雖然同步化學放射治療合併食道切除手術提升了食道癌的治療成果，整體食道癌的預後仍不理想。因此，一個可以準確預測預後的客觀生物標記，對於幫忙個別病患選擇最佳的治療策略有很大的助益。本前瞻性研究目的在探討接受放射治療的食道癌病患其血清中C-Reactive Protein (CRP) 的濃度能否用來預測其預後。本研究以2002年11月到2007年7月接受放射治療的新診斷食道癌個案為研究族群，於治療開始之前，前瞻性地檢測每一名研究對象血清中CRP的濃度，回溯分析血清中CRP濃度與其他臨床病理因子的相關性，並以統計學的方法來評定預後因子。總共有123位食道癌個案進入本研究，包含120位男性與3位女性，其中81位(65.9%)的血清中CRP濃度較高(大於5 mg/L)，而血清中CRP濃度大於或等於 5 mg/L的個案，有較短的存活期 (P = 0.000)。CRP濃度小於5 mg/L 的個案相較於CRP濃度大於或等於5 mg/L的個案，其二年活存率分別為78.4％與7.8%。血清中白蛋白濃度過低(小於3.5g/dL)在單變數分析中，明顯有較短的存活期。血清中CRP濃度與白蛋白濃度在多變數分析中都是食道癌的顯著預後因子。治療前血清中CRP濃度與白蛋白濃度，都是可以簡單檢測且客觀的生物標記，同時也都是食道癌的顯著預後因子。當這兩種指標和傳統食道癌分期系統一起使用時，可以更準確地預測對食道癌個案存活率。

Although there had been some improvement of treatment results by the combination of concurrent chemoradiotherapy with esophagectomy, the overall prognosis for patients with esophageal cancer remained poor. Selection of optimal treatment strategy for individual patients would be improved by an objective biomarker that can predict prognosis accurately. The aim of this prospective study was to evaluate whether serum concentration of C-reactive protein (CRP) can be used as a prognostic factor to predict the survival of esophageal cancer patients treated with radiotherapy. Between Nov 2002 and July 2007, patients undergoing radiotherapy for newly diagnosed esophageal cancer were eligible for inclusion into this study. Serum CRP concentration was measured prospectively before the initiation of treatment. The relationship between the serum CRP levels and clinicopathological parameters were analyzed retrospectively. The prognosis factors of esophageal cancer were statistically determined. A total of 123 patients consisting of 120 males and 3 females were enrolled in this study. 81 patients (65.9%) had high CRP levels (greater than 5 mg/L). Patients with CRP levels higher than 5 mg/L had a shorter overall survival (P < 0.001). The 2-year survival was 78.4% for patients with CRP < 5 mg/L compared with 7.8% with CRP≧5 mg/L. Hypoalbuminemia (albumin< 3.5g/dL) was significantly related to shorter survival in univariate analysis. Multivariate analysis demonstrated that higher serum CRP concentration and hypoalbuminemia were both independent prognostic factors for esophageal cancer. Pretreatment serum CRP and albumin levels are easily measurable biomarkers and are significant prognostic factors for esophageal cancer. They can be used in combination with the conventional staging system to predict survival and stratify patients with esophageal cancer treated with radiotherapy more accurately.

