台灣第 1c 期攝護腺癌病患接受根除性 恥骨後攝護腺切除術之臨床研究

Transcription

1 台灣第 1c 期攝護腺癌病患接受根除性 恥骨後攝護腺切除術之臨床研究 Clinical Study of Radical Retropubic Prostatectomy in Taiwanese Patients with T1c Prostate Cancer 歐宴泉 M.D, Ph.D 台中榮總泌尿科攝護腺疾病防治中心 大林慈濟醫院大愛 2F 第一會議室 7:30-8:30 Dec. 6, 2005

2 台中榮總 整合性攝護腺病 防治中心 簡介 1. 前言 2. 攝護腺疾病 3. 攝護腺癌之國內 外現況 4. 本院近年來之成果 5. 成立本中心之必要性 6. 業務分組 7. SWOT 分析 8. 本中心目標

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4 一 前言 攝護腺疾病是全球性的公共衛生及醫療問題 台灣民眾重視醫療 人口老化 生活飲食西化

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6 台灣老年人口比率 65 歲以上老年人口比率 (%) (%) 65 歲以上老年人口比率 (%) 年度

7 二 攝護腺疾病 1. 慢性攝護腺炎 2. 攝護腺肥大合併下泌尿道 2. 症候群 3. 攝護腺癌

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9 慢性攝護腺炎 1. 發生於 歲及 >70 歲, 病因不明 2. 症狀 : 疼痛 ( 會陰 睪丸 龜頭 恥骨上 ) 頻尿 夜尿 影響生活品質 3. 病人遊走各醫院 4. 需長期服藥, 治療方式五花八門, 但效果均不佳, 國內 外均無標準療法 另類療法 : 中藥 中藥湯 膏藥 針灸.

10 Clinical stage of prostatitis as defined by the NIH-CPCRN Categories Hallmark Symptoms Traditional treatment Category 1 Acute bacterial Pain Antibiotics, urinary drainage Category 2 Chronic bacterial Pain, recurrent UTI Antibiotics Category 3 Chronic Prostatitis/Chronic pelvic pain (CP/CPPS) Discomfort and pain in pelvic region for 3 or more months, impact on voiding, sexual function, and QOL Anitibiotics, α- adrenergic agents, 5αreductase inhibitors, NSAIDs and COX-2 inhibitors Category 3A Inflammatory Presence of white blood cells Pentosan polysulfate Category 3B Noninflammatory No white blood cells Physical therapy Prostatic massage Category 4 Asymptomatic No symptoms No intervention

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12 Clinical: Presence of Moderate to Severe Symptoms (IPSS >7) Patients (%) 總有一天 會等到你 Asia China Australia USA Canada Holland France Age (years) Oishi et al. 4th Int Cons BPH, 1997.

13 三 攝護腺癌之國內 外現況

14 台灣地區食物攝取成份改變 3500 ( ) 每日攝取量大卡 Total Calori Intake Carbohydrate Fat Year Protein 行政院農委會, 2003

15 Changes of Dietary Components USA Taiwan South Korea Japan Calorie (Kcal) Protein (g) Fat (g) CHO (g) 3,400 3,800 2,807 3,129 2,687 2,991 2,088 2, Directorate-General of Budget, Accounting and Statistics, Executive Yuan, ROC

16 Age-Standardized Incidence in Taiwan (n=2,012) Incidence (per 100,000) Year Department of Health, ROC

17 台灣地區攝護腺癌死亡人數及粗死亡率 申報人數 死亡率 %( 每十萬人 ) 人 死亡數 粗死亡率 每十萬 Year 0

18 四 本院近年來之成果 近五年台中榮總泌尿科經直腸攝護腺超音波切片數目 數量 % % % % % 78 超音波超音波切攝護腺癌 50 0 民 89 年民 90 年民 91 年民 92 年民 93 年 年度

19 附件一 The Diagnosed New Case of Prostate Cancer in Taichung-VGH 台中榮民總醫院每年申報攝護腺癌數目 Year No. case

20 各醫院攝護腺癌申報數 Case No. 北榮 林口長庚 台大 中榮高雄長庚奇美和信彰基中國馬偕成大國泰三總高榮新光慈濟台中仁愛高醫羅東博愛萬芳聖馬爾定北醫恩主公 附件二 ( 資料來源 : 2005 衛生署癌症登記報告 )

21 附件三 Annual cases of radical prostatectomy in TCVGH 台中榮民總醫院每年根除性攝護腺癌切除術病例數 Year No. case

