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 台中榮總 「整合性攝護腺病 防治中心」簡介 1. 2. 3. 4. 5. 6. 7. 8. 前言 攝護腺疾病 攝護腺癌之國內、外現況 本院近年來之成果 成立本中心之必要性 業務分組 SWOT分析 本中心目標 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 台灣老年人口比率 65歲以上老年人口比率(%) 7.1 7.4 7.6 7.9 8.1 8.3 8.4 8.6 8.8 9 9.2 9.5 10 9 8 7 6 4 3 2 1 年 度 82 0 83 84 85 86 87 88 89 90 91 92 93 (%) 5 65歲以上老年人口比率(%) 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 症候群 3. 攝護腺癌 慢性攝護腺炎 1. 發生於20-49歲及>70歲,病因不明 2. 症狀:疼痛(會陰、睪丸、龜頭、 恥骨上)、頻尿、 3. 4. 夜尿、影響生活品質 病人遊走各醫院 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………. 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, αadrenergic 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 Clinical: Presence of Moderate to Severe Symptoms (IPSS >7) Asia 60 總有一天 會等到你 Patients (%) USA 44 40 40 20 Australia 49 50 30 China 56 36 33 33 31 29 27 26 24 37 36 31 30 15 Canada 36 Holland 27 France 14 8 10 0 50-59 60-69 70-79 Age (years) Oishi et al. 4th Int Cons BPH, 1997. 三、攝護腺癌之國內、外現況 台灣地區食物攝取成份改變 3500 每日 攝 取量 (大卡 ) 3000 Total Calori Intake 2500 2000 Carbohydrate 1500 Fat 1000 500 0 1965 Protein 1970 1975 1980 1985 Year 1990 1995 2000 行政院農委會, 2003 Changes of Dietary Components USA 1984 Calorie (Kcal) Protein (g) Fat (g) CHO (g) Taiwan 1994 1987 South Korea 1997 1985 1995 Japan 1985 1995 3,400 3,800 2,807 3,129 2,687 2,991 2,088 2,042 102 110 89 101 87 98 79 82 162 159 97 131 52 80 57 60 401 491 386 373 … … 298 280 Directorate-General of Budget, Accounting and Statistics, Executive Yuan, ROC 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Incidence (per 100,000) Age-Standardized Incidence in Taiwan 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 30 16.3 (n=2,012) Year Department of Health, ROC 台灣地區攝護腺癌死亡人數及粗死亡率 750 800 6.54 693 死亡數 700 6 6.07 死亡率%(每十萬人) 635 5.59 600 4.78 500 463 4.82 4.2 4 3.39 3 3.37 300 269 223 2.24 200 2.5 223 2 2.19 1 100 0 0 1991 1992 1993 1994 1995 1996 1997 Ye a r 1998 1999 2000 2001 2002 每 十 萬 人 ﹂ 371 366 5 4.97 粗 死 亡 率 ﹁ 561 540 531 申 報 400 人 數 7 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 385 400 385 378 373 351 350 300 250 數 量 229 超音波 超音波切 攝護腺癌 200 143 150 27% 95 121 23% 108 90 21% 82 100 25% 95 95 50 0 民89年 民90年 民91年 年度 民92年 民93年 21% 78 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 140 120 100 80 60 40 20 0 No. case 83 Year84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 23 34 18 32 44 66 48 55 56 84 70 87 101 73 86 100 18 2000 2001 200 133 115 12 0 恩主公 北醫 聖馬爾定 萬芳 羅東博愛 高醫 台中仁愛 慈濟 新光 2000 高榮 三總 國泰 500 成大 馬偕 中國 彰基 和信 奇美 高雄長庚 中榮 台大 林口長庚 北榮 Case No. 附件二 各醫院攝護腺癌申報數 600 2001 400 300 200 100 (資料來源: 2005 衛生署癌症登記報告) 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 50 40 30 20 10 0 Year 84 No. case 2 85-87 88 89 90 91 92 93 94 95 96 97 98 99 0 2 5 3 10 5 16 17 19 20 30 29 32 2000 2001 2002 2003 2004 44 44 49 45 43 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-Rei Yang, Yen-Chuan Ou, Hao-Chung Ho, Yu-Lin Kao, Chen-Li Cheng, Jung- 2. 3. 4. 5. 6. 7. 8. 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, p33-39. 