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初診伴有脊柱轉(zhuǎn)移的前列腺癌生存相關(guān)因素分析

2015-12-21 08:46單露玲韓秀鑫張超任志午梁守磊王國(guó)文
中國(guó)腫瘤臨床 2015年17期
關(guān)鍵詞:轉(zhuǎn)移性持續(xù)時(shí)間內(nèi)分泌

單露玲 韓秀鑫 張超 任志午 梁守磊 王國(guó)文

·臨床研究與應(yīng)用·

初診伴有脊柱轉(zhuǎn)移的前列腺癌生存相關(guān)因素分析

單露玲 韓秀鑫 張超 任志午 梁守磊 王國(guó)文

目的:探討初診時(shí)伴有脊柱轉(zhuǎn)移的前列腺癌患者與生存相關(guān)的因素。方法:收集2005年1月至2010年12月天津醫(yī)科大學(xué)腫瘤醫(yī)院接受內(nèi)分泌治療的前列腺癌脊柱轉(zhuǎn)移患者49例,針對(duì)患者的堿性磷酸酶(ALP)、治療前有無(wú)骨相關(guān)事件(SREs)、Gleason評(píng)分、治療后PSA最低值、激素敏感持續(xù)時(shí)間、有無(wú)化療行單因素分析,并對(duì)存在統(tǒng)計(jì)學(xué)意義者進(jìn)行多因素分析。結(jié)果:平均隨訪時(shí)間64.1個(gè)月,死亡41例,中位生存時(shí)間為27個(gè)月,1、3、5年生存率分別是81.6%、40.8%、20.4%。單因素分析結(jié)果顯示,有無(wú)聯(lián)合化療、ALP水平、治療前是否出現(xiàn)SRE、Gleason評(píng)分、治療后PSA最低值及激素敏感持續(xù)時(shí)間與總生存率(OS)有關(guān)(P<0.05)。Cox回歸模型多因素分析顯示,激素敏感持續(xù)時(shí)間≥19個(gè)月及聯(lián)合化療是較長(zhǎng)生存時(shí)間的獨(dú)立預(yù)后因素(P<0.05)。結(jié)論:激素敏感持續(xù)時(shí)間及進(jìn)展為去勢(shì)抵抗性前列腺癌(castration resistant prostate cancer,CRPC)后是否聯(lián)合化療是前列腺癌脊柱轉(zhuǎn)移患者的預(yù)后獨(dú)立因素。

前列腺癌 脊柱轉(zhuǎn)移 化療 內(nèi)分泌治療 預(yù)后因素

世界范圍內(nèi),前列腺癌是男性中第二大常見(jiàn)惡性腫瘤[1],且發(fā)病率呈上升趨勢(shì)。在西方國(guó)家,早期診斷未有遠(yuǎn)處轉(zhuǎn)移的前列腺癌患者,其5年生存率可達(dá)100%,若診斷時(shí)即出現(xiàn)遠(yuǎn)處轉(zhuǎn)移,5年生存率僅為33%[2]。在我國(guó)很多前列腺癌患者在就診時(shí)即為晚期,并伴有脊柱轉(zhuǎn)移,對(duì)這一患者群體缺乏統(tǒng)一規(guī)范的治療策略。

對(duì)于轉(zhuǎn)移性去勢(shì)抵抗性前列腺癌(metastatic castration resistant prostate cancer,mCRPC)患者生存相關(guān)的預(yù)后因素的分析顯示血清ALP水平、激素敏感持續(xù)時(shí)間、治療前PSA值、首次骨轉(zhuǎn)移出現(xiàn)時(shí)間、血紅蛋白等是mCRPC的獨(dú)立預(yù)后因素[3-4],但對(duì)于初診即伴有脊柱轉(zhuǎn)移的前列腺癌患者的預(yù)后因素分析報(bào)道較少。本研究回顧性分析初診時(shí)伴有脊柱轉(zhuǎn)移的前列腺癌患者的臨床資料,探討影響其生存時(shí)間的因素。

1 材料與方法

1.1 臨床資料

收集2005年1月至2010年12月天津醫(yī)科大學(xué)腫瘤醫(yī)院初診伴有脊柱轉(zhuǎn)移的前列腺癌患者49例,年齡54~81歲,平均為(70.27±7.13)歲,其中年齡<60歲患者為5例,60~70歲患者為17例,年齡>70歲患者為27例。13例在進(jìn)展為CRPC后給予多西他賽化療,22例以劇烈疼痛就診,20例行脊柱轉(zhuǎn)移病灶放療,2例行椎體穿刺活檢+椎體成形術(shù),本研究中未納入病理性骨折或截癱的患者。