22 附件四 泌尿外科近五年來攝護腺相關論文發表十六篇 (SCI:11( 篇 ) 1. (SCI: 0.822)Chi Chi-Rei Yang,, Yen-Chuan Ou, Hao-Chung Ho, Yu-Lin Kao, Chen-Li Cheng, Jung- Ta Chen, Lai-Ping Chen and William l. Ho. Unsuspected prostate carcinoma and prostatic intraepithelial neoplasm in Taiwanese patients undergoing cystoprostatectomy. Molecular Urology 1999, Vol. 3, No. 1, p Hao-Chung Ho,, Chi-Rei Yang, Yen-Chuan Ou,, Chen-Li Cheng, Yu-Lin Kao, Chia-Hsiang Lin, Chung-Kuang Su, Kun-Yuan Chiu. Orthotopic neobladder (Studer pouch) after radical cystoprostatectomy: Experience in Taichung Veterans General Hospital. J UROL ROC Vol.11 No.3, Sep. 2000, p (SCI: 2.461)Chaeyong Jung,, Yen-Chuan Ou,, Fan Yeung,, Henry F. Frierson Jr., Chinghai Kao. Osteocalcin is incompletely spliced in non-osseous osseous tissues. Gene 271 (2001) (SCI: 0.691)Yen Yen-Chuan Ou,, Jung-Ta Chen, Chi-Rie Yang, Chen-Li Cheng, Hao-Chung Ho, Yu- Lin Kao, Jiunn-Liang Ko,, and Yih-Shou Hsieh. Preoperative prediction of extracapsular tumor extension at radical retropubic prostatectomy in Taiwanese patients with T1c prostate cancer. Jpn J Clin Oncol 2002; 32(5) (SCI: 0.691)Yen Yen-Chuan Ou,, Jung-Ta Chen, Chi-Rie Yang, Chen-Li Cheng, Hao-Chung Ho, Jiunn-Liang Ko and Yih-Shou Hsieh. Predicting prostate specific antigen failure after radical retropubic prostatectomy for T1c prostate cancer. Jpn J Clin Oncol 2002; 32(12) (SCI: 1.447) Chi-Rei Yang,, Yen-Chuan Ou,, Yu-Ye Ye Horng and Hong-Shen Lee. The Variation of Percent Free Prostate-Specific Antigen Determined by Two Different Assays. Anticancer Research 23: (2003). 7. Weng-Ming Chen,, Chi-Rei Yang, Yen-Chuan Ou,, Chen-Li Cheng, Yu-Lin Kao, Hao-Chung Ho, Chung-Kwang Su, Kun-Yuan Chiu, Jung-Ta Chen. Clinical Outcome of Patients with Stage T1a Prostate Cancer. J Chin Med Assoc 2003;66: (SCI: 1.447) Yen-Chuan Ou,, Jung-Ta Chen, Chi-Rei Yang, Jiunn-Liang Ko, Yih-Shou Hsieh, Chinghai Kao. Expression of osteocalcin in prostate cancer before and after hormonal therapy. Anticancer Research 23: (2003).

23 9. (SCI: 0.691) Yen-Chuan Ou,, Jung-Ta Chen, Chen-Li Cheng, Hao-Chung Ho, Chi-Rei Yang. Radical prostatectomy for prostate cancer petients with prostate-specific specific antigen > 20 ng/ml. Jpn J Clin Oncol 2003; 33(11) (SCI: 2.456) Wen-Ming Chen,, Chi-Rei Yang, Chen-Li Cheng, Yen-Chuan Ou.. Novel Technique to Facilitate Urethral Stump Exposure After Radical Retropubic Prostatectomy. Urology 63: , 1171, Yu-Lin Kao, Chi-Rei Yang, Cheng-Hshu Chen. Urinary exenteration on a renal transplant recipient with multifocal urothelial cancers and prostatic adenocarcinoma.. J Chin Med Assoc 2004;67: Yun-Yuan Yuan Chiu, Chi-Rei Yang. Effects of Finasteride on Prostate Volume and Prostate- Specific Antigen. J Chin Med Assoc Vol. 67, No. 11, 1-4, (SCI:1.347) 1.347)Chi-Rei Yang, Chung-Knang Su, Kun-Yuan Chiu, Hao-Chung Ho, Yen-Chuan Ou,, Cheng-Li Cheng, and Huei Lee. Free/Total Prostate Specific Antigen Ratio for Prsotate Cancer Detection: A Prospective Blind Study. Anticancer Research 25: xx-xx, xx, (SCI:0.667) 0.667)Wen-Ming Chen, Chi-Rei Yang, Yen-Chuan Ou, Hao-Chung Ho, Chung-Kuang Su and Kun-Yuan Chiu, Chen-Li Cheng. Combination Regimen in the Treatment of Chronic Prostatitis.. Archives of Andrology.. xx-xx, xx, (SCI: 2.456)Twu CM, Ou YC, Yang CR, Cheng CL, Ho HC. Predicting risk factors for inguinal hernia after radical retropubic prostatectomy Urology Oct;66(4): 晚期攝護腺癌之第二線荷爾蒙治療 : 泌尿科創新及爭議性議題, 九州圖書文物有限公司 2004 年版 P