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, p114-1119. (SCI: 2.461)Chaeyong Jung, Yen-Chuan Ou, Fan Yeung, Henry F. Frierson Jr., Chinghai Kao. Osteocalcin is incompletely spliced in non-osseous tissues. Gene 271 (2001) 143-150. (SCI: 0.691)Yen-Chuan Ou, Jung-Ta Chen, Chi-Rie Yang, Chen-Li Cheng, Hao-Chung Ho, YuLin 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)172-176. (SCI: 0.691)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) 536-542. (SCI: 1.447) Chi-Rei Yang, Yen-Chuan Ou, Yu-Ye Horng and Hong-Shen Lee. The Variation of Percent Free Prostate-Specific Antigen Determined by Two Different Assays. Anticancer Research 23: 707-712 (2003). 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: 236-240. (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: 3807-3812 (2003). 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 antigen > 20 ng/ml. Jpn J Clin Oncol 2003; 33(11) 574-579. 10. (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: 1170-1171, 2004. 11. 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;67:422-424. 12. Yun-Yuan Chiu, Chi-Rei Yang. Effects of Finasteride on Prostate Volume and ProstateSpecific Antigen. J Chin Med Assoc Vol. 67, No. 11, 1-4, 2004. 13. (SCI: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, 2005. 14. (SCI: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, 2005. 15. (SCI: 2.456)Twu CM, Ou YC, Yang CR, Cheng CL, Ho HC. Predicting risk factors for inguinal hernia after radical retropubic prostatectomy Urology. 2005 Oct;66(4):814-8 16. 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P67-78. 附件五 近六年有關攝護腺之研究計劃 (11 件) 1. 2. 3. 4. 5. 6. 7 8. 9. 10. 11. Finasteride & Doxazsin對攝護腺出血及勃起機制在 動物之研究(TCVGH-935001A) 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-935003A) 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-935005D) 賀昊中 930101-931231 陳文銘 930101-931231 程千里 930101-931231 鳥苷酸環化酶在注射環磷醯胺引發出血性膀胱炎上 所扮演角色之探討 (TCVGH-NGHU937605) 腹腔鏡輔助之攝護腺根除 (TCVGH 925002A) 雌性素受體β在攝護腺癌扮演促進生長角色之研究 (TCVGH 925003A) Finasteride治療後的人體前列腺組織的5-α還原同位 脢 (TCVGH 915003A) 原發性膀胱頸阻塞的基因表現(TCVGH905002A) 程千里 930101-931231 裘坤元 920101~ 921231 陳文銘 920101~ 921231 高育琳 910101~ 911231 高育琳 900101~ 901231 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) 攝護腺癌細胞死亡訊息及攔截受體之表現 (TCVGH-895001C) 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-895003A) 裘坤元 900101~ 901231 楊啟瑞 880701-890630 歐宴泉 880701-890630 附件六 近四年攝護腺疾病相關之臨床試驗(共七件) 編 號 研究計劃題目 國際 國內 贊助廠 商 主持 人 期間 1. Terazopin treatment for benign prostate hyperplasia 國內 衛達藥廠 楊啟瑞 歐宴泉 91/0293/02 2. Doxazosin XL treatment for benign prostate hyperplasia 國內 輝瑞藥廠 程千里 93/0193/12 3. The clinical study of Rofecoxib in reducing the risk of prostate cancer in patients with benign prostate hyperplasia 國際 MSD美商 楊啟瑞 默沙東 歐宴泉 92/0393/05 4. Tolterodine L-Tartrate (Detrusitol FC) treatment for overactive bladder 國內 東洋公司 蘇重光 93/02- 5. An observational, multicenter study of Zometa® in bone metastatic breast cancer, prostate cancer or multiple myeloma patients under conditions of normal clinical practice 國內 Novartis 歐宴泉 台灣諾華 94/11- 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 國際 Novartis 國際 歐宴泉 95/01 審核中 7. The optimal dosage of cytoproterone (androcur) in treating Taiwanese prostate cancer 國內 德國先靈 楊啟瑞 藥廠 歐宴泉 94/11- 五、成立本中心之必要性 1. 