臺灣博碩士論文加值系統

背景與目的：在台灣，初診斷即為攝護腺癌即為第四期骨骼轉移的比率比美國高。本研究之目的為統計中部某醫學中心接受荷爾蒙治療之骨轉移攝護腺癌的存活狀態，並分析死亡族群與存活族群之間之差異，同時探討治療前後血清攝護腺抗原值、骨轉移之緩解性放射治療及化學治療與預後之關係，以期確認影響骨轉移攝護腺癌存活的預後因子。
方法：本研究以中部某醫學中心為對象，統計自民國七十二年元月到民國九十七年十二月底，共有257位病患初診斷即為骨轉移攝護腺癌接受荷爾蒙治療及追蹤之病例，進行存活分析。研究採病例回朔性、橫斷式之分析，統計則包括跨描述性統計、雙變項分析並以Cox 回歸模型以及 Kaplan-Meier 存活分析來評估臨床因子與存活的相關性。
結果：病人的平均年齡為72 歲(±8.4歲)。初始血清攝護腺特定抗原值的中位數則是 155 ng/mL(Q1-Q3 為92.04至600 ng/mL)。在平均追蹤時間為36.4個月(±29.1個月) 而追蹤時間的中位數為58.08個月。。根據 Kaplan-Meier 存活分析顯示整體五年總存活率為60%，十年為33%。治療後最低血清攝護腺特定抗原值，小於1 ng/mL、1-10 ng/mL及大於10 ng/mL之五年存活率分別為70%、61%及52%( p= 0.113)。多變項Cox proportional hazard model結果顯示，治療前初始血清攝護腺特定抗原值大於300 ng/mL病例之預後優於初始血清攝護腺特定抗原值小於100 ng/mL病例(死亡相對危險性：0.66， 95%信賴區間：0.35-1.23，p= 0.187)。治療後最低血清攝護腺特定抗原值大於10 ng/mL病例相較於最低血清攝護腺特定抗原值小於1 ng/mL病例，預後較差(死亡相對危險性：3.07，95%信賴區間：1.47-6.43，p= 0.003)。接受合併男性荷爾蒙阻斷療法治療者預後較僅接受去勢治療者佳(死亡相對危險性：0.37，95%信賴區間：0.19-0.72，p= 0.003)。而有接受骨轉移之緩解性放射治療(死亡相對危險性：1.78， 95%信賴區間：0.96-3.30，p= 0.070)及化學治療(死亡相對危險性：1.79，95%信賴區間：0.96-3.33，p= 0.065)者，為預後不良之相關因子。
結論： 本研究顯示治療前初始血清攝護腺特定抗原值、治療後血清攝護腺特定抗原最低值、是否接受合併男性荷爾蒙阻斷療法、緩解性放射治療及化學治療，將對於初始診斷為骨骼轉移攝護腺癌病患的預後有影響。最低血清攝護腺特定抗原值為一有效的預後因子，將有助於判定哪些病患對治療效果較差，進而規劃下一步的治療計畫。

Background and Objectives:The proportion of men with metastatic prostate cancer disease at first diagnosis is greater in Taiwanese men than in American men. This study aims to determine the survival rate of metastatic prostate cancer treated with hormone therapy patient treated and followed in a medical center of central Taiwan. Furthermore, this study wants to discover the differences between the death group and the survival group. Finally , this study attempts to investigate if various clinical parameters in patients with bone metastatic prostate cancer and determine whether the pretreatment and nadir serum PSA level, palliative metastatic radiotherapy for metastatic bone and advanced chemotherapy can be used as a prognostic factor.
Methods:From January 1983 to December 2008, there were total 257 patients admitted to cased hospital diagnosed as having bone metastatic prostate cancer treated with hormone therapy. Charts records were retrospectively. Statistical methods included descriptive statistics, bibariate analyses, Kaplan-Meier survival analyses and Cox regression analysis for investgating the relationship between the clinical factors and disease survival.