中文摘要 i
英文摘要Abstract ii
英文縮寫表Abbreviation iii
1. INTRODUCTION 1
2. MATERIALS AND METHODS 3
2.1. Patient population 3
2.2. Pretreatment evaluation 3
2.3. Chemotherapy 3
2.4. Radiotherapy 4
2.5. Response assessment before esophagectomy 4
2.6. Follow-up 5
2.7. Measurement of CRP 5
2.8. Statistical analysis 5
3. RESULTS 6
3.1. Patient characteristics 6
3.2. Correlation between CRP levels and clinicopathological parameters 6
3.3. Clinical predictors of survival 7
4. DISCUSSION 9
4.1. Prognostic factors of esophageal cancer undergoing radiotherapy 9
4.2. CRP as a marker implying aggressiveness of esophageal cancer 9
4.3. Threshold of serum CRP concentration 11
4.4. CRP-based prognostic score 11
4.5. Elevation of serum CRP levels as a result of proinflammatory stimulus 12
REFERENCES 15
表Tables 20
Table 1. Relationship between serum CRP levels and clinical characteristics 21
Table 2. Relationship between levels of serum CRP and relevant continuous variables 22
Table 3. Univariate analysis of prognostic factors 23
Table 4. Multivariate analysis of all potential prognostic factors 24
Table 5. Multivariate analysis of prognostic factors of significance in univariate analysis 25
Table 6. Multivariate analysis of all prognostic factors with GPS replacing CRP and albumin 26
圖 Figures 27
Figure 1. Overall survival in patients with stage I-II versus stage III-IV 28
Figure 2. Overall survival in patients with normal versus high pretreatment CRP levels 29
Figure 3. Overall survival in patients with normal versus lower pretreatment albumin (< 3.5 g/dL) levels 30
Figure 4. The relationship between GPS and overall survival in patients with esophageal cancer 31
Figure 5. The receiver operating characteristic (ROC) curve based on CRP levels for detection of distant metastasis in esophageal cancer 32

1. Department of Health EY, Republic of China (TAIWAN). Statistics of Causes of Death, 2005. Taipei: Department of Health, Executive Yuan, Republic of China (TAIWAN). 2006.
2. Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 2007;17:2-9.
3. Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same disease? Semin Radiat Oncol 2007;17:38-44.
4. Wu IC, Lu CY, Kuo FC, et al. Interaction between cigarette, alcohol and betel nut use on esophageal cancer risk in Taiwan. Eur J Clin Invest 2006;36:236-241.
5. Lee CH, Lee JM, Wu DC, et al. Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan. Int J Cancer 2005;113:475-482.
6. Schneider BJ, Urba SG. Preoperative chemoradiation for the treatment of locoregional esophageal cancer: the standard of care? Semin Radiat Oncol 2007;17:45-52.
7. Suntharalingam M. Definitive chemoradiation in the management of locally advanced esophageal cancer. Semin Radiat Oncol 2007;17:22-28.
8. Kodama J, Miyagi Y, Seki N, et al. Serum C-reactive protein as a prognostic factor in patients with epithelial ovarian cancer. Eur J Obstet Gynecol Reprod Biol 1999;82:107-110.
9. McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 2003;90:215-219.
10. McMillan DC, Elahi MM, Sattar N, et al. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 2001;41:64-69.
11. Crozier JE, McKee RF, McArdle CS, et al. The presence of a systemic inflammatory response predicts poorer survival in patients receiving adjuvant 5-FU chemotherapy following potentially curative resection for colorectal cancer. Br J Cancer 2006;94:1833-1836.
12. Nozoe T, Saeki H, Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator of prognosis in esophageal carcinoma. Am J Surg 2001;182:197-201.
13. Forrest LM, McMillan DC, McArdle CS, et al. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 2003;89:1028-1030.
14. Ikeda M, Natsugoe S, Ueno S, et al. Significant host- and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg 2003;238:197-202.
15. Shimada H, Kitabayashi H, Nabeya Y, et al. Treatment response and prognosis of patients after recurrence of esophageal cancer. Surgery 2003;133:24-31.
16. Shimada H, Nabeya Y, Okazumi S, et al. Elevation of preoperative serum C-reactive protein level is related to poor prognosis in esophageal squamous cell carcinoma. J Surg Oncol 2003;83:248-252.
17. Shimada H, Nabeya Y, Okazumi S, et al. Prediction of survival with squamous cell carcinoma antigen in patients with resectable esophageal squamous cell carcinoma. Surgery 2003;133:486-494.
18. Crumley AB, McMillan DC, McKernan M, et al. An elevated C-reactive protein concentration, prior to surgery, predicts poor cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer. Br J Cancer 2006;94:1568-1571.
19. Guillem P, Triboulet JP. Elevated serum levels of C-reactive protein are indicative of a poor prognosis in patients with esophageal cancer. Dis Esophagus 2005;18:146-150.
20. Murri AM, Bartlett JM, Canney PA, et al. Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer. Br J Cancer 2006;94:227-230.
