預後及預測因子應用在新的治療策略以改善大腸直腸癌病人的治療結果

The prognostic and predictive factors in new therapeutic strategies to improve clinical outcomes of patients with colorectal cancer

黃敬文(Ching-Wen Huang)

指導教授 ： 王照元

高雄醫學大學/醫學院/醫學研究所博士班/博士(2018年)

摘要

大腸直腸癌是全世界第三常見的癌症，也是全世界第四常見的癌症死因，在台灣，大腸直腸癌的發生率逐年增加，根據行政院衛生福利部國民健康署(Ministry of Health and Welfare, the Executive Yuan, Republic of China)癌症登記報告指出，自民國95年起大腸直腸癌已經超越肝癌，成為年發生率第一名的癌症，而且死亡率也逐年增加，是第三常見的癌症死因，所以大腸直腸癌已是全世界與台灣既重要又沉重的健康問題。
一些臨床病理因子已被證實會增加很多種癌症(其中包括大腸直腸癌)發生的危險性，例如糖尿病（Diabetes mellitus, DM)。因為糖尿病與大腸直腸癌有一些共同的危險因子，例如西方飲食型態、都市化的生活型態如久坐少動、肥胖等，所以糖尿病已被許多文獻證實會增加罹患大腸直腸癌的危險性，糖尿病病人罹患大腸直腸癌的危險性，比沒有糖尿病的人增加24到60%。至於糖尿病對大腸直腸癌患者預後的影響，目前的研究結果卻是差異很大，所以仍然有所爭議。我們的回溯性研究，是來評估糖尿病對台灣的大腸直腸癌患者預後之影響。1197位於2002年1月到2008年12月在本院接受手術治療的大腸直腸癌患者列入研究，共有283位(23.6%)患者同時罹患糖尿病，與沒有罹患糖尿病的大腸直腸癌患者相比較，同時罹患糖尿病的大腸直腸癌患者其年紀明顯比較大，同時罹患心臟病的比例也明顯較高，罹患第二種癌症的比例也明顯較高，但其他的臨床病因子則無明顯差異。在預後方面，這兩群病人的總存活時間與癌症特異性存活時間無明顯差異。而且經由單變數與多變數分析，發現糖尿病不是影響總存活時間與癌症特異性存活時間的統計上顯著的較差預後因子。所以不論有無同時罹患糖尿病的大腸直腸癌患者，應接受同樣的治療模式(包括手術及化學治療)。而且必須要有較大規模的多中心研究，來探討同時罹患糖尿病對大腸直腸癌患者癌症預後的影響。
右側大腸癌及左側大腸癌有一些差異，包括流行病學、病理組織學、細胞遺傳學、分子特徵、以及癌症形成機轉的差異(Bufill et al., 1990)。在臨床預後方面，右側大腸癌及左側大腸癌也有一些差異，但結果仍有爭議。因為文獻上探討原發腫瘤的位置(左右側大腸)對大腸直腸癌患者預後的影響，研究的結果有很大的差異，所以目前仍有爭議，因此吾人就組織了一個回溯性的研究，來評估原發腫瘤的位置對台灣的大腸直腸癌患者預後之影響。1095位於2002年1月到2008年12月在本院接受手術治療的大腸直腸癌患者列入研究，249位(22.7%)患者罹患右側大腸癌與846位(77.3%)患者罹患左側大腸癌。右側大腸癌患者的總存活時間與癌症特異性存活時間，比左側大腸癌患者明顯較差，而且這個存活時間的差異在第三期患者特別明顯。這個存活時間的差異可能是因為腫瘤的臨床病理特徵，然而腫瘤分子生物學的差異，例如微衛星不穩定的狀態，可能也是重要的因子。因此，需要更多的研究，去證實腫瘤分子生物學的差異與大腸直腸癌病人預後的相關性。
雖然表皮生長因子受器(EGFR)的過度表現之前被認為與較晚期的大腸直腸癌有關，而且也被認為與較差的預後有關。文獻上研究表皮生長因子受器對大腸直腸癌病人預後的影響，得到的結果不一致，所以目前仍然有所爭議。就轉移性大腸直腸癌病人臨床結果而言，KRAS基因的突變對病人存活率的影響，研究的結果有很大的差異，所以目前仍然有所爭議。因此吾人就組織了一個回溯性的研究，來評估表皮生長因子受器(EGFR)的表現反應以及KRAS基因的突變狀況，對台灣的同步性與非同步性轉移性大腸直腸癌患者預後之影響。研究發現，表皮生長因子受器表現反應僅在非同步性轉移性大腸直腸癌患者中有預測預後的價值，而且是總存活時間與無疾病的存活時間之獨立預後因子，但在同步性轉移性大腸直腸癌患者中就沒有此種價值。因此，分析表皮生長因子受器表現反應，可以幫助我們在非同步性轉移性大腸直腸癌患者中，找出需要接受較積極的治療模式的患者。然而，不論是在非同步性的或同步性轉移性大腸直腸癌的患者中，KRAS基因突變狀況就沒有預測預後的價值。