確診時(shí)ALP為53~1 141 U/L,中位數(shù)為179 U/L,治療前即出現(xiàn)骨相關(guān)事件(SRE)的為17例,Gleason評(píng)分5~6分為14例,7分為8例,8~10分為27例,治療后PSA最低值為0.03~5 328 μg/L,激素敏感持續(xù)時(shí)間為0~49個(gè)月,中位數(shù)為19個(gè)月。

1.2 方法

1.2.1 納入標(biāo)準(zhǔn) 1)前列腺或轉(zhuǎn)移病灶病理結(jié)果確診;2)影像學(xué)或組織活檢確診脊柱轉(zhuǎn)移;3)經(jīng)治療后轉(zhuǎn)變?yōu)镃RPC。排除標(biāo)準(zhǔn):1)伴有骨外遠(yuǎn)處轉(zhuǎn)移;2)伴有全身其他影響生存的其他疾病,如心臟病、其他癌癥等。

1.2.2 治療 26例行雙側(cè)睪丸切除術(shù),23例給予亮丙瑞林或戈舍瑞林,同時(shí)均輔助應(yīng)用抗雄激素藥物,其中13例在病情進(jìn)展后給予多西他賽化療。

1.3 統(tǒng)計(jì)學(xué)方法

應(yīng)用SPSS 19.0統(tǒng)計(jì)軟件對(duì)隨訪結(jié)果進(jìn)行分析。采用Kaplan-Meier法行生存相關(guān)單因素分析,并行Log-rank檢驗(yàn),采用Cox模型行多因素分析。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 生存分析

平均隨訪時(shí)間64.1個(gè)月,至隨訪截止。死亡41例,中位生存時(shí)間為27個(gè)月,1、3、5年生存率分別是81.6%、40.8%、20.4%。

2.2 單因素生存分析

合并化療、確診時(shí)ALP值<179 U/L、治療前未出現(xiàn)SRE、Gleason評(píng)分<7分、PSA最低值<10 μg/L以及激素敏感持續(xù)時(shí)間≥19個(gè)月與較長(zhǎng)OS有關(guān)(P<0.05,表1)。

2.3 多因素生存分析

Cox回歸模型多因素生存分析結(jié)果顯示,疾病進(jìn)展后合并化療及激素敏感持續(xù)時(shí)間≥19個(gè)月是較長(zhǎng)生存時(shí)間的獨(dú)立預(yù)后因素(P<0.05,表1,圖1,2)。

表1 變量的生存相關(guān)分析Table 1 Survival-related analysis of the variables

圖1 不同治療方式的生存曲線Table 1 Survival curves of various treatment methods

圖2 PSA敏感時(shí)間相關(guān)生存曲線Table 2 PSA sensitization time-related survival curves

3 討論

前列腺是骨轉(zhuǎn)移瘤的第二大原發(fā)病灶,是男性骨轉(zhuǎn)移瘤最常見(jiàn)的原發(fā)病,其中脊柱是骨轉(zhuǎn)移的高發(fā)部位。與脊柱外骨轉(zhuǎn)移相比,前列腺癌脊柱轉(zhuǎn)移往往更早出現(xiàn)癥狀,且能夠造成劇烈疼痛、麻木、癱瘓等不良后果,同時(shí)由于前列腺癌對(duì)內(nèi)分泌治療敏感,生存期相對(duì)較長(zhǎng),為改善患者生活質(zhì)量,一部分患者需要外科干預(yù),而脊柱外骨轉(zhuǎn)移則多以前列腺癌綜合治療為主。在我國(guó),很大一部分前列腺癌患者以脊柱轉(zhuǎn)移癥狀起病,目前缺乏對(duì)這些患者的標(biāo)準(zhǔn)治療,研究影響這一患者群的預(yù)后因素可以有效指導(dǎo)臨床治療。