21. Crumley AB, McMillan DC, McKernan M, et al. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 2006;94:637-641.
22. Ramsey S, Lamb GW, Aitchison M, et al. Evaluation of an inflammation-based prognostic score in patients with metastatic renal cancer. Cancer 2007;109:205-212.
23. McMillan DC, Crozier JE, Canna K, et al. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 2007;22:881-886.
24. Glen P, Jamieson NB, McMillan DC, et al. Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology 2006;6:450-453.
25. Hashimoto K, Ikeda Y, Korenaga D, et al. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer 2005;103:1856-1864.
26. Erlinger TP, Platz EA, Rifai N, et al. C-reactive protein and the risk of incident colorectal cancer. Jama 2004;291:585-590.
27. Trichopoulos D, Psaltopoulou T, Orfanos P, et al. Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol Biomarkers Prev 2006;15:381-384.
28. Nakanishi H, Araki N, Kudawara I, et al. Clinical implications of serum C-reactive protein levels in malignant fibrous histiocytoma. Int J Cancer 2002;99:167-170.
29. Gockel I, Dirksen K, Messow CM, et al. Significance of preoperative C-reactive protein as a parameter of the perioperative course and long-term prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus. World J Gastroenterol 2006;12:3746-3750.
30. Deans DA, Wigmore SJ, Gilmour H, et al. Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer. Br J Cancer 2006;95:1568-1575.
31. Elahi MM, McMillan DC, McArdle CS, et al. Score based on hypoalbuminemia and elevated C-reactive protein predicts survival in patients with advanced gastrointestinal cancer. Nutr Cancer 2004;48:171-173.
32. Nozoe T, Matsumata T, Sugimachi K. Serum level of C-reactive protein may be a marker for proliferation of esophageal carcinoma. Hepatogastroenterology 2000;47:1622-1623.
33. Nozoe T, Korenaga D, Futatsugi M, et al. Immunohistochemical expression of C-reactive protein in squamous cell carcinoma of the esophagus - significance as a tumor marker. Cancer Lett 2003;192:89-95.
34. Joshi N, Johnson LL, Wei WQ, et al. Gene expression differences in normal esophageal mucosa associated with regression and progression of mild and moderate squamous dysplasia in a high-risk Chinese population. Cancer Res 2006;66:6851-6860.
35. Scott HR, McMillan DC, Forrest LM, et al. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer 2002;87:264-267.
36. Andreyev HJ, Norman AR, Oates J, et al. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 1998;34:503-509.
37. Canna K, McArdle PA, McMillan DC, et al. The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 2005;92:651-654.
38. Cho Y, Miyamoto M, Kato K, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res 2003;63:1555-1559.
39. Schumacher K, Haensch W, Roefzaad C, et al. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 2001;61:3932-3936.
40. Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify? Am J Med 2006;119:166 e117-128.
41. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-454.
42. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001;38:189-197.
43. Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem 2004;279:48487-48490.
44. Wigmore SJ, Fearon KC, Sangster K, et al. Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytokine concentrations in patients with pancreatic cancer. Int J Oncol 2002;21:881-886.
45. Strassmann G, Fong M, Freter CE, et al. Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo. J Clin Invest 1993;92:2152-2159.
46. Yuan A, Yang PC, Yu CJ, et al. Interleukin-8 messenger ribonucleic acid expression correlates with tumor progression, tumor angiogenesis, patient survival, and timing of relapse in non-small-cell lung cancer. Am J Respir Crit Care Med 2000;162:1957-1963.
47. O'Riordain MG, Falconer JS, Maingay J, et al. Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism. Int J Oncol 1999;15:823-827.
48. Emmert-Buck MR, Bonner RF, Smith PD, et al. Laser capture microdissection. Science 1996;274:998-1001.
49. Goydos JS, Brumfield AM, Frezza E, et al. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 1998;227:398-404.
50. Piancatelli D, Romano P, Sebastiani P, et al. Local expression of cytokines in human colorectal carcinoma: evidence of specific interleukin-6 gene expression. J Immunother (1997) 1999;22:25-32.
51. Jee SH, Shen SC, Chiu HC, et al. Overexpression of interleukin-6 in human basal cell carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency. Oncogene 2001;20:198-208.
52. Martignoni ME, Kunze P, Hildebrandt W, et al. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res 2005;11:5802-5808.