24 附件五 近六年有關攝護腺之研究計劃 (11 件 ) 1. Finasteride & Doxazsin 對攝護腺出血及勃起機制在動物之研究 (TCVGH A) 2. 良性及惡性人類攝護腺組織運用免疫化學及生物化學偵測男性荷爾蒙 黃體素 雌激素感受器之研究 (TCVGH A) 3. 挫傷引起之脊髓外傷所誘發下泌尿道功能異常之評估 : 神經滋養因子之研究 (TCVGH D) 賀昊中 陳文銘 程千里 鳥苷酸環化酶在注射環磷醯胺引發出血性膀胱炎上 程千里 所扮演角色之探討 (TCVGH-NGHU937605) 5. 腹腔鏡輔助之攝護腺根除 裘坤元 ~ (TCVGH A) 6. 雌性素受體 β 在攝護腺癌扮演促進生長角色之研究 陳文銘 ~ (TCVGH A) 7 Finasteride 治療後的人體前列腺組織的 5-α 還原同位 高育琳 ~ 脢 (TCVGH A) 8. 原發性膀胱頸阻塞的基因表現 (TCVGH905002A) 高育琳 ~ 藉血清中攝護腺特異抗原指數來區別台中及苗栗縣居民之攝護腺癌之盛行率 (TCVGH905003A) 10. 攝護腺癌細胞死亡訊息及攔截受體之表現 (TCVGH C) 11. 骨鈣質在原發性及轉移性攝護腺癌之表現 轉移性攝護腺癌之新靶子基因 (TCVGH A) 裘坤元 ~ 楊啟瑞 歐宴泉

25 編號 近四年攝護腺疾病相關之臨床試驗 ( 共七件 ) 研究計劃題目 6. A phase III, parallel group, randomized, open-label, multi-center clinical trial of Zometa in males receiving Androgen Deprivation Therapy for advanced prostate cancer 7. 附件六 Terazopin treatment for benign prostate hyperplasia Doxazosin XL treatment for benign prostate hyperplasia The clinical study of Rofecoxib in reducing the risk of prostate cancer in patients with benign prostate hyperplasia Tolterodine L-Tartrate (Detrusitol FC) treatment for overactive bladder An observational, multicenter study of Zometa in bone metastatic breast cancer, prostate cancer or multiple myeloma patients under conditions of normal clinical practice The optimal dosage of cytoproterone (androcur)) in treating Taiwanese prostate cancer 國際國內 國內 國內 國際 國內 國內 國際 國內 贊助廠商 衛達藥廠 輝瑞藥廠 MSD 美商默沙東 東洋公司 Novartis 台灣諾華 Novartis 國際 德國先靈藥廠 主持人 楊啟瑞歐宴泉 期間 91/02-93/02 程千里 93/01-93/12 楊啟瑞歐宴泉 92/03-93/05 蘇重光 93/02- 歐宴泉 94/11- 歐宴泉 95/01 審核中 楊啟瑞歐宴泉 94/11-

26 五 成立本中心之必要性 1. 提昇病人照護醫療品質 2. 本科空間及人員不足發展受限 整合本科之人力及資源 3. 整合本科之人力及資源 4. 各醫學中心及醫學院的威脅 5. 增加攝護腺癌之診斷病例以配合 達文西機器人 設置

27 附件七 姓名楊啟瑞主任程千里主任 泌尿外科各主治醫師執掌 負責項目外科部主任健保審查 尿失禁業務 人體試驗委員 新藥臨床中心委員 備註 中山 國防授課 賀昊中醫師 健保審查 教育委員 評鑑委員 器官移植勸募小組負責人 病歷審查 月 月中山授課 陳文銘醫師裘坤元醫師歐宴泉醫師蘇重光醫師 醫療品管 腹腔鏡業務 藥事委員 健保聯合窗口 榮民不給付審查 人事室人評會 UGY 導師 醫療品質審議委員會指標負責人 醫學研究委員 PGY1 導師 UGY 導師 PGY 主任 腫瘤業務 教育委員 人體試驗委員 醫學倫理及法律中心副主任 動物實驗委員 實證醫學種子教官 人事成本小組 安寧療護委員 移植業務 腹腔鏡業務 臨床路徑 醫療品質審議委員會指標負責人 實證醫學種子教官 出國進修 病歷審查 ; 支援台安醫院門診 ; 教學門診暨大 中華醫事技術學院授課 支援台安醫院門診教學門診病歷審查 月中山 暨大 中台授課 病歷審查 月 中山授課

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30 達文西機器人 : 三總, 振興, 中榮義大, 長庚,

