陳 健,嚴(yán)維剛,李漢忠,紀(jì)志剛,周 毅,周智恩,麥智鵬
中國(guó)醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院 北京協(xié)和醫(yī)院泌尿外科,北京100730
近距離治療聯(lián)合外放射治療及內(nèi)分泌治療對(duì)局部高危前列腺癌的療效
陳 健,嚴(yán)維剛,李漢忠,紀(jì)志剛,周 毅,周智恩,麥智鵬
中國(guó)醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院 北京協(xié)和醫(yī)院泌尿外科,北京100730
目的 研究近距離治療聯(lián)合外放射治療及內(nèi)分泌治療對(duì)局部高危前列腺癌的療效。方法 2003年12月至2007年12月北京協(xié)和醫(yī)院泌尿外科收治前列腺癌近距離治療患者132例,其中局部高?;颊?7例,局部中、低危患者35例。通過(guò)門診隨訪,監(jiān)測(cè)患者術(shù)后血清前列腺特異性抗原 (prostate specific antigen,PSA)水平,記錄患者出現(xiàn)生化復(fù)發(fā)、進(jìn)展至去勢(shì)抵抗性前列腺癌 (castration-resistant prostate cancer,CRPC)或腫瘤遠(yuǎn)處轉(zhuǎn)移、死亡等事件,了解患者無(wú)生化復(fù)發(fā)生存率 (biochemical progression-free survival,bPFS)、疾病特異性生存率 (cause-specific survival,CSS)及總體生存率 (overall survival,OS)。結(jié)果 132例患者bPFS、CSS、OS分別為83.3%、91.7%、84.8%,局部高危患者為81.4%、88.7%、81.4%,局部低、中?;颊邽?8.6%、100%、94.3%。局部高?;颊遙PFS及OS與局部低、中?;颊呦啾炔町悷o(wú)統(tǒng)計(jì)學(xué)意義 (P=0.433,0.098);而局部低、中危患者CSS明顯高于局部高?;颊?(P=0.037)。按不同Gleason評(píng)分、TNM臨床分期、術(shù)前PSA水平分別分組,各組患者間bPFS差異均無(wú)統(tǒng)計(jì)學(xué)意義 (P=0.084,0.537,0.850)。結(jié)論 對(duì)于局部高危前列腺癌患者,近距離治療聯(lián)合外放射治療或內(nèi)分泌治療可有效控制PSA水平并延緩生化復(fù)發(fā)。
局部高危前列腺癌;近距離治療;無(wú)生化復(fù)發(fā)生存率
Med J PUMCH,2016,7(2):104-109
對(duì)前列腺癌進(jìn)行危險(xiǎn)因素等級(jí)分析,有助于指導(dǎo)治療和評(píng)估預(yù)后。美國(guó)國(guó)家綜合癌癥網(wǎng)絡(luò) (National Comprehensive Cancer Network,NCCN)根據(jù)血清前列腺特異性抗原 (prostate specific antigen,PSA)水平、Gleason評(píng)分和TNM臨床分期將前列腺癌分為低、中、高危三個(gè)等級(jí)[1]。對(duì)于局部低、中危前列腺癌 (T1~T2b),近距離治療與前列腺癌根治性切除、前列腺癌外放射治療效果相當(dāng),均能達(dá)到根治水平[2-8]。而局部高危前列腺癌,甚至包括Gleason評(píng)分為5分的前列腺癌,單純近距離治療效果欠佳[9-11]。本研究探討近距離治療聯(lián)合外放射治療及內(nèi)分泌治療對(duì)局部高危前列腺癌的療效。
對(duì)象
2003年12月至2007年12月北京協(xié)和醫(yī)院泌尿外科收治前列腺癌近距離治療患者132例,其中局部高?;颊?7例,局部中、低?;颊?5例?;颊咝g(shù)前均經(jīng)會(huì)陰前列腺穿刺活檢病理證實(shí),并行B超、胸腹盆CT或磁共振成像、全身骨掃描證實(shí)腫瘤無(wú)遠(yuǎn)處轉(zhuǎn)移及包膜外侵犯。
儀器設(shè)備
前列腺癌近距離治療系統(tǒng) (美國(guó)CMS公司)包括實(shí)時(shí)圖像捕獲、自動(dòng)粒子紡織、三維劑量編輯和成像的內(nèi)植入治療計(jì)劃軟件 (3.2版本),AccuSeed定位儀和定位架,西門子SONOLINE Adara SLC數(shù)字化增強(qiáng)型超聲,Mick 200粒子植入器,Premier靜電計(jì)和便攜式放射量調(diào)查計(jì),標(biāo)準(zhǔn)影像3000活度儀。
治療方法
患者治療前3~5 d先經(jīng)直腸超聲行預(yù)計(jì)劃,明確125I粒子數(shù)及粒子分布情況,預(yù)訂粒子。常規(guī)進(jìn)行粒子活度檢測(cè),粒子活度偏差<5%。手術(shù)采用聯(lián)合阻滯麻醉。粒子分布計(jì)劃按照西雅圖模式,即修正均勻布源法則,處方劑量為144 Gy,以Mick槍將粒子推入前列腺內(nèi)。
