羅 游 付生軍 王志平 楊 立

蘭州大學(xué)第二醫(yī)院泌尿外科，蘭州大學(xué)第二醫(yī)院泌尿外科研究所，

甘肅省泌尿系疾病臨床醫(yī)學(xué)中心，甘肅省泌尿系疾病重點(diǎn)實(shí)驗(yàn)室（蘭州 730000）

臨床局限性前列腺癌根治性切除與觀察等待預(yù)后比較的Meta分析

羅 游 付生軍 王志平 楊 立*

蘭州大學(xué)第二醫(yī)院泌尿外科，蘭州大學(xué)第二醫(yī)院泌尿外科研究所，

甘肅省泌尿系疾病臨床醫(yī)學(xué)中心，甘肅省泌尿系疾病重點(diǎn)實(shí)驗(yàn)室（蘭州 730000）

目的比較臨床局限性前列腺癌行根治性切除（radical prostatectomy, RP）和觀察等待（watchful waiting, WW）對(duì)患者生存的影響。方法通過計(jì)算機(jī)檢索Medline、Cochrane Library、ISI web of knowledge、SinoMed文獻(xiàn)檢索平臺(tái)，搜集國內(nèi)外2014年7月前發(fā)表的關(guān)于早期前列腺癌根治性切除與主動(dòng)監(jiān)測的預(yù)后的隨機(jī)、半隨機(jī)對(duì)照試驗(yàn)或觀察性研究，預(yù)后評(píng)價(jià)指標(biāo)包括總體死亡、前列腺癌特異死亡；由2位研究者根據(jù)納入與排除標(biāo)準(zhǔn)獨(dú)立進(jìn)行文獻(xiàn)篩選、資料提取和質(zhì)量評(píng)價(jià)后，采用RevMan5.2進(jìn)行統(tǒng)計(jì)分析。結(jié)果納入3個(gè)隨機(jī)對(duì)照試驗(yàn)和10個(gè)臨床隊(duì)列研究，其中RCT共1 537例、隊(duì)列研究共186 590例患者；Meta分析結(jié)果顯示兩種治療方法（RP/WW）的總體死亡（ACM）風(fēng)險(xiǎn)為HR=0.59 [95%CI（0.51，0.69），P＜0.00001]，前列腺癌特異死亡（CSM）風(fēng)險(xiǎn)HR=0.43 [95%CI（0.32，0.58），P＜0.00001]，且不論RCT組還是隊(duì)列研究組，結(jié)果均一致傾向RP。結(jié)論 早期前列腺癌根治性切除可減少總體死亡及前列腺癌特異死亡風(fēng)險(xiǎn)，對(duì)于早期局限性前列腺癌選擇觀察等待應(yīng)當(dāng)十分慎重。

前列腺腫瘤/外科學(xué); 存活率分析; 綜述; Meta分析

前列腺癌是男性泌尿系統(tǒng)常見的惡性腫瘤，其發(fā)病率逐年上升，2013年美國統(tǒng)計(jì)新發(fā)病例238 590例，位居男性腫瘤第一位，也是第二大腫瘤死亡原因[1]。隨著前列腺特異性抗原（PSA）檢測的普及，前列腺癌的發(fā)病率呈顯著增加趨勢，同時(shí)，也帶來了前列腺癌根治手術(shù)的增加，對(duì)于是否因此而造成早期前列腺癌的過度診斷與治療，以及PSA篩查的必要性均存在著爭議[2,3]。前列腺癌的治療手段主要以治愈性目的為主，包括根治性前列腺切除（radical prostatectomy, RP）、放療，伴或不伴雄激素去勢治療，治愈性治療方案常伴隨著發(fā)生率較高的陽痿、尿路功能障礙、生活質(zhì)量的顯著降低以及高昂的治療費(fèi)用等[4-9]。觀察等待（watchful waiting, WW）的定義是指在病程監(jiān)測過程中，當(dāng)患者癥狀或PSA水平出現(xiàn)進(jìn)展時(shí)予以姑息性治療[10]，其內(nèi)容與觀察性治療基本一致或可認(rèn)為是其另一種表達(dá)方式，觀察等待是保守治療策略的一種。前列腺癌“緩慢、惰性”的自然史表現(xiàn)可能并未使治愈性手段獲得更顯著療效優(yōu)勢，也使得觀察等待成為可能[11,12]。雖然觀察等待在歐洲泌尿科學(xué)會(huì)（EAU）及美國國立綜合癌癥網(wǎng)絡(luò)（NCCN）均已被寫進(jìn)前列腺癌診療指南[10,13]，但對(duì)于根治性切除與觀察等待兩者的預(yù)后效果在不同文獻(xiàn)報(bào)道存在差異[14,15]。本文擬對(duì)早期局限性前列腺癌的不同干預(yù)效果進(jìn)行系統(tǒng)評(píng)價(jià)及分析，為臨床早期前列腺癌的治療決策提供參考。