31 達文西機器人成敗的關鍵在於 : 整合性攝護腺疾病防治中心之執行成效

32 台中榮總泌尿科達文西機器人參觀訓練行程 時間醫院人員 1. 10/24-10/25 10/25 Indiana University-Prudue University Indianapolis (IUPUI) 2. 10/25-10/26 10/26 Memorial Sloan-Kettering Kettering Cancer Center, New York 3a. 10/27-10/28 10/28 Ohio State University Medical Center (OSU) 3b. 11/22-11/23 11/23 Ohio State University Medical Center (OSU) 4. 10/24 Henry Ford Hospital, Detroit 歐宴泉 李建儀 楊啟瑞 裘坤元 楊啟瑞 歐宴泉 裘坤元 程千里 賀昊中 蘇重光 程千里

33 六 業務分組 1. 衛教組 : 2. 治療組 : 3. 試驗組 : 4. 研發組 : 病人衛教組 ; 癌症篩檢組 攝護腺肥大 慢性攝護炎組 ; 放射治療及化學治療組 臨床試驗組 ; 資料分析組 手術研發組 ; 基礎研發組

34 七 SWOT 分析 Strength 優勢 1. 榮民 老年病患多 2. 攝護腺癌治療標準化成效卓越 3. 根除性攝護腺癌切除術是本院之招牌手術 4. 國際之臨床試驗之能力及經驗佳 4. 保持優勢 建立不可取代的地位

35 Weakness 缺點 1. 主治醫師臨床負荷大, 且兼太多行政及教學工作, 人力明顯不足 2. 資料頗多, 臨床研究之結果發表尚嫌不足, 研究計劃未寫成論文 3. 基礎研究投入時間太少, 缺少醫學院, 不易有學校老師及研究生加入研究 4. 空間極小, 規劃不當, 無法發揮整體功能 檢討缺點 還有許多改進的空間

36 Opportunity 機會 1. 配合購置 達文西機器人 施行腹腔鏡 根除性攝護腺切除術發揮潛力 2. 國內尚未有攝護腺疾病整合中心的設 3. 置, 本院地處中科發展中心 3. 聯合健檢中心, 泌尿科歷年之校友, 4. 各榮院及中部醫院建立轉診合作 4. 建立治療模式, 增加自費門診及自費 手術

37 本科歷年來離職人員姓名地址吳立智旅美張勳張勳泌尿科診所院長陳明村書田醫院院長林榮生中國醫藥學院附設醫院北港分院主任盧松貴苗栗盧松貴泌尿外科診所院長蔡宗欣成大泌尿科主任黃一勝新光醫院泌尿科主任唐麗光台東基督教醫院泌尿科主治醫師陳建光桃園榮院泌尿科主任吳錫金中國醫藥大學醫學系主任張兆祥中國醫藥學院泌尿科主任張吉隆署立嘉義醫院外科部主任林合興省立中興醫院泌尿科主任張元耀東勢協和醫院副院長郭振華仁愛醫院主任陳順郎中山醫院泌尿科主治醫師吳劭文嘉義大林慈濟醫院泌尿科主任石宏文澄清醫院泌尿科主治醫師林嘉祥義守醫院泌尿科主任陳炫達竹東榮院泌尿科主任郭佳隴埔里榮院泌尿科主任盧嘉文仁慈醫院泌尿科主治醫師林修名署立豐原醫院泌尿科主治醫師高育琳中山醫院泌尿科主任王宗偉埔里榮院泌尿科主治醫師王賢祥竹東榮院泌尿科主治醫師何君彥永康榮院泌尿科主治醫師陳卷書嘉義榮院泌尿科主治醫師

38 Threat 威脅 1. 中部醫院 ( 中國 中山 仁愛 ) 從本院出去的泌尿科醫師積極經營 ( 尤其攝護腺手術 ) 2. 中部部分醫院採 BOT 放射治療拉攏病人 3. 腹腔鏡根除性攝護腺癌切除術, 目前臺大醫院及中國醫藥大學超越本院 4. 中部之醫院及醫學院 ( 中國 中山 彰基 ) 臨床及基礎已整合 5. 秀傳彰濱醫院將由前台大校長陳維昭主持成立一般醫學及全民健保示範醫院 危機就是轉機直到失去機會 機會落在事先規劃的人你才會體會到它的重要

39 八 本中心目標 近程 ( 一年 ): 成立病友會, 設立專屬網站, 院內篩檢與社區醫學網聯繫, 讓中部地區民眾了解本院攝護腺治療之實力與成果 ; 增加自費手術項目 中程 ( 一年至二年 ): 與國內各大醫學中心 醫學院交流 ; 建立攝護腺疾病治療標準流程 ; 建立訓練制度 ; 加強創新性手術之進展 ; 成立達文西機器人訓練中心 ; 增加自費門診項目 遠程 ( 二年至三年 ): 成立攝護腺基礎醫學研究室, 由博士級研究員負責, 將分子醫學 開發新療法, 達到世界一流醫學中心水準