參考美國(guó)近距離治療協(xié)會(huì) (American Brachytherapy Society,ABS)推薦[12],低危前列腺癌患者僅行單純近距離治療;對(duì)中?;颊哌x擇近距離治療聯(lián)合6個(gè)月內(nèi)分泌治療,并根據(jù)術(shù)后PSA水平變化,決定是否追加外放射治療;而對(duì)高危患者,則在近距離治療基礎(chǔ)上聯(lián)合6個(gè)月以上內(nèi)分泌治療,并根據(jù)術(shù)后PSA水平變化,決定是否聯(lián)合外放射治療。117例患者(88.6%)接受最大限度雄激素阻斷內(nèi)分泌治療,包括黃體生成素釋放激素類似物及雄激素受體拮抗劑。25例患者 (18.9%)除接受內(nèi)分泌治療外,還接受外放射治療,照射劑量為45~50 Gy/5周,每日照射劑量為1.8~2.0 Gy,每周5次。
隨訪方法
術(shù)后患者前3個(gè)月每月復(fù)查PSA,之后每3個(gè)月復(fù)查1次,2年后每6個(gè)月復(fù)查1次,5年后每12個(gè)月復(fù)查1次,以觀察記錄PSA變化規(guī)律,反映治療療效。對(duì)隨訪過(guò)程中出現(xiàn)PSA升高、骨痛等癥狀的患者復(fù)查胸腹盆CT及全身骨掃描,明確是否出現(xiàn)局部或遠(yuǎn)處轉(zhuǎn)移。
生化復(fù)發(fā)標(biāo)準(zhǔn)參照 PSA在最低值基礎(chǔ)上升高0.40 μg/L或以上[13]?;颊叱霈F(xiàn)腫瘤遠(yuǎn)處轉(zhuǎn)移或進(jìn)展為去勢(shì)抵抗性前列腺癌 (castration-resistant prostate cancer,CRPC)即認(rèn)為治療失敗。隨訪終點(diǎn)包括生化復(fù)發(fā)、遠(yuǎn)處轉(zhuǎn)移或CRPC、死亡,計(jì)算患者無(wú)生化復(fù)發(fā)生存率 (biochemical progression-free survival,bPFS)、疾病特異性生存率 (cause-specific survival,CSS)和總體生存率 (overall survival,OS)。
統(tǒng)計(jì)學(xué)處理
采用SPSS 19.0軟件處理數(shù)據(jù)。正態(tài)分布資料結(jié)果用均數(shù)±標(biāo)準(zhǔn)差表示。分別使用Kaplan-Meier法及Log-rank檢驗(yàn)繪制整體樣本及各亞組的生存曲線并進(jìn)行比較;使用卡方檢驗(yàn)比較高危組與低、中危組的bPFS、CSS及OS差異;使用Cox回歸分析評(píng)估影響bPFS、CSS和OS的風(fēng)險(xiǎn)因素。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
一般臨床資料
132例患者平均年齡為 (73.0±6.2)歲 (48~84歲),治療前PSA為 (20.23±13.55)μg/L(0.36~56.40 μg/L),前列腺體積為 (31.3±12.6)ml(12.5~71.7 ml),穿刺病理Gleason評(píng)分為 (7.02±1.20)分(4~9分),穿刺針數(shù)陽(yáng)性比例為 (57±29.5)% (9.1% ~100%),D90為 (135.4±14.4)Gy(88~162 Gy)?;颊呒膊?yán)重程度、合并癥及治療等臨床資料見表1。
表1 132例前列腺癌患者臨床資料
隨訪情況
132例患者平均隨訪時(shí)間 (79.3±23.1)個(gè)月 (9~114個(gè)月)。至隨訪結(jié)束,20例患者死亡,其中12例死于前列腺癌,另8例分別因直腸癌、胃癌、膽管細(xì)胞癌、胰腺癌、肺癌、心肌梗死、肺部感染及慢性腎功能衰竭死亡。
預(yù)后及生存分析結(jié)果
132例患者bPFS為83.3%,CSS為91.7%,OS為84.8%(圖1)。局部高?;颊吆途植康汀⒅形;颊唛g bPFS及 OS相比較差異無(wú)統(tǒng)計(jì)學(xué)意義 (P= 0.433,0.098),而局部低、中?;颊逤SS明顯高于局部高?;颊?(P=0.037) (表2)。按Gleason評(píng)分分組,Gleason≤6、7及≥8三組的 bPFS分別為82.6%、75.6%、92.7% (P=0.084);按臨床分期分組,T1~T2a、T2b及T2c~T3三組的bPFS分別為89.3%、82.6%、81.5% (P=0.537);按術(shù)前PSA水平分組,PSA<10 μg/L、10~19.9 μg/L及≥20 μg/L三組的bPFS分別為85.7%、81.8%、83.7% (P=0.850)(圖2)。
預(yù)后及生存影響因素