脊柱轉(zhuǎn)移瘤包括成骨型、溶骨型與混合型。溶骨型X線平片表現(xiàn)為椎體骨質(zhì)破壞、變扁,但椎間隙多保持正常、椎弓根多受侵蝕;CT表現(xiàn)為低密度缺損區(qū),常伴有軟組織腫塊。成骨型X線片表現(xiàn)為斑片狀或結(jié)節(jié)樣高密度影、椎體不壓縮變扁,CT表現(xiàn)為松質(zhì)骨內(nèi)的高密度灶,一般無(wú)軟組織腫塊。MRI表現(xiàn)以T1加權(quán)像最為明顯,表現(xiàn)為與正常骨髓脂肪高信號(hào)高度對(duì)比的低信號(hào)?;旌闲图嬗谐晒切团c溶骨型的表現(xiàn)。

前列腺癌脊柱轉(zhuǎn)移以成骨型病變?yōu)橹?,臨床上晚期前列腺癌脊柱轉(zhuǎn)移以混合型病變?yōu)橹?。而其他?lái)源的脊柱轉(zhuǎn)移,如肺癌、腎癌、肝癌等多以溶骨型病變?yōu)橹?,且相?duì)于前列腺癌脊柱轉(zhuǎn)移,局灶病變進(jìn)展較快。內(nèi)分泌治療是激素依賴(lài)型前列腺癌骨轉(zhuǎn)移患者主要的治療手段,內(nèi)分泌治療引起的骨丟失會(huì)促進(jìn)轉(zhuǎn)移性前列腺癌細(xì)胞在骨內(nèi)生長(zhǎng)[5],這會(huì)加速引起SRE的發(fā)生,增加死亡風(fēng)險(xiǎn)并降低生活質(zhì)量,因此需要對(duì)骨轉(zhuǎn)移病灶行針對(duì)性治療。作為重要的骨保護(hù)劑,唑來(lái)膦酸可降低SREs的發(fā)生率[6-7],地諾單抗被證實(shí)可延緩非轉(zhuǎn)移性去勢(shì)抵抗性前列腺癌(non-metastatic castration resistant prostate cancer, nm-CRPC)患者發(fā)生骨轉(zhuǎn)移[8]。對(duì)于出現(xiàn)頑固性疼痛、骨折及脊髓壓迫癥狀的患者可選擇局部放療或手術(shù),放療可緩解骨轉(zhuǎn)移引起的骨痛,手術(shù)可緩解疼痛、預(yù)防/固定骨折、提高生存質(zhì)量等[9]。20世紀(jì)80年代以前手術(shù)治療脊柱轉(zhuǎn)移瘤尚未得到認(rèn)可,放療是脊柱轉(zhuǎn)移的標(biāo)準(zhǔn)治療。Nguyen等[10]研究顯示傳統(tǒng)的放療可以在治療3個(gè)月后有效緩解疼痛,并對(duì)患者的心理變化有積極影響。最新研究顯示單純立體定向放療或聯(lián)合開(kāi)放手術(shù)可有效控制局灶病變,改善神經(jīng)功能[11]。本研究中20例患者進(jìn)行了轉(zhuǎn)移病灶放療,2例患者行姑息性手術(shù),但均與OS無(wú)關(guān)。臨床上部分伴有截癱的前列腺癌脊柱轉(zhuǎn)移患者經(jīng)手術(shù)治療后可恢復(fù)或改善神經(jīng)功能,同時(shí)可明顯緩解疼痛。

自2004年以來(lái)多西他賽聯(lián)合潑尼松已成為轉(zhuǎn)移性CRPC的標(biāo)準(zhǔn)一線治療方案[12],但臨床中轉(zhuǎn)移性前列腺癌的治療仍不規(guī)范。本研究顯示初診伴有脊柱轉(zhuǎn)移的前列腺癌患者經(jīng)綜合治療后中位生存期為27個(gè)月,內(nèi)分泌治療后約19個(gè)月進(jìn)展為去勢(shì)抵抗性前列腺癌,進(jìn)展為mCRPC后給予多西他賽化療可有效延長(zhǎng)患者生存期,對(duì)于多西他賽治療失敗的mCRPC患者,多項(xiàng)臨床試驗(yàn)進(jìn)行相關(guān)研究證實(shí)卡巴他賽可延長(zhǎng)多西他賽耐藥患者的總生存期(OS)及無(wú)進(jìn)展生存期(PFS),阿比特龍可延長(zhǎng)OS及增加PSA反應(yīng)率[13-14]。此外,轉(zhuǎn)移性前列腺癌經(jīng)一線內(nèi)分泌治療進(jìn)展后可選擇二線內(nèi)分泌治療,包括更換/暫??剐奂に厮幬铮褂么萍に氐?。Narimoto等[15]的研究指出CRPC患者治療時(shí),將抗雄激素藥