Results:The average age was 72 years(±8.4 years). The median value of pretreatment serum PSA level was 155 ng/mL(Q1-Q3 92.04-600 ng/mL). The average follow-up times was 36.4 months (±29.1 months) and median survival times was 58.08 months . Using Kaplan-Meier survival analyses, the overall 5-year survival rate was 60%. The 5-year survival rates for nadir PSA level less than 1ng/mL,1-10 ng/mL and more than 10ng/mL were 70%、61%及52% (P_ 0.113) . Multivariate Cox regressionhazard model revealed that those pretreatment serum PSA level more than 300ng/mL tended to have good prognosis than those less than 100ng/mL (HR：0.66， 95% CI：0.35-1.23，p= 0.187). In addition, those post-treatment nadir serum PSA level more than 10ng/mL have higher death probability than those less than 1ng/mL (HR：3.07， 95% CI：1.47-6.43，p= 0.003). Further significant factors include: those treated with combined androgen blockade had higher survival rate when compared with those treated with castration only (HR：0.37， 95%CI：0.19-0.72，p= 0.003). In those with palliative radiotherapy for metastatic bone will have shorter survival periods than those without radiotherapy (HR：1.78， 95%CI：0.96-3.30，p= 0.070). Moreover, those with advanced chemotherapy will have poorer prognosis when comparing with those without chemotherapy (HR：1.79， 95%CI：0.96-3.33，p= 0.065).
Conclusions: This study found that pretreatment serum PSA level, post-treatment nadir serum PSA level and the treatment modality significantly influenced the survival of patient with bone metastatic prostate cancer . Prognostic factors are also helpful in identifying which patients are less likely to respond to treatment; this information also would help to counsel patients. The nadir PSA level is a valuable prognostic factor for survival in patients initially diagnosed with bone metastatic prostate cancer treated with hormone therapy.

致謝………………………………………………………………………………………I
中文摘要………………………………………………………………………………III
英文摘要…………………………………………………………………………………V
目錄……………………………………………………………………………………VII
圖目錄 …………………………………………………………………………………IX
表目錄……………………………………………………………………………………X
附圖目錄 ………………………………………………………………………………XI
附表目錄………………………………………………………………………………XII





第一章 緒論
第一節 研究背景與動機………………………………………………1
第二節 研究問題的陳述………………………………………………1
第三節 研究問題的顯著性……………………………………………2
第四節 研究目標………………………………………………………2
第二章 文獻查證
第一節 攝護腺癌概論…………………………………………………7
第二節 攝護腺癌的相關預後因子……………………………………11
第三章 研究方法
第一節 研究架構………………………………………………………23
第二節 研究樣本及資料………………………………………………23
第三節 研究方法………………………………………………………23
第四節 統計分析方法…………………………………………………24
第四章 研究結果
第一節 敘述統計………………………………………………………29
第二節 雙變數分析……………………………………………………30
第三節 存活分析………………………………………………………30
第四節 柯克斯比例危險性模式………………………………………31
第五章 討論
第一節 臨床特徵與疾病預後之關係…..……………………………33
第二節 治療前血清攝護腺特定抗原值與疾病預後之關係…………33
第三節 最低血清攝護腺特定抗原值與疾病預後之關係……………34
第四節 雄性素去除療法與疾病預後之關係…………………………34
第五節 骨轉移之緩解性放射治療與疾病預後之關係………………34
第六節 化學治療與疾病預後之關係…………………………………35
第六章 結論建議與限制………………………………………………………………36
第七章 圖表……………………………………………………………………………38
第八章 參考文獻………………………………………………………………………55
附錄……………………………………………………………………………61

1.年齡標準化發生率長期趨勢及76-96各年癌症相對存活率。（2005）。Retrieved from http://tcr.cph.ntu.edu.tw/main.php?Page=A5B2
2.九十七年癌症登記報告。（2008）。Retrieved from http://www.bhp.doh.gov.tw/bhpnet/portal/Statistics.aspx
3.國家衛生研究院癌症研究所，臺灣癌症臨床研究合作組織（2004）。攝護腺癌臨床診療指引。台灣：臺灣癌症臨床研究合作組織攝護腺癌工作群編撰小組。
4.吳肇毅（2007）。台灣前列腺癌病人基因多型性之研究。中國醫藥大學。
5.許士昌（2009）。新編解剖學（頁 17-9）。台灣：永大書局有限公司。
6.陳明庭, & 曾國藩（2000）。臨床大體解剖學（頁 170-171）。台灣：金名圖書有限公司。
7.陳建華（2009）。以攝護腺特定抗原做為侵犯性攝護腺癌患者接受荷爾蒙療法後發生生化惡化的預後因子之研究。 臺灣大學。
8.黃書彬（2004）。台灣南部地區攝護腺癌分子流行病學之研究。高雄醫學大學。
9.Androgen deprivation therapy for Prostate cancer (Publication (2011). Retrieved from EBSCO: http://dynaweb.ebscohost.com/Detail?sid=d4e068cc-aaf8-47d0-a2de-8c1d66cf5105@sessionmgr15&vid=&db=dme&ss=AN+%22483438%22&sl=ll
10.Prostate cancer (Publication (2011). Retrieved from EBSCO: http://dynaweb.ebscohost.com/Detail?id=AN+114483&sid=d4e068cc-aaf8-47d0-a2de-8c1d66cf5105@sessionmgr15
11.Prostate cancer screen (Publication (2011). Retrieved from EBSCO: http://dynaweb.ebscohost.com/Detail?sid=d4e068cc-aaf8-47d0-a2de-8c1d66cf5105@sessionmgr15&vid=&db=dme&ss=AN+%22113802%22&sl=ll
12.Akaza, H., Hinotsu, S., Usami, M., Arai, Y., Kanetake, H., Naito, S., et al. (2009). Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer, 115(15), 3437-3445.