患者前列腺穿刺陽(yáng)性比例 (P=0.001)、T分期(P=0.010)、近距離治療是否聯(lián)合內(nèi)分泌治療 (P= 0.029)及內(nèi)分泌治療的時(shí)間 (P=0.009)影響患者bPFS。而患者 CSS僅與前列腺穿刺陽(yáng)性比例 (P= 0.021)相關(guān)。患者OS與手術(shù)時(shí)年齡 (P=0.032)、前列腺穿刺陽(yáng)性比例 (P=0.013)、是否聯(lián)合內(nèi)分泌治療 (P=0.003)及內(nèi)分泌治療的時(shí)間 (P=0.043)有顯著相關(guān)性 (表3)。
2004年,Stock等[14]首次報(bào)道對(duì)于局部高危前列腺癌,近距離治療聯(lián)合外放射治療及內(nèi)分泌治療在控制PSA水平、提高bPFS方面效果良好。此后,越來(lái)越多的研究顯示,前列腺癌近距離治療聯(lián)合外放射治療,或聯(lián)合內(nèi)分泌治療,10~15年的 bPFS可達(dá)61% ~90%[15-21]。與既往高危前列腺癌采用單純前列腺外放射治療或前列腺癌根治性切除的研究相比,在控制PSA水平及延長(zhǎng)無(wú)生化復(fù)發(fā)生存上更顯優(yōu)勢(shì)[22-29]。Bittner等[30]統(tǒng)計(jì)131例前列腺癌近距離治療聯(lián)合外放射治療或內(nèi)分泌治療患者資料,隨訪9年的bPFS、CSS及OS分別為91.0%、86.5%、87.3%;隨訪12年的bPFS、CSS及OS分別為87.3%、70.5%、60.5%。
圖1 132例前列腺癌患者的無(wú)生化復(fù)發(fā)生存率 (A)、疾病特異性生存率 (B)和總體生存率 (C) CRPC:去勢(shì)抵抗性前列腺癌
圖2 按Gleason評(píng)分 (A)、TNM分期 (B)及手術(shù)前PSA水平 (C)分組患者的無(wú)生化復(fù)發(fā)生存率PSA:同表1
表2 局部低、中危組與局部高危前列腺癌患者預(yù)后及生存比較
表3 前列腺癌預(yù)后及生存相關(guān)因素分析P值
但各研究中高危患者比例的差異及前列腺癌惡性程度的不同,也可能導(dǎo)致治療結(jié)果有較大差別。在RTOG 94-13研究中,患者平均術(shù)前PSA水平為22 μg/L,Gleason評(píng)分≥7分者比例及TNM分期為T2c~T3者比例均為70%[31-32],說(shuō)明該研究患者腫瘤惡性程度普遍較高。而大部分局部高危前列腺癌近距離治療聯(lián)合外放射治療或內(nèi)分泌治療的研究中,患者腫瘤惡性程度偏低,這也可能導(dǎo)致此類研究治療效果優(yōu)于既往單純外放射治療或根治切除治療。
本研究132例患者,以ABS推薦[12]為原則,對(duì)低危前列腺癌患者行單純近距離治療,對(duì)中、高危前列腺癌患者行近距離治療聯(lián)合內(nèi)分泌治療和外放射治療。具體治療方案的選擇綜合考慮了多方面因素,包括患者對(duì)內(nèi)分泌治療的耐受性及不良反應(yīng),對(duì)外放射治療后下尿路癥狀的耐受程度,以及患者的經(jīng)濟(jì)狀況。最終132例患者bPFS為83.3%,CSS為91.7%,OS為84.8%。治療效果也優(yōu)于單純外放射治療或前列腺癌根治性切除術(shù)[22-29]。本研究患者平均術(shù)前PSA水平為20.23 μg/L,T2c~T3患者比例為61.4%,均低于RTOG 94-13研究;而Gleason評(píng)分≥7分者比例為68.9%,與RTOG 94-13研究持平。說(shuō)明本研究患者的腫瘤惡性程度也較RTOG 94-13研究低,可能是導(dǎo)致治療結(jié)果較好的原因之一。
本研究顯示高危組患者與低、中危組患者在bPFS上差異無(wú)統(tǒng)計(jì)學(xué)意義。而高危組前列腺癌患者在出現(xiàn)生化復(fù)發(fā)以后,進(jìn)展為CRPC或出現(xiàn)遠(yuǎn)處轉(zhuǎn)移的可能性較低、中危組患者大。但兩組的OS亦無(wú)明顯差別。這說(shuō)明局部高危前列腺癌患者選擇近距離治療聯(lián)合外放射治療或聯(lián)合內(nèi)分泌治療,可取得良好的效果。而對(duì)患者按Gleason評(píng)分、TNM分期和術(shù)前PSA水平分別分組,各組間的bPFS差異均無(wú)統(tǒng)計(jì)學(xué)意義。該結(jié)果進(jìn)一步說(shuō)明,存在前列腺癌高危因素任意一項(xiàng),選擇近距離治療聯(lián)合外放射治療或內(nèi)分泌治療,療效與低、中危患者相當(dāng)。
綜上,近距離治療聯(lián)合外放射治療及內(nèi)分泌治療,對(duì)于局部高危前列腺癌患者,可有效控制PSA水平及延緩生化復(fù)發(fā)。其bPFS、CSS與OS與單純外放射治療及前列腺癌根治性切除相比,效果相當(dāng)甚至更佳。并且在bPFS與OS方面,療效與低、中危前列腺癌患者無(wú)明顯差別。
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Effectiveness of Brachytherapy Combined with External Beam Radiation Therapy and Hormonal Therapy in Treating Localized High-risk Prostate Cancer