資料與方法

一、文獻(xiàn)納入與排除標(biāo)準(zhǔn)

（一）納入標(biāo)準(zhǔn)

（1）研究類型為隨機(jī)或非隨機(jī)對(duì)照研究；（2）經(jīng)病理或細(xì)胞學(xué)確診為早期或局限性的前列腺癌患者（T1～2Nx～0Mx～0），不限年齡、種族；（3）文章內(nèi)容包含有RP和WW兩者統(tǒng)計(jì)數(shù)據(jù)的臨床研究；（4）結(jié)局內(nèi)容包括總體和（或）疾病特異死亡預(yù)后指標(biāo)；（5）語種限定為中文及英文。

（二）排除標(biāo)準(zhǔn)

（1）標(biāo)題摘要雖描述為臨床局限性前列腺癌但實(shí)際包含了大量T3及以上分期的高風(fēng)險(xiǎn)前列腺癌的研究；（2）最長隨訪時(shí)間低于5年的研究；（3）重復(fù)發(fā)表的文獻(xiàn)。

二、評(píng)價(jià)指標(biāo)

評(píng)價(jià)兩種不同干預(yù)措施效果的結(jié)局指標(biāo)有：總體死亡風(fēng)險(xiǎn)和前列腺癌特異死亡風(fēng)險(xiǎn)。

三、檢索策略

計(jì)算機(jī)檢索Medline、Cochrane Library、ISI we of knowledge、SinoMed平臺(tái)2014年7月前發(fā)表的關(guān)于早期RP與WW對(duì)比預(yù)后的相關(guān)文獻(xiàn)，同時(shí)查詢納入文獻(xiàn)的參考文獻(xiàn)。英文檢索式：radical prostatectom AND（observational therapy OR watchful waiting O expectant management OR deferred treatment OR delaye therapy OR conservative management）AND（earl prostate cancer OR localized prostate cancer OR low ris prostate cancer）AND（mortality OR survival），限定語種為英語。 中文檢索式：（早期前列腺癌 OR 局限性前列腺癌 OR 低危前列腺癌 OR 低風(fēng)險(xiǎn)前列腺癌）AND（根治 OR 手術(shù)）AND （觀察等待 OR 觀察等待 OR 延緩治療 OR 保守治療 OR 監(jiān)測）。

四、文獻(xiàn)的篩選、數(shù)據(jù)提取和質(zhì)量評(píng)價(jià)

由兩位研究者根據(jù)納入與排除標(biāo)準(zhǔn)獨(dú)立進(jìn)行文獻(xiàn)篩選、資料提取與質(zhì)量評(píng)價(jià)，并進(jìn)行交叉核對(duì)，如遇分歧則通過討論或征求第三方的意見解決。數(shù)據(jù)的提取盡量以文獻(xiàn)原始數(shù)據(jù)為準(zhǔn)，當(dāng)資料不全或未詳細(xì)描述時(shí)采用以下兩種方法獲取數(shù)據(jù)：（1）郵件聯(lián)系作者獲得原始數(shù)據(jù)；（2）對(duì)于文獻(xiàn)未明確給出相關(guān)數(shù)據(jù)的可采用Tierney等[16]提出的數(shù)據(jù)提取方法和EXCEL表格計(jì)算HR和95%CI值；并參考AHR的一篇循證綜述提供的結(jié)果[17]。質(zhì)量評(píng)價(jià)RCT采用Cochrane 系統(tǒng)評(píng)價(jià)員手冊(cè)5.1.0[18]中隨機(jī)試驗(yàn)的偏倚風(fēng)險(xiǎn)評(píng)估工具，觀察性研究采用NOS（Newcastle Ottawa Scale）量表對(duì)納入研究的質(zhì)量進(jìn)行評(píng)價(jià)，5星以上考慮有較高質(zhì)量。