2. 3. 4. 5. 提昇病人照護醫療品質 本科空間及人員不足發展受限 整合本科之人力及資源 各醫學中心及醫學院的威脅 增加攝護腺癌之診斷病例以配合「達 文西機器人」設置 附件七 姓名 楊啟瑞主任 程千里主任 賀昊中醫師 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 健保審查、教育委員、評鑑委員、器官移植勸 募小組負責人 陳文銘醫師 備註 中山、國防授課 病歷審查9404-6月、 9504-6月 中山授課 出國進修 裘坤元醫師 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 病歷審查9401-3、 9501-03; 支援台安醫院 門診;教學門診 暨大、中華醫事技術學 院授課 歐宴泉醫師 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 支援台安醫院門診 教學門診 病歷審查9410-12月 中山、暨大、中台授課 蘇重光醫師 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 病歷審查9407-09月、 中山授課 達文西機器人:三總, 振興,中榮,義大,長庚 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 台中榮總泌尿科達文西機器人參觀訓練行程 時 間 1. 醫 院 10/24-10/25 Indiana University-Prudue University Indianapolis (IUPUI) 2. 10/25-10/26 Memorial Sloan-Kettering Cancer Center, New York 3a. 10/27-10/28 Ohio State University Medical Center (OSU) 3b. 11/22-11/23 Ohio State University Medical Center (OSU) 4. 10/24 Henry Ford Hospital, Detroit 人 員 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 六、業務分組 1. 衛教組: 病人衛教組; 癌症篩檢組 2. 治療組: 攝護腺肥大、慢性攝護炎組; 放射治 療及化學治療組 3. 試驗組: 臨床試驗組; 資料分析組 4. 研發組: 手術研發組; 基礎研發組 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 保持優勢 建立不可取代的地位 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 Opportunity機會 1. 配合購置 ” 達文西機器人 ”施行腹腔鏡 2. 3. 4. 根除性攝護腺切除術發揮潛力。 國內尚未有攝護腺疾病整合中心的設 置, 本院地處中科發展中心。 聯合健檢中心,泌尿科歷年之校友, 各榮院及中部醫院建立轉診合作。 建立治療模式,增加自費門診及自費 手術。 本科歷年來離職人員 姓名 吳立智 張 勳 陳明村 林榮生 盧松貴 蔡宗欣 黃一勝 唐麗光 陳建光 吳錫金 張兆祥 張吉隆 林合興 張元耀 郭振華 陳順郎 吳劭文 石宏文 林嘉祥 陳炫達 郭佳隴 盧嘉文 林修名 高育琳 王宗偉 王賢祥 何君彥 陳卷書 地 址 旅美 張勳泌尿科診所院長 書田醫院院長 中國醫藥學院附設醫院北港分院主任 苗栗盧松貴泌尿外科診所院長 成大泌尿科主任 新光醫院泌尿科主任 台東基督教醫院泌尿科主治醫師 桃園榮院泌尿科主任 中國醫藥大學醫學系主任 中國醫藥學院泌尿科主任 署立嘉義醫院外科部主任 省立中興醫院泌尿科主任 東勢協和醫院副院長 仁愛醫院主任 中山醫院泌尿科主治醫師 嘉義大林慈濟醫院泌尿科主任 澄清醫院泌尿科主治醫師 義守醫院泌尿科主任 竹東榮院泌尿科主任 埔里榮院泌尿科主任 仁慈醫院泌尿科主治醫師 署立豐原醫院泌尿科主治醫師 中山醫院泌尿科主任 埔里榮院泌尿科主治醫師 竹東榮院泌尿科主治醫師 永康榮院泌尿科主治醫師 嘉義榮院泌尿科主治醫師 Threat威脅 1. 中部醫院(中國、中山、仁愛)從本院出去的泌尿科 2. 3. 4. 5. 醫師積極經營(尤其攝護腺 手術) 中部部分醫院採BOT放射治療拉攏病人 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 中部之醫院及醫學院(中國、中山、彰基)臨床及基 礎已整合 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 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。 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, 1919-2000 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 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) 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 Background of the Study (I) 1. Prostate cancer (PC): most commonly 2. 3. diagnosed cancer in most countries, major public health concern PC: 6th commonly diagnosed cancer, 8th cause of cancer death in Taiwan 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). Frequency of unsuspected prostate cancer detected by autopsy and cystoprostatectomy Authors Incidence(%) Method of study No. case studied Franks, 1954 Scott, 1969 McNeal, 1969 Baron and Angrist, 1941 Yatani R, 1988 38 46 36 41 34.6 Autopsy Autopsy Autopsy Autopsy Autopsy 