因為表皮生長因子受器(EGFR)的表現反應對於非同步性轉移性大腸直腸癌病人有預測預後的價值，而且在台灣，第三期大腸直腸癌病人5年的總存活時間為59.9%，局部晚期的大腸直腸癌病人，如果接受輔助性化學治療，5年內復發的風險是26.7%。因此就更進一步做了一個回溯性的研究，來評估對於第三期的大腸直腸癌病人，在接受手術切除與輔助性FOLFOX處方的化學治療後，表皮生長因子受器的表現反應之預測預後的價值。結果發現，與表皮生長因子受器表現陰性反應的患者比較，表皮生長因子受器表現陽性反應的患者有明顯較高的比例會產生術後復發與術後早期復發。而且，表皮生長因子受器表現陽性反應的患者有明顯較差的無疾病的存活時間與總存活時間。因此，如果結合表皮生長因子受器表現反應與術後血中CEA，就可以發現表皮生長因子受器表現陽性反應及術後血中CEA異常的患者，有最高的術後復發、術後早期復發、與死亡的風險，而且有明顯最差的無疾病的存活時間與總存活時間。然後特別注意這群患者，並研究這群患者是否須給予維持性的化學治療，以延緩復發或轉移的產生，延長無疾病的存活時間，進而延長總存活時間，還須給予較為積極的追蹤，以期能早日發現復發或轉移，早日提供更積極的治療，例如手術切除復發或轉移的病灶，或合併給予化學治療與標靶治療。
吾人更進一步的研究發現，第三期的大腸直腸癌病人，在接受手術切除與輔助性FOLFOX處方的化學治療後，是否給予口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，是術後復發與術後死亡的獨立預測因子。此外，Kaplan-Meier存活分析也發現，是否給予口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，也是無疾病的存活時間與總存活時間的獨立預後因子。但是大腸直腸癌患者是異質性的，若以腫瘤細胞表皮生長因子受器表現反應將患者區分為陽性及陰性，再做次族群分析，發現雖然腫瘤細胞表皮生長因子受器表現陽性反應的患者有較差的預後，但是這些病人如果能以口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，他們的預後就可以改善，而與腫瘤細胞表皮生長因子受器表現陰性反應的患者之預後相似。此外，本研究也發現，腫瘤細胞表皮生長因子受器表現陰性反應的患者，無法經由使用口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，來得到改善預後的好處。所以，腫瘤細胞表皮生長因子受器(EGFR)表現陽性反應的患者，應該要使用口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，來延長無疾病的存活時間，進而延長總存活時間；但對於腫瘤細胞表皮生長因子受器(EGFR)表現陰性反應的患者，若以口服的Capecitabine (Xeloda®)當作節拍式維持性化學治療，無法延長無疾病的存活時間，也無法延長總存活時間，所以可能就不需要給予。
過去30年來，許多方面的進步，使得直腸癌患者的臨床結果有大幅的改善，例如全直腸系膜切除(total mesorectal excision, TME)手術，就很明顯地改善直腸癌患者的臨床結果。再者，術前的同步放化療會大大地降低局部復發率，而且毒性也較低以及有較好的生活品質。所以，對於局部晚期直腸癌患者而言，術前的同步放化療，之後再加上全直腸系膜切除(TME)手術，就變成標準的治療模式。另外近幾年因為科技的進步，發展出醫用機械手臂，例如達文西機械手臂手術系統就有許多優點，可以幫助手術醫師在受限的骨盆腔內，從事更精準的剝離與其他的手術動作。因此，我們使用高位淋巴結廓清與低位動脈結紮「high dissection and low ligation」技術，為術前同步放化療的直腸癌患者，進行達文西機械手臂直腸癌手術，而且也分析這些直腸癌患者的短期臨床結果。結果發現這樣的治療模式是安全可行的，而且可以獲得適當數目的apical lymph node，可是這些患者的癌症治療結果需要更長的追蹤來更進一步的確認。
因為大腸直腸癌的成因是多重因子的，包含腫瘤患者本身的身體狀況、腫瘤細胞的基因變化、及腫瘤與患者間的相互作用等，所以本論文從大腸直腸癌患者本身的身體狀況(糖尿病)研究起，再來探討腫瘤位置與腫瘤細胞的基因變化，對腫瘤的行為(例如復發與轉移)的影響，進而研究對藥物治療的影響。藉由這些研究結果可以為臨床癌症治療及追蹤的方式提供規劃之依據，在選擇治療藥物時能更有效益，提升癌症病人的治療效果和存活率，以期能達到癌症病患個人化醫療的目標。