40 Ultimately, the secret of quality is love. You have to love your patient, you have to love your profession, you have to love your God. If you have love, you can then work backward to monitor and improve the system. Avedis Donabedian,

41 Prostate (Patient) Disease Center: 三類疾病, 三大責任, 三核心價值, 三方合作, 三大願景 P,BPH, PSA; D, inflammatory disease, DRE; C, cancer, center Red: 服務, 視病猶親, 病人, 立足臺灣 Yellow: 教學, 品質優先, 醫護, 胸懷亞洲 Blue: 研究, 研究創新, 行政, 放眼全世界

42 喜樂關懷協會 : 病友合作分享, 醫護關懷照顧, 攜手共創喜樂生命 喜樂的心乃是良藥 ( 箴言 17:22)

43 台灣第 1c 期攝護腺癌病患接受根除性 恥骨後攝護腺切除術之臨床研究 Clinical Study of Radical Retropubic Prostatectomy in Taiwanese Patients with T1c Prostate Cancer

44 Background of the Study (I) 1. Prostate cancer (PC): most commonly diagnosed cancer in most countries, major public health concern 2. PC: 6th commonly diagnosed cancer, 8th cause of cancer death in Taiwan 3. Prevalence of clinical prostate cancers between Asians and Whites: quite difference. Incidence of latent PC in Taiwan was 33%, similar to Japan and USA (Yang( CR, 1999;Yatani R, 1988; Kabalin JN, 1988).

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47 Frequency of unsuspected prostate cancer detected by autopsy and cystoprostatectomy Authors Incidence(%) Method of study No. case studied Franks, Autopsy 180 (>50 yrs) Scott, Autopsy 158 (>70 yrs) McNeal, Autopsy 122 (>40 yrs) Baron and Angrist, Autopsy 50 (>50 yrs) Yatani R, Autopsy 660 (>50 yrs) Winfield, Cystoprostatectomy 80 (>43 yrs) Pritchett, Cystoprostatectomy 165 (>34 yrs) Montie, Cystoprostatectomy 84 (>34 yrs) Kabalin, Cystoprostatectomy 66 (>31 yrs) Yang, Cystoprostatectomy 49 (>45 yrs)

48 Background of the Study (II) 4. Digital rectal examination (DRE( DRE) ) and serum prostate specific antigen (PSA( PSA): detect early prostate cancer? 5. PSA screening test and systematic prostate biopsies under transrectal ultrasound (TRUS)-guidance, T1c PC has increased from 2.7% in 1989 to 47.2% in 1994 (Pound( CR,1997) ) and 78% (screening( study, Humphrey PA, 1996).

49 PSA < 4ng/ml

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51 PSA Circulating Forms in Serum Bound form Free form PSA ACT PSA PSA PSA bound to α-2 PSA bound to α-1- macroglobulin antichymotrypsin (ACT) =occult form =complex form

52 Principle of Assays: use of monoclonal antibodies ACT < PSA > < PSA > Complex form Free form ACT < PSA < PSA > PSA-RIACT FPSA-RIACT

53 The impact of PSA and TRUS-guidance sextant biopsy on stage migration of prostate cancer in Taichung Veterans General Hospital Stage ( % ) Period T1a T1b T1c T2 T3 D* Pre-PSA era( ) PSA era( ) TRUS Bx. era ( ) PSA screening era ( ) * D: node or bone metastasis

54 Aim of the Study We endeavor to detect early prostate cancer and reported the clinical outcome of stage T1a, T1b and T1c in the literature. To understand the clinicopathological features and outcome of Taiwanese patients with stage T1c prostate cancer

55 MATERIALS AND METHODS (I) 1.Fifty-five five patients with stage T1c PC received radical retropubic prostatectomy (RRP) Jan to Dec (14.3%, 55/ 385 PC) 2. Clinical data: patient age, PSA, free-to to-total total (F/T) PSA ratio. 3. Sextant biopsies of the prostate. A 18-gauze biopsy gun (Bard, USA) under transrectal urologic ultrasound (TRUS)-guidance (Bruel( and Kjer 3535, Denmark). The PSA density (PSAD)= PSA/ prostate volume

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59 MATERIALS AND METHODS (II) 4. Needle biopsy were assessed : Gleason score, number of cancer positive cores, maximum % cancer of one core, more % cancer of one lobe. % cancer of biopsies= area of cancer at site 1 + area of cancer at site / total area in all sextant biopsies x 100%). 5. Whole-mount prostatectomy specimens were processed. The tumors were evaluated for Gleason score, tumor location and tumor volume = areas x thickness (3 mm) x tissue shrinkage factor (1.5). RRP was classified as extracapsular tumor extension (ECE) or organ-confined disease (OCD). 6. PSA failure as two serial serum PSA > 0.2 ng/ml.