五、統(tǒng)計(jì)分析

采用RevMan 5.2軟件進(jìn)行meta分析。本文研究預(yù)后問題均使用計(jì)數(shù)資料，采用風(fēng)險(xiǎn)比（HR）作為效應(yīng)量。以各效應(yīng)量及其95% CI表示結(jié)果。首先采用x檢驗(yàn)對(duì)納入研究結(jié)果進(jìn)行異質(zhì)性檢驗(yàn)。若P≥0.1且I≤50%，提示各研究結(jié)果間無統(tǒng)計(jì)學(xué)異質(zhì)性，采用固定效應(yīng)模型進(jìn)行Meta分析；若P＜0.1但I(xiàn)2≤50%，提示各研究結(jié)果間存在異質(zhì)性，但在可接受范圍內(nèi)，采用隨機(jī)效應(yīng)模型行Meta分析；若P＜0.1或P≥0.1且I2＞50%，認(rèn)為各研究結(jié)果間異質(zhì)性較大，對(duì)其異質(zhì)性來源進(jìn)行分析，并對(duì)可能導(dǎo)致異質(zhì)性的因素進(jìn)行亞組分析，若無明顯臨床異質(zhì)性，采用隨機(jī)效應(yīng)模型進(jìn)行Meta分析。Meta分析的檢驗(yàn)水準(zhǔn)設(shè)為α=0.05，Meta分析結(jié)果采用森林圖呈現(xiàn)。

結(jié) 果

一、文獻(xiàn)檢索結(jié)果

通過相關(guān)檢索式初檢出715篇相關(guān)文獻(xiàn)，逐層篩選后最終納入3個(gè)隨機(jī)對(duì)照試驗(yàn)（RCT）和10個(gè)隊(duì)列研究涉及共18篇文獻(xiàn)[14,15,19-34]，包括188 127例患者，根治性前列腺切除105 213例，觀察等待82 914例。18篇均為英文文獻(xiàn)，無中文文獻(xiàn)。篩選流程及結(jié)果如圖1，納入文獻(xiàn)基本特征如表1。

二、納入研究的質(zhì)量評(píng)價(jià)

如表1顯示RCT中美國退伍軍人管理局泌尿外科研究合作組（VACURG）[23,24]試驗(yàn)偏倚風(fēng)險(xiǎn)較高，而前列腺癌干預(yù)與對(duì)比研究（PIVOT）[14]和斯堪地那維亞前列腺癌研究4組（SPCG-4）[15,19-22]的偏倚風(fēng)險(xiǎn)分別為中度、低度；隊(duì)列研究質(zhì)量評(píng)價(jià)均在可接受范圍。

表1 納入研究的基本特征

圖1 文獻(xiàn)篩選流程及結(jié)果

三、Meta分析結(jié)果

（一）總體死亡

3個(gè)RCT和8個(gè)隊(duì)列研究的合并效應(yīng)及11個(gè)研究的總體效應(yīng)均顯示RP對(duì)比WW顯著減少總體死亡（ACM）風(fēng)險(xiǎn)HR=0.59 [95%CI（0.51，0.69），＜0.00001]，見圖2。

（二）腫瘤特異死亡

2個(gè)RCT和7個(gè)隊(duì)列研究的合成效應(yīng)以及9個(gè)研究的總體效應(yīng)均顯示RP組前列腺癌特異死亡（CSM）要顯著低于WW組 HR=0.43 [95%C（0.32，0.58），P＜0.00001]，見圖3。