13.Anuurad, E., Shiwaku, K., Nogi, A., Kitajima, K., Enkhmaa, B., Shimono, K., et al. (2003). The new BMI criteria for asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers. J Occup Health, 45(6), 335-343.
14.Armstrong, A. J., Garrett-Mayer, E. S., Yang, Y. C., de Wit, R., Tannock, I. F., & Eisenberger, M. (2007). A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res, 13(21), 6396-6403.
15.Bournakis, E., Efstathiou, E., Varkaris, A., Wen, S., Chrisofos, M., Deliveliotis, C., et al. (2011). Time to castration resistance is an independent predictor of castration-resistant prostate cancer survival. Anticancer Res, 31(4), 1475-1482.
16.Che, M., DeSilvio, M., Pollack, A., Grignon, D. J., Venkatesan, V. M., Hanks, G. E., et al. (2007). Prognostic value of abnormal p53 expression in locally advanced prostate cancer treated with androgen deprivation and radiotherapy: a study based on RTOG 9202. Int J Radiat Oncol Biol Phys, 69(4), 1117-1123.
17.Chen, C. H., Tzai, T. S., Huang, S. P., Wu, H. C., Tai, H. C., Chang, Y. H., et al. (2008). Clinical outcome of Taiwanese men with metastatic prostate cancer compared with other ethnic groups. Urology, 72(6), 1287-1292.
18.Chen, S. S., Chen, K. K., Lin, A. T., Chang, Y. H., Wu, H. H., & Chang, L. S. (2002). The correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis. BJU Int, 89(7), 710-713.
19.Chodak, G. W., Vogelzang, N. J., Caplan, R. J., Soloway, M., & Smith, J. A. (1991). Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. The Zoladex Study Group. Jama, 265(5), 618-621.
20.Collette, L., de Reijke, T. M., & Schroder, F. H. (2003). Prostate specific antigen: a prognostic marker of survival in good prognosis metastatic prostate cancer? (EORTC 30892). Eur Urol, 44(2), 182-189; discussion 189.
21.Crawford, E. D., & Allen, J. A. (1990). Treatment of newly diagnosed state D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, intergroup study 0036. J Steroid Biochem Mol Biol, 37(6), 961-963.
22.Dawson, N. A. (2011). Overview of treatment for advanced prostate cancer. In M. E. Ross (Ed.): UpToDate.
23.de Reijke, T., & Derobert, E. (2002). Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update. Eur Urol, 42(2), 139-146.
24.Efstathiou, J. A., Chen, M. H., Renshaw, A. A., Loffredo, M. J., & D'Amico, A. V. (2007). Influence of body mass index on prostate-specific antigen failure after androgen suppression and radiation therapy for localized prostate cancer. Cancer, 109(8), 1493-1498.
25.Eisenberger, M. A., Crawford, E. D., Wolf, M., Blumenstein, B., McLeod, D. G., Benson, R., et al. (1994). Prognostic factors in stage D2 prostate cancer; important implications for future trials: results of a cooperative intergroup study (INT.0036). The National Cancer Institute Intergroup Study #0036. Semin Oncol, 21(5), 613-619.
26.Gates, J. D., Carmichael, M. G., Benavides, L. C., Holmes, J. P., Hueman, M. T., Woll, M. M., et al. (2009). Longterm followup assessment of a HER2/neu peptide (E75) vaccine for prevention of recurrence in high-risk prostate cancer patients. J Am Coll Surg, 208(2), 193-201.