60 RESULTS

61 Mr. 謝, 65 y/o, T1c, PSA: 7.6, PV: 30ml, Bx G:2+3=5, 7% TV: 0.23 ml (TZ), G:2+3=5, organ-confined disease post-op op PSA<0.01, freedom-from from PSA failure at 5y 9m

62 Mr. 白, 69 y/o,t1c, PSA:80, PV: 52 ml, Bx G:3+3=6, 15% TV:11.22ml (TZ), G:3+4=7, ECE(+) post-op op PSA<0.01, PSA failure at 2 yrs. 10 mos.

63 TABLE I. Preoperative clinical characteristics of 55 patients with stage T1c prostate cancer Clinical characteristic Organ-confined disease Extracapsular extension (number: 37) (number: 18) Age (year) 68.8± ±5.2 PSA level (ng/ml) 8.3± ±21.3** PSA density 0.226± ±0.498 # Cancer-positive biopsy core 1.4± ±0.81 Percentage of cancer in biopsy % cancer of biopsies 12.0± ±14.6** % cancer of one lobe 22.3± ±18.9* % cancer of one core 45.5± ±21.4* Biopsy Gleason score 4.5± ±1.9** key: * p<0.05 **p<0.01 #p<0.0001

64 TABLE II. Pathologic findings of surgical specimens from patients with stage T1c prostate cancer Clinical characteristic Organ-confined disease Extracapsular extension (number: 37) (number: 18) Gleason score 5.9± ±0.9* Tumor location Peripheral lobe 13 (35.1%) 1 (5.6%) Transitional lobe 11 (29.8%) 2 (11.1%) Peripheral + transitional lobe 13 (35.1%) 15 (83.3%)** Tumor volume (ml) 1.86± ±6.73 # < (29.7%) 0 (0%) (54.1%) 8 (44.4%) 4 6 (16.2%) 10 (55.6%)** key: * p<0.05 **p<0.01 #p<0.0001

65 TABLE III. Preoperative predictors of extracapsular tumor extension in patients with stage T1c prostate cancer Variable* Cases of extracapsular Relative risk p value extension/case number PSA ng/ml 10 9/15 (60%) < 10 9/40 (22.5%) PSA density /14 (78.6%) < /41 (17.1%) % cancer of biopsies 20% 9/15 (60%) < 20% 9/40 (22.5%) % cancer of one lobe 30% 10/21 (47.6%) < 30% 8/34 (23.5%) % cancer of one core 50% 13/29 (44.8%) < 50% 5/26 (19.2%) Biopsy Gleason score 6 12/20 (60%) < 6 6/35 (17.1%)

66 TABLE IV. Best model to predict tumor extracapsular extension (ECE) in stage T1c prostate cancer receiving retropubic radical prostatectomy Condition PSAD Biopsy Gleason Percent cancer PSA (ng/ml) Incidence of score in biopsies ECE % (9/10) % 83.3% (5/6) % (9/11) % 100% (5/5) % (8/9) % % (5/5) % 80% (8/10) % (8/9) % % (5/5) 10 20% % (5/6)

67 Table V. Preoperative clinical characteristics of 55 patients with stage T1c prostate cancer classified by PSA failure Clinical characteristic PSA(-) n=40 mean±std PSA(+) n=15 mean±std P valve Age (year) 69.0 ± ± PSA level (ng/ml) 8.3± ± * Free/total PSA ratio 19.3 ± ± PSA density ± ± % cancer of biopsies 12.7 ± ± * Biopsy Gleason score 4.5 ± ± ** * P<0.05 **P<0.01

68 TABLE VI. Pathologic findings of surgical specimens from patients with stage T1c prostate cancer classified by PSA failure Pathology characteristic PSA(-) n=40 PSA(+) n=15 P valve Gleason score 6.0 ± ± * ECE(-) / ECE(+) 33/7 4/ ** Tumor location * Peripheral lobe 14 (35%) 0 ( 0%) Transitional lobe 10 (25%) 3 (20%) Peripheral + transitional lobe 16 (40%) 12 (80%) Tumor volume (ml) 2.71 ± ± ** < (27.5%) 0 ( 0 %) 0.015* (50 %) 8 (53.3%) 4 9 (22.5%) 7 (46.7%)