（三）敏感性分析

在Meta分析時(shí)發(fā)現(xiàn)，Iversen 1995[24]因年代太久、隨訪質(zhì)量低而被敏感性剔除后，所有結(jié)果仍然顯示不論RCT組還是非隨機(jī)對(duì)照試驗(yàn)（NRCT）組、ACM還是CSM均顯著支持RP（結(jié)果未展示）。

（四）發(fā)表偏倚

圖4和圖5顯示合并效應(yīng)中線兩側(cè)研究數(shù)量接近，無明顯發(fā)表偏倚見。；在敏感性分析時(shí)的同樣未見顯著發(fā)表偏倚（漏斗圖未給出）。

圖2 總體死亡--研究類型分組

圖3 前列腺癌特異死亡--研究類型分組

討 論

對(duì)于早期局限性前列腺癌的保守治療策略分為兩類即“觀察等待”和“主動(dòng)監(jiān)測”，兩者的最大區(qū)別在于對(duì)疾病進(jìn)展的處理策略，主動(dòng)監(jiān)測傾向于治愈性治療方案如根治、放療，而觀察等待在疾病進(jìn)展時(shí)往往予以姑息性處理如TURP、姑息性去勢治療；其次在隨訪中主動(dòng)監(jiān)測可能更多涉及穿刺活檢。NCCN指南2014最新版指出主動(dòng)監(jiān)測（AS）適用于極低、低風(fēng)險(xiǎn)并且生存期望≥10年的早期前列腺癌患者，推薦監(jiān)測頻率PSA不低于6個(gè)月，直腸指檢及穿刺活檢不低于12個(gè)月，除非在有臨床提示的情況下；而觀察等待無特定的適應(yīng)指證，一般在T1-2期且壽命期望＜10年的可以考慮，也適用于各種治療反應(yīng)不佳的患者[10]。

圖4 總體死亡漏斗圖

勃起功能障礙（ED）和尿路功能障礙是根治性手術(shù)的兩大并發(fā)癥，對(duì)于相對(duì)年輕人群及性生活需求顯著的患者尤為重要。Bill-Axelson等[19]的研究報(bào)道手術(shù)后1年ED率58.1%，尿瘺率32.2%；對(duì)于ED目前提倡神經(jīng)保留手術(shù)，保留神經(jīng)有利于術(shù)后性功能的恢復(fù)[35]，但保留神經(jīng)手術(shù)帶了來手術(shù)切緣腫瘤陽性率增加的風(fēng)險(xiǎn)[36]，術(shù)后應(yīng)用磷酸二酯酶-5型抑制劑有助于改善勃起功能及其恢復(fù)[37-39]。生活質(zhì)量也是治療方案選擇的重要影響因素，研究表明手術(shù)后的生活質(zhì)量RP對(duì)比WW明顯變差[5,40,41]，表現(xiàn)在性行為的不滿意帶來的心理障礙、社交活動(dòng)的心理負(fù)擔(dān)、焦慮、抑郁等方面。醫(yī)療費(fèi)用也是值得考慮的另一個(gè)決定因素，保守治療對(duì)比根治手術(shù)能夠相對(duì)減少治療費(fèi)用[8]。

從本研究結(jié)果看來無論是總體死亡還是前列腺癌特異死亡，根治手術(shù)均優(yōu)于觀察等待。但其中兩個(gè)十分重要的RCT結(jié)果卻不盡相同，PIVOT實(shí)驗(yàn)結(jié)果顯示不論ACM還是CSM，RP與WW的預(yù)后無顯著差異，而SPCG-4在ACM和CSM上均顯著支持RP。對(duì)于這兩個(gè)研究結(jié)果的差異，有學(xué)者認(rèn)為該差異是因?yàn)镻IVOT是PSA時(shí)代的產(chǎn)物而SPCG-4研究在前PSA時(shí)代，從而PIVOT研究包含了更多的經(jīng)PSA篩選的T1c期患者。另一方面，PSA帶來的另一個(gè)影響是作為前列腺癌進(jìn)展的監(jiān)測指標(biāo)，或許能有益于患者的管理而提高生存，但這兩個(gè)研究的跟蹤隨訪中均有PSA監(jiān)測指標(biāo)。Vuong等[42]對(duì)這兩個(gè)研究比較分析后認(rèn)為期望壽命以及隨訪時(shí)間的不同是PIVOT難以證實(shí)RP受益的重要原因。而Xia等[43]的假設(shè)分析認(rèn)為PSA篩選時(shí)代的前置期和過度診斷是PIVOT顯示很低絕對(duì)受益的原因，因而不能作為RP無效的有力證據(jù)。作者對(duì)這兩個(gè)研究的隨機(jī)化服從情況比較分析可以看出PIVOT研究中不服從隨機(jī)到WW組（75/367）遠(yuǎn)高于SPCG-中的不服從率（30/348），P＜0.0001；同樣不服從隨機(jī)到RP組比例PIVOT（83/364）比SPCG-4（54/347）卻無顯著差異，P=0.098。這可能是PIVOT無法顯示出RP受益的重要原因。