180 (>50 yrs) 158 (>70 yrs) 122 (>40 yrs) 50 (>50 yrs) 660 (>50 yrs) Winfield, 1987 Pritchett, 1987 Montie, 1988 Kabalin, 1989 Yang, 1998 28 27 46 38 32.7 Cystoprostatectomy Cystoprostatectomy Cystoprostatectomy Cystoprostatectomy Cystoprostatectomy 80 (>43 yrs) 165 (>34 yrs) 84 (>34 yrs) 66 (>31 yrs) 49 (>45 yrs) Background of the Study (II) 4. Digital rectal examination (DRE) and serum prostate specific antigen (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). PSA < 4ng/ml PSA Circulating Forms in Serum Bound form PSA PSA bound to α-2 macroglobulin =occult form Free form ACT PSA PSA PSA bound to α-1antichymotrypsin (ACT) =complex form Principle of Assays: use of monoclonal antibodies ACT < PSA > < PSA > PSA-RIACT Complex form Free form ACT < PSA < PSA > FPSA-RIACT 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(19831989) 24 0 16 10 50 PSA era(19901994) 10 4 37 24 25 TRUS Bx. era (1995-1998) 10 14 41 16 19 PSA screening era (1999-2002) 7 24 35 17 17 * D: node or bone metastasis 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 MATERIALS AND METHODS (I) 1.Fifty-five patients with stage T1c PC received radical retropubic prostatectomy (RRP) Jan. 1996 to Dec. 2000. (14.3%, 55/ 385 PC) 2. Clinical data: patient age, PSA, free-to-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 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 2 +..../ 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. RESULTS 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 PSA<0.01, freedom-from PSA failure at 5y 9m 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 PSA<0.01, PSA failure at 2 yrs. 10 mos. 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) PSA level (ng/ml) 68.8±4.3 8.3±3.7 69.2±5.2 18.4±21.3** PSA density Cancer-positive biopsy core Percentage of cancer in biopsy % cancer of biopsies % cancer of one lobe % cancer of one core Biopsy Gleason score 0.226±0.133 1.4±0.65 0.556±0.498# 1.8±0.81 12.0±7.7 22.3±13.4 45.5±17.3 4.5±1.3 20.0±14.6** 32.2±18.9* 58.6±21.4* 5.6±1.9** key: * p<0.05 **p<0.01 #p<0.0001 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±1.3 6.8±0.9* Tumor location Peripheral lobe Transitional lobe Peripheral + transitional lobe 13 (35.1%) 11 (29.8%) 13 (35.1%) 1 (5.6%) 2 (11.1%) 15 (83.3%)** Tumor volume (ml) <0.5 0.5-3.9 ≧4 1.86±1.77 11 (29.7%) 20 (54.1%) 6 (16.2%) 8.27±6.73# 0 (0%) 8 (44.4%) 10 (55.6%)** key: * p<0.05 **p<0.01 #p<0.0001 TABLE III. Preoperative predictors of extracapsular tumor extension in patients with stage T1c prostate cancer Variable* Cases of extracapsular extension/case number Relative risk p value 9/15 (60%) 9/40 (22.5%) 2.7 0.0213 PSA ng/ml ≧10 < 10 PSA density ≧0.35 < 0.35 11/14 (78.6%) 7/41 (17.1%) 4.6 0.00006 % cancer of biopsies ≧20% < 20% % cancer of one lobe ≧30% < 30% % cancer of one core ≧50% < 50% 9/15 (60%) 9/40 (22.5%) 10/21 (47.6%) 8/34 (23.5%) 13/29 (44.8%) 5/26 (19.2%) 2.7 0.0213 2.0 0.0815 2.3 0.05 Biopsy Gleason score ≧6 <6 12/20 (60%) 6/35 (17.1%) 3.5 0.0023 TABLE IV. Best model to predict tumor extracapsular