關鍵字

預後及預測因子 ； 大腸直腸癌 ； 糖尿病 ； 左右側大腸癌 ； 表皮生長因子受器 ； 節拍式維持性治療 ； 高淋巴結廓清與低動脈結紮術

並列摘要

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death worldwide. In Taiwan, CRC is the most common type of cancer since 2006; its prevalence has increased rapidly, and it has been the third leading cause of cancer-related death since 2015. Colorectal cancer is one of the most important public problems worldwide and in Taiwan. Some clinicopathological factors has been shown to be associated with increased risk of many types of cancer, including diabetes mellitus (DM). There are some same risk factors for DM and CRC including western diet style, sedentary lifestyle and obesity. Therefore, DM has been shown to be associated with increased risk of CRC. Many studies have shown a 24-60 % increased risk of developing CRC in DM patients. Though the impact of preexisting diabetes on the outcomes of patients with newly diagnosed CRC has been evaluated previously, results have varied from different countries. There are controversies about the impact of preexisting diabetes on the outcomes of patients with newly diagnosed CRC. A retrospective study was conducted to evaluate the survival impact of preexisting diabetes on the outcomes of Taiwanese patients with newly diagnosed CRC. 1197 consecutive patients with histologically proven CRC who received surgical treatment with curative intent from January 2002 to December 2008 were included. There were 283 (23.6 %) patients diagnosed with diabetes mellitus. Patients in the DM group were significantly older than patients in the non-diabetes group. Higher percentage of concurrent cardiac disease was also noted in patient with DM when compared to patients without DM. However, there were no significant differences in gender, tumor size, tumor location, histological type, AJCC/UICC cancer stage, vascular invasion, perineural invasion, the percentages of patients receiving chemotherapy, and comorbidity of pulmonary disease and renal disease. There is no significant survival impact of DM on survival (overall survival (OS) and cancer-specific survival (CSS)) in patients with newly diagnosed CRC. Using univariate and multivariate analysis, DM were statistically significant poor prognostic factors of overall survival and cancer-specific survival. Therefore, CRC patients with DM should be treated with the same modalities (including surgery and chemotherapy) as those without DM.
There were various differences between the proximal and distal colon, including embryological, biological, genetic, molecular biology, and carcinogenetic differences. There are still controversies regarding differences in the clinical outcomes of patients with right colon and left colon. In order to help resolve these controversies, we conducted a retrospective study to evaluate the clinicopathologic features and clinical outcomes of Taiwanese CRC patients with right colon cancer versus those with left colon cancer according to the various cancer stages. 1095 consecutive patients with histologically proven CRC who received surgical treatment with curative intent from January 2002 to December 2008 were included. Of the 1095 patients, 249 (22.7%) had right-sided colon cancers and 846 (77.3%) had left-sided colon cancers. Patients with right-sided colon cancer had significantly worse OS and CSS than patients with left-sided colon cancer. The differences in OS and CSS were still significant only in patients with stage III CRC. These survival differences may be the result of clinicopathologic characteristics, while aspects of tumor biology, such as microsatellite instability (MSI) status, may be another crucial factor. Additional studies are needed to verify the relationship between tumor biology and prognosis for patients with CRC.
Epidermal growth factor receptor (EGFR) overexpression was previously thought to be associated with more advanced disease and worse prognoses. The prognostic value of EGFR in CRC has been investigated extensively, but it remains controversial. The prognostic value of KRAS mutation in synchronous and metachronous mCRC remains controversial. Therefore, we conducted a retrospective study to evaluate the prognostic value of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastastatic CRC (mCRC). EGFR expression has prognostic value only for patients with metachronous mCRC, while having no such value for patients with synchronous mCRC. Our data indicate EGFR as an independent negative prognostic factor for OS and DFS in patients with metachronous mCRC. Analyzing EGFR expression may help identify high-risk patients requiring more aggressive therapeutic modalities in the setting of metachronous mCRC. However, KRAS mutation did not have prognostic value for patients with metachronous or synchronous mCRC.