CHEN Jian,YAN Wei-gang,LI Han-zhong,JI Zhi-gang,ZHOU Yi,ZHOU Zhi-en,MAI Zhi-peng
Department of Urology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100730,China
YAN Wei-gang Tel:010-69152510,E-mail:ywgemailbox@sina.com
Objective To evaluate the effectiveness of brachytherapy combined with external beam radiation therapy and hormonal therapy in treating localized high-risk prostate cancer patients.Methods We retrospectively analyzed 132 prostate cancer patients treated with brachytherapy from December 2003 to December 2007 in Department of Urology,Peking Union Medical College Hospital,including 97 localized high-risk patients,and 35 localized low-to intermediate-risk patients.Postoperative prostate specific antigen(PSA)level was monitored regularly in follow-up visits.Biochemical relapse,progression to castration-resistant prostate cancer(CRPC)or metastasis,and deaths were documented.Biochemical progression-free survival(bPFS),causespecific survival(CSS),and overall survival(OS)of the patients were evaluated.Results The bPFS,CSS,and OS of the 132 patients were 83.3%,91.7%,and 84.8%,respectively;those indexes of the 97 localized high-risk patients were 81.4%,88.7%,and 81.4%,respectively;and those of the 35 localized low-to inter-mediate-risk patients were 88.6%,100%,and 94.3%,respectively.No significant difference was observed in bPFS and OS between high-risk and low-to intermediate-risk patients(P=0.433,0.098),while CSS was significant higher in low-to intermediate-risk patients than in high-risk patients(P=0.037).After patients were grouped based on Gleason score,tumor-node-metastasis(TNM)clinical stage,or preoperative PSA levels,differences in bPFS among groups were not statistically significant(P=0.084,0.537,0.850).Conclusion Brachytherapy combined with external beam radiation therapy and hormonal therapy may effectively control PSA level and delay biochemical relapse in localized high-risk prostate cancer.
localized high-risk prostate cancer;brachytherapy;biochemical progression-free survival
嚴(yán)維剛 電話:010-69152510,E-mail:ywgemailbox@sina.com
R737.25
A
1674-9081(2016)02-0104-06
10.3969/j.issn.1674-9081.2016.02.005
2014-04-30)