extension (ECE) in stage T1c prostate cancer receiving retropubic radical prostatectomy Condition PSAD 1 2 3 4 5 6 7 8 9 10 ≧0.35 ≧0.35 ≧0.35 ≧0.35 ≧0.35 ≧0.35 Biopsy Gleason score Percent cancer in biopsies PSA (ng/ml) ≧6 ≧20% ≧10 ≧6 ≧6 ≧6 ≧6 ≧6 ≧6 ≧20% ≧20% ≧20% ≧20% ≧20% ≧10 ≧10 ≧10 ≧10 ≧10 Incidence of ECE 90% (9/10) 83.3% (5/6) 81.8% (9/11) 100% (5/5) 88.9% (8/9) 100% (5/5) 80% (8/10) 88.9% (8/9) 100% (5/5) 83.3% (5/6) Table V. Preoperative clinical characteristics of 55 patients with stage T1c prostate cancer classified by PSA failure P valve PSA(-) n=40 PSA(+) n=15 mean±std mean±std Age (year) 69.0 ± 4.3 68.8 ± 5.4 0.932 PSA level (ng/ml) 8.3± 3.7 20.5 ± 22.8 0.038* Free/total PSA ratio 19.3 ± 6.8 15.9 ± 9.4 PSA density 0.246 ± 0.144 0.570 ± 0.548 0.071 % cancer of biopsies 12.7 ± 9.1 19.8 ± 14.0 0.031* Biopsy Gleason score 4.5 ± 1.3 5.9 ± 1.7 0.002** Clinical characteristic * P<0.05 **P<0.01 0.092 TABLE VI. VI Pathologic findings of surgical specimens from patients with stage T1c prostate cancer classified by PSA failure PSA(+) n=15 P valve Pathology characteristic PSA(-) n=40 Gleason score 6.0 ± 1.3 6.7 ± 0.7 0.037* 33/7 4/11 0.0002** ECE(-) / ECE(+) Tumor location 0.0123* Peripheral lobe 14 (35%) 0 ( 0%) Transitional lobe 10 (25%) 3 (20%) Peripheral + transitional lobe 16 (40%) 12 (80%) Tumor volume (ml) 2.71 ± 3.20 7.27 ± 7.35 0.0005** 0.015* <0.5 11 (27.5%) 0 ( 0 %) 0.5 - 3.9 20 (50 %) 8 (53.3%) ≧4 9 (22.5%) 7 (46.7%) TABLE VII. Clinical parameter predictors of PSA failure with stage T1c prostate cancer Varibalbe Cases of PSA failure /case number Relative risk ( 95% CI ) P valve * P < 0.05 **P< 0.01 PSA ng/ml ≧10 7/15 (46.7%) 2.3 <10 8/40 ( 20 % ) ( 1.03 - 5.31 ) ≧0.35 7/14 ( 50 % ) 2.6 <0.35 8/41 (19.5%) ( 1.14 - 5.78 ) ≧20% 7/15 (46.7%) 2.3 <20% 8/40 ( 20 % ) ( 1.03 - 5.31 ) ≧6 11/20 ( 55 % ) 4.8 <6 4/35 (11.4%) ( 1.76 - 13.1 ) 0.086 PSA density 0.039* % cancer of biopsies 0.086 Biopsy Gleason score 0.001** TABLE VIII. Pathologic parameter predictors of PSA failure in patients with stage T1c prostate cancer Varibalbe Cases of PSA Failure /case number Relative risk ( 95% CI ) P valve * P < 0.05 **P< 0.001 Pathology Gleason score ≧6 14/36 (38.9%) 7.4 <6 1/19 ( 5.3% ) ( 1.05 - 51.9 ) 0.019* Pathology Gleason score ≧7 11/28 (39%) 2.6 <7 4/27 (15%) (0.96 – 7.32 ) 0.0829 Extracapsular tumor extension (ECE) Presence 11/18 (61.1%) 5.7 Absence 4/37 (10.8%) ( 2.09 - 15.3 ) ≧2.5 ml 14/26 (53.9%) 15.6 <2.5 ml 1/29 ( 3.5% ) ( 2.2 - 110.6 ) 0.0002** Tumor volume 0.0001** TABLE IX. IX Multivariate survival analysis for Cox proportional hazardous model in clinical parameter predictors Model Risk Coefficients Relative risk Factors (SE) (95% CI) P valueb 1 0.001* I Biopsy Gleason score <6 (n=35) ≧6 (n=20) a 1.786 5.964 ( 0.591 ) (1.874-18.978 ) 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 Table X. Multivariate survival analysis for Cox proportional hazardous model in pathologic parameter predictors Model Risk Coefficients Relative risk Factors (SE) (95% CI) P valueb II 0.129 