In Taiwan, the OS rates of patients with stage III CRC was 59.9%. Patients with locally advanced CRC who underwent adjuvant chemotherapy had an approximately 26.7% risk of having a relapse in 5 years. We conducted a retrospective study herr to evaluate the prognostic value of EGFR expression in patients with stage III CRC following radical resection and FOLFOX adjuvant chemotherapy. A significantly higher proportion of the patients with positive EGFR expression in the present study developed postoperative relapse and postoperative early relapse than did those with negative EGFR expression. The patients with positive EGFR expression had significantly poorer DFS and OS. By combining of EGFR expression and postoperative serum carcinoembryonic antigen (CEA level, the patients with positive EGFR expression and an abnormal postoperative serum CEA level had a higher risk of postoperative relapse, postoperative early relapse, and mortality and poorer DFS and OS than did those with negative EGFR expression and a normal postoperative serum CEA level. Therefore, high-risk patients requiring more aggressive therapeutic modalities can be identified.
By univariate and multivariable analyses, metronomic maintenance therapy with capecitabine (Xeloda®) was demonstrated as an independent predictive factor for postoperative relapse and mortality in our patients with histologically confirmed stage III CRC who had received surgical treatment and adjuvant chemotherapy with the FOLFOX regimen. By Kaplan-Meier survival analysis, metronomic maintenance therapy with capecitabine (Xeloda®) was also demonstrated to be an independent prognostic factor for both DFS and OS. However, patients with CRC are heterogeneous. Therefore, we performed subgroup analyses according to EGFR expression and treatment group to determine predictive factors for postoperative relapse and mortality. Although patients with positive expression of EGFR had worse prognoses, if these patients underwent metronomic maintenance therapy with capecitabine (Xeloda®), the prognoses could be improved as good as those of patients with negative expression of EGFR. Furthermore, the patients with negative expression of EGFR did not have survival benefit with metronomic maintenance therapy with capecitabine (Xeloda®). Therefore, patients with positive expression of EGFR should undergo metronomic maintenance therapy with capecitabine (Xeloda®) to improve the DFS and OS. However, patients with negative expression of EGFR could not undergo metronomic maintenance therapy with capecitabine (Xeloda®).
During the previous 3 decades, several advancements have improved the clinical outcomes of rectal cancers. For example, the total mesorectal excision (TME) surgery reported by Heald and Ryall helps remarkably improve clinical outcomes in patients with rectal cancer. A German study reported considerable decrease in local recurrence in patients receiving preoperative concurrent chemoradiotherapy (CCRT). In additional, lower toxicities and a satisfactory quality of life were observed in patients receiving preoperative CCR. Therefore, CCRT followed by TME is the standard treatment for patients with locally advanced rectal cancer (LARC). The robotic system (da Vinci® Surgical System, Intuitive Surgical, Inc., Sunnyvale, CA) has several advantage, which helps perform more precise dissection in the confined pelvic cavity. We present the results of a retrospective study and the short-term clinical outcomes of patients with rectal cancer who underwent preoperative CCRT followed by robotic surgery by using the high dissection and low ligation of the IMA technique. This treatment modality is safe and feasible with considerable apical node harvest; however, its oncological outcome needs to be further confirmed through a long-term follow up.
The carcinogenesis of CRC is multifactorial, including comorbidity of patients, genetic change of cancer cell, and interaction between patient and cancer. At first, I studied the the survival impact of preexisting diabetes on the outcomes of Taiwanese patients with newly diagnosed CRC. Thereaftere, I studied the the impacts of tumor location and genetic change on the clinical behavior of CRC, including recurrence and metastasis, and therapeutic modalities. According to the results, we could developed new modalities of treatment and follow-up to improve the therapeutic effects and survival of patients with CRC. Finally, personalized medicine could be provided to patients with CRC.

並列關鍵字

prognostic and predictive factor ； colorectal cancer ； diabetes mellitus ； right- and left-sided colon cancer ； epidermal growth factor receptor ； metronomic maintenance therapy ； high dissection and low ligation

參考文獻

1. Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet. 1994;344:707-711.

2. Ahmed J, Nasir M, Flashman K, Khan J, Parvaiz A. Totally robotic rectal resection: an experience of the first 100 consecutive cases. Int J Colorectal Dis. 2016;31:869-876.

3. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634.

4. Arnold D, Stein A. New developments in the second-line treatment of metastatic colorectal cancer: potential place in therapy. Drugs. 2013;73:883-891.

5. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109-3116.