27.Glass, T. R., Tangen, C. M., Crawford, E. D., & Thompson, I. (2003). Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol, 169(1), 164-169.
28.Hoffman, R. M. (2011). Screening for prostate cancer. In D. M. Rind (Ed.): UpToDate.
29.Hussain, A. (2011). Chemotherapy in castrate-resistant prostate cancer. In M. E. Ross (Ed.): UpToDate.
30.Jorgensen, T., Kanagasingam, Y., Kaalhus, O., Tveter, K. J., Bryne, M., Skjorten, F., et al. (1997). Prognostic factors in patients with metastatic (stage D2) prostate cancer: experience from the Scandinavian Prostatic Cancer Group Study-2. J Urol, 158(1), 164-170.
31.Kantoff, P. W. (2011). Clinical presentation, diagnosis, and staging of prostate cancer. In M. E. Ross (Ed.): UpToDate.
32.Keuppens, F., Whelan, P., Carneiro de Moura, J. L., Newling, D., Bono, A., Denis, L., et al. (1993). Orchidectomy versus goserelin plus flutamide in patients with metastatic prostate cancer (EORTC 30853). European Organization for Research and Treatment of Cancer--Genitourinary Group. Cancer, 72(12 Suppl), 3863-3869.
33.Kwak, C., Jeong, S. J., Park, M. S., Lee, E., & Lee, S. E. (2002). Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol, 168(3), 995-1000.
34.Matzkin, H., Perito, P. E., & Soloway, M. S. (1993). Prognostic factors in metastatic prostate cancer. Cancer, 72(12 Suppl), 3788-3792.
35.Montgomery, R. B., Goldman, B., Tangen, C. M., Hussain, M., Petrylak, D. P., Page, S., et al. (2007). Association of body mass index with response and survival in men with metastatic prostate cancer: Southwest Oncology Group trials 8894 and 9916. J Urol, 178(5), 1946-1951; discussion 1951.
36.Moul, J. W. (2011). Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification. In M. E. Ross (Ed.): UpToDate.
37.Petrylak, D. P., Tangen, C. M., Hussain, M. H., Lara, P. N., Jr., Jones, J. A., Taplin, M. E., et al. (2004). Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 351(15), 1513-1520.
38.Roach, M., 3rd, Krall, J., Keller, J. W., Perez, C. A., Sause, W. T., Doggett, R. L., et al. (1992). The prognostic significance of race and survival from prostate cancer based on patients irradiated on Radiation Therapy Oncology Group protocols (1976-1985). Int J Radiat Oncol Biol Phys, 24(3), 441-449.
39.Roach, M., Lu, J., Pilepich, M. V., Asbell, S. O., Mohiuddin, M., Terry, R., et al. (2000). Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int J Radiat Oncol Biol Phys, 47(3), 609-615.
40.Sartor, A. O. (2011). Risk factors for prostate cancer. In M. E. Ross (Ed.): UpToDate.
41.Sylvester, R. J., Denis, L., & de Voogt, H. (1998). The importance of prognostic factors in the interpretation of two EORTC metastatic prostate cancer trials. European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Tract Cancer Cooperative Group. Eur Urol, 33(2), 134-143.
42.Tannock, I. F., de Wit, R., Berry, W. R., Horti, J., Pluzanska, A., Chi, K. N., et al. (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 351(15), 1502-1512.
43.Vergis, R., Corbishley, C. M., Thomas, K., Horwich, A., Huddart, R., Khoo, V., et al. (2010). Expression of Bcl-2, p53, and MDM2 in localized prostate cancer with respect to the outcome of radical radiotherapy dose escalation. Int J Radiat Oncol Biol Phys, 78(1), 35-41.
44.Wo, J. Y., Chen, M. H., Nguyen, P. L., Renshaw, A. A., Loffredo, M. J., Kantoff, P. W., et al. (2009). Evaluating the combined effect of comorbidity and prostate-specific antigen kinetics on the risk of death in men after prostate-specific antigen recurrence. J Clin Oncol, 27(35), 6000-6005.
45.Yigitbasi, O., Ozturk, U., Goktug, H. N., Gucuk, A., & Bakirtas, H. (2011). Prognostic factors in metastatic prostate cancer. Urol Oncol, 29(2), 162-165.