69 TABLE VII. Clinical parameter predictors of PSA failure with stage T1c prostate cancer Varibalbe PSA ng/ml Cases of PSA failure /case number Relative risk ( 95% CI ) P valve 10 7/15 (46.7%) <10 8/40 ( 20 % ) ( ) PSA density /14 ( 50 % ) * <0.35 8/41 (19.5%) ( ) % cancer of biopsies 20% 7/15 (46.7%) <20% 8/40 ( 20 % ) ( ) Biopsy Gleason score 6 11/20 ( 55 % ) ** <6 4/35 (11.4%) ( ) * P < 0.05 **P< 0.01

70 Varibalbe TABLE VIII. Pathologic parameter predictors of PSA failure in patients with stage T1c prostate cancer Pathology Gleason score Cases of PSA Failure /case number Relative risk ( 95% CI ) P valve * P < 0.05 **P< /36 (38.9%) * <6 1/19 ( 5.3% ) ( ) Pathology Gleason score 7 11/28 (39%) <7 4/27 (15%) ( ) Extracapsular tumor extension (ECE) Presence 11/18 (61.1%) ** Absence 4/37 (10.8%) ( ) Tumor volume 2.5 ml 14/26 (53.9%) ** <2.5 ml 1/29 ( 3.5% ) ( )

71 TABLE IX. Multivariate survival analysis for Cox proportional hazardous model in clinical parameter predictors Risk Coefficients Relative risk Model Factors (SE) (95% CI) P value b I Biopsy Gleason score <6 (n=35) * 6 (n=20) ( ) ( ) a Four variables parameters including PSA, PSA density, % cancer of biopsies and biopsy Gleason score ( classified by 6 or <6) were put into Cox proportional hazardous model (forward regression method) for multivariate survival analysis. b P value by Wald statistic. * P<0.01

72 Table X. Multivariate survival analysis for Cox proportional hazardous model in pathologic parameter predictors Risk Coefficients Relative risk Model Factors (SE) (95% CI) P value b II Extracapsular tumor extension (ECE) absence (n=37) 1 presence (n=18) ( ) ( ) Tumor volume 0.029* <2.5 (n=29) (n=26) ( ) ( ) a Four variables parameters including pathology biopsy Gleason score ( classified by 6 or <6), extracapsular tumor extension, tumor location and tumor volume were put into Cox proportional hazardous model (forward regression method) for multivariate survival analysis. b P value by Wald statistic. * P<0.05

73 Table XI. Multivariate survival analysis for Cox proportional hazardous model in clinical and pathologic parameter predictors Risk Coefficient Relative risk Model Factors (SE) (95% CI) P value b III PSA ng/ml * <10 (n=40) 1 10 (n=15) ( ) ( ) Tumor volume * <2.5 (n=29) (n=26) ( ) ( ) a Eight variables parameters including PSA, PSA density, % cancer of biopsies, biopsy Gleason score ( classified by 6 or <6), pathology biopsy Gleason score ( classified by 6 or <6), extracapsular tumor extension, tumor location and tumor volume were put into Cox proportional hazardous model (forward regression method) for multivariate survival analysis. b P value by Wald statistic. * P<0.05

74 Tumor volume< 2.5ml (Total: 29 cases, Number Events= 1 cases, Number Censored= 28 cases) Tumor volume 2.5ml (Total: 26 cases, Number Events= 14 cases, 1 Number Censored= 12 cases) p< Year Figure. I Freedom from PSA failure survival in 55 patients received radical retropubic prostatectomy for T1c prostate cancer calssified by tumor volume 2.5ml or <2.5 ml.

75 DISCUSSION

76 Discussion (I) RRP vs. ECE RRP with neurovascular (NV) bundle preservation for localized PC (Walsh( PC, 1983). Preoperative prediction of ECE at RRP is important for NV preserving. Since PC with ECE might not be cured by a RRP with NV preserving. ECE in 38-50% of patients who had undergone bilateral NV-sparing RRP presumed OCD (Catalona( WJ, 1990; Bigg SW 1990).

77 Discussion (II) T1c : Variety Stage T1c PC is a unique group which may include insignificant cancer, localized PC, locally-advanced advanced PC or metastatic PC. Disease-free survival in T1c group was similar to T1a to T2a group but better than in the T2b/c group (Lerner( SE, 1996) ). T1c PC are pathologically similar to stage T2 PC (Cookson( MS, 1997)

78 Comparison the insignificant and minimal disease of T1c prostate cancer among Epstein s, Carter s and this series Series Number Insignificant Minimal Moderate Advanced This series ( ) n=55 3.6% 12.7% 40% 43.6% Epstein ( ) n=157 16% 10% 37% 37% Carter( ) n=240 17% 12% 52% 19% 1. Insignificant ( OCD,tumor< 0.2 ml, Gleason score< 7). 2. Minimal ( OCD, tumor ml, Gleason < 7). 3. Moderate ( tumor 0.5 ml, or ECE, Gleason <7) 4. Advanced (ECE with Gleason score 7 or more, or SM(+), SV(+),LN(+) OCD: organ-confined disease; ECE: extracapsular tumor extension SM: surgical margin; SV: seminal vesicle; LN: lymph node

