
Table 5. Univariate and multivariate analyses of Pre-CCRT NLR and PLR for overall survival (OS) by different cut-off value 44
Table 6. Stratified analyses of NLR and PLR for disease free survival (DFS) and overall survival (OS) by post-neoadjuvant pathological (yp) stage 45
Table 7. Stratified analyses of NLR and PLR by different cut-off value for disease free survival (DFS) and overall survival (OS) by post-neoadjuvant pathological (yp) stage 46
List of Figures
Figure 1. Study flow diagram 47
Figure 2. Receiver operating characteristic analysis comparing the ability of NLR and PLR to predict pathological complete response (pCR) 48
Figure 3. Kaplan-Meier plot of disease-free survival (DFS) between NLR ≤3.5 and NLR 〉3.5 49
Figure 4. Kaplan-Meier plot of disease-free survival (DFS) between PLR ≤188 and PLR 〉188 50
Figure 5. Kaplan-Meier plot of overall survival (OS) between NLR ≤3.5 and NLR 〉3.5 51
Figure 6. Kaplan-Meier plot of overall survival (OS) between PLR ≤188 and PLR 〉188 52
Figure 7. Kaplan-Meier plot of disease-free survival (DFS) between NLR ≤2.6 and NLR 〉2.6 53
Figure 8. Kaplan-Meier plot of disease-free survival (DFS) between PLR ≤112.2 and PLR 〉112.2 54
Figure 9. Kaplan-Meier plot of overall survival (OS) between NLR ≤2.6 and NLR 〉2.6 55
Figure 10. Kaplan-Meier plot of overall survival (OS) between PLR ≤112.2 and PLR 〉112.2 56
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