Extracapsular tumor extension (ECE) absence (n=37) presence (n=18) Tumor 1 0.999 2.715 ( 0.659 ) ( 0.747-9.872) 0.029* volume <2.5 (n=29) ≧2.5 (n=26) 1 2.525 12.486 ( 1.154 ) ( 1.301-119.844) 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 a Table XI. XI Multivariate survival analysis for Cox proportional hazardous model in clinical and pathologic parameter predictors Coefficient Relative risk Risk Model Factors (SE) (95% CI) P valueb III PSA ng/ml 0.0406* <10 (n=40) ≧10 (n=15) 1 1.129 3.093 ( 0.551 ) ( 1.050-9.111 ) Tumor volume 0.0019* <2.5 (n=29) ≧2.5 (n=26) 1 3.314 27.494 ( 1.070 ) ( 3.37-223.75 ) 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 a 1 1.0 0.9524 .9 .8 Tumor volume< 2.5ml (Total: 29 cases, Number Events= 1 cases, Number Censored= 28 cases) 0.7308 11 .7 .6 0.5329 .5 Tumor volume ≧2.5ml (Total: 26 cases, Number Events= 14 cases, Number Censored= 12 cases) .4 .3 0.3947 1 p<0.0001 .2 .1 0.0 0 1 2 3 4 5 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. 6 DISCUSSION 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). Discussion (II) T1c : Variety • Stage T1c PC is a unique group which may include insignificant cancer, localized PC, locally-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) Comparison the insignificant and minimal disease of T1c prostate cancer among Epstein’s , Carter’s and this series Series Number Insignificant Minimal This series (1996-2000) n=55 3.6% 12.7% 40% 43.6% Epstein (1988-1992) n=157 16% 10% 37% 37% Carter(1994-1996) n=240 17% 12% 52% 19% 1. Insignificant ( OCD,tumor< 0.2 ml , Gleason score< 7). 2. Minimal ( OCD, tumor 0.2-0.5 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 Moderate Advanced 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) 3.96 3.94 6.4 Nil <0.5 ml 20% 11% Nil 33% 0.5-3.9ml 50.9% 49% Nil 62% ≧4.0 ml 29.1% 29% Nil 5% 5.1 6.2 Nil Nil 67.2% 59% 53% 72% 9% 13% 12% 4% Gleason score Pathologic stage OCD SV(+) or L N(+) OCD: organ-confined disease; SV: seminal vesicle; LN: lymph node Pathologic staging in patients with nonpalpable stage T1c disease receiving radical prostatectomy Series Year No. of Pts Organ Confined Surgical Margin (SM) Positive Lymph node(LN) Positive Oesterling et al. 1993 208 53% 34% 3% Epstein et al. 1994 157 51% 17% 4% Scaletsky et al. 1994 142 68% 28% 1.4% Humphrey et al. 1996 78 59% 35% 0 Carter et al. 1997 240 72% N/A 4% (+SV) Ogawa et al. 1998 54 59% N/A 13% (+SV) Present series 2001 55 67% 26% 4% * +SV : seminal vesicle involvement 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 OCD. 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). >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. 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. 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 freedomfrom PSA disease survival for TV <2.5 ml was 95%, and for TV ≧2.5ml was 39%. 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. 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 and the presence of ECE.
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