79 Pathologic findings and tumor volume of patients with stage T1c prostate cancer from different series. Number This series (n=55) Ogawa 1998 (n=54) Oesterling 1993 (n=208) Carter 1997 (n=240) Tumor volume Mean (ml) Nil <0.5 ml 20% 11% Nil 33% ml 50.9% 49% Nil 62% 4.0 ml 29.1% 29% Nil 5% Gleason score Nil Nil Pathologic stage OCD 67.2% 59% 53% 72% SV(+) or L N(+) 9% 13% 12% 4% OCD: organ-confined disease; SV: seminal vesicle; LN: lymph node

80 Pathologic staging in patients with nonpalpable stage T1c disease receiving radical prostatectomy Series Year No. of Pts Organ Confined Surgical Margin (SM) Positive Oesterling et al % 34% 3% Epstein et al % 17% 4% Scaletsky et al % 28% 1.4% Humphrey et al % 35% 0 Lymph node(ln) Positive Carter et al % N/A 4% (+SV) Ogawa et al % N/A 13% (+SV) Present series % 26% 4% * +SV : seminal vesicle involvement

81 Discussion (III) ECE vs. PSAD,Gleason From our data, PSAD and biopsy Gleason score were the two best predictors for ECE, with the best cut-off values being PSAD 0.35 and biopsy Gleason score 6. Ogawa O, 1998: PSAD 0.3 as a good predictor for ECE in T1c PC. Carter HB, 1997: the best pretreatment predictors of significant tumor were PSAD >0.15 with the needle biopsy findings. Wills M. 1998: biopsies with a Gleason score 7 and > 1/6 (+) only 10% were

82 Discussion (IV) ECE vs. PSA, F/T PSA As PSA increases, the incidence of ECE increased (Ogawa( O, 1998; Sanwick JM, 1998; Cookson MS, 1996; Partin AW, 1993). Cut off of 10 ng/ ml (Cookson). PSA cut-off of 17 ng/ml : 90% of OCD (Ogawa). F/T PSA ratio provides useful prediction of pathological features of patients with T1c PC. (Morote J, 1999; Southwick PC, 1999; Elgamal AA, 1996). (Southwick >15% free PSA favorable outcome (Southwick PC, 1999).. It seemed not to be a good predictor in this study, because different assays and limited cases.

83 Discussion (V) ECE vs. Biopsy Preoperative sextant needle biopsy (number of cores, site positive, % of positive cores, % cancer in all cores) to predict pathologic features (Sanwick JM1998,; Wills ML, 1998; Epstein JI 1999; Sebo TJ, 2000). Our results revealed the relative risks of ECE were 2.7, 2.0 and 2.3 with 20% cancer in biopsies, 30% cancer in one lobe and 50% cancer in one core, respectively.

84 Discussion (VI) PSA failure vs. TV PSA failure was 49% for tumor > 4 ml and 26% for tumor < 4ml in patients with clinical T2 PC who received RRP (Epstein( JI, 1993), or a relative risk of progression of 1.9 fold. In our series, we classify tumor volume (TV) 4ml or < 4ml, the relative risk of PSA failure was only 2.1 fold. TV 2.5 ml as cutoffs, the relative risk of PSA failure as 12.5 to 27.5 folds in univariate and multivariate survival analysis. Four year freedom- from PSA disease survival for TV <2.5 ml was 95%, and for TV 2.5ml was 39%.

85 Discussion (VI) PSA failure vs. PSA, Gleason Five-year freedom from PSA failure survival was 81% for low risk (PSA<10 ng/ml, Gleason score <7) and 40% for high risk (PSA>10 ng/ml, Gleason score 7) (Kupelian PA, 1997). In our series, preoperative biopsy Gleason score is a good predictor, with the relative risk of PSA failure 4.8 fold higher for biopsy Gleason score 6 vs. <6. Preoperative PSA (RR: 3.09 fold, 10 vs. <10) to be a good predictor of PSA failure in multivariate analysis.

86 CONCLUSION This is the first report related to prediction of extracapsular tumor extension (ECE) and PSA failure among Taiwanese patients with stage T1c prostate cancer in an area with low age-specific prevalence of clinical prostate cancers. The 4 strongest predictors for ECE were PSAD 0.35, biopsy Gleason score 6, 20 percent cancer in biopsies and PSA 10 ng/ml. The single most significant predictor for PSA failure was tumor volume 2.5 ml.. Other significant predictors included PSA 10 ng/ml, biopsy Gleason score 6, PSAD 0.35, pathology Gleason score 6 6 and the presence of ECE.