圖5 前列腺癌特異死亡漏斗圖

本研究的局限性表現(xiàn)在納入研究中僅3個(gè)RCT，且質(zhì)量參差不齊，其余均為回顧性隊(duì)列研究，同時(shí)納入的隊(duì)列研究中部分存在觀察地區(qū)的交叉，這些可能造成不同程度的風(fēng)險(xiǎn)偏倚；另一方面，研究結(jié)果僅限于總體人群，因不同研究以不同分層方式報(bào)道亞組結(jié)果而無法進(jìn)行亞組合成分析（比如不同腫瘤風(fēng)險(xiǎn)、Gleason評(píng)分、PSA水平等），亞組分析可能能夠更加細(xì)致的探討觀察等待的適應(yīng)人群。

本Meta分析結(jié)果提示：RP對(duì)總體和前列腺癌特異死亡均有顯著優(yōu)勢，早期前列腺癌根治性切除可減少總體死亡及前列腺癌特異死亡風(fēng)險(xiǎn)，對(duì)于早期局限性前列腺癌選擇觀察等待應(yīng)當(dāng)十分慎重，治療方案的選擇需要結(jié)合患者其他因素綜合考慮。

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（2014-08-30收稿）

Radical prostatectomy versus watchful waiting for clinically localized prostate cancer: A Meta-Analysis

Luo You, Fu Shengjun, Wang Zhiping, Yang Li*Department of Urology, Lanzhou University Second Hospital; Institute of Urology, Lanzhou University Second Hospital; Institute of Gansu Nephro-Urological Clinical Center; Key laboratory of urological disease of Gansu province, Lanzhou
730000, China

Yang Li, E-mail: yuze250@163.com

ObjectiveTo compare the survival effect of clinically localized prostate cancer treated by radical prostatectomy (RP) and watchful waiting (WW) .MethodsRandomized controlled trials or observational studies were searched from database of Medline, Cochrane Library, ISI web of knowledge and SinoMed for the evaluation of prognosis of clinically localized prostate cancer treated by RP versus WW. Prognosis evaluation parameter included all-cause mortality and prostate cancer specif c mortality. The latest retrieval date was July 2014. The data extraction and the quality assessment of included studies were independently conducted by 2 reviewers. RevMan5.2 software was used to perform data synthesis.Results3 RCTs involving 1 537 patients (772 RP versus 765 WW) and 10 retrospective cohort studies involving 186 590 patients (104441 RP versus 82149 WW) were enrolled f nally. The results of meta-analysis showed that both the hazard of allcause mortality and prostate cancer specif c mortality in RP group were signif cantly lower than that of WW group, all-cause mortality risk was HR=0.59 [95%CI (0.51, 0.69),P<0.00001], and prostate cancer specif c mortality risk was HR=0.43 [95%CI (0.32, 0.58),P<0.00001]. All outcomes favored radical prostatectomy regardless of study type stratification.ConclusionRadical prostatectomy reduces the hazard of all-cause mortality and cancer specif c mortality of clinically localized prostate cancer, which may push more deliberations when physicians take watchful waiting in consideration.

prostatic neoplasms/surgery; survival analysis; review, systematic; Meta-analysis

10.3969/j.issn.1008-0848.2014.12.005

R 737.25

*通訊作者, E-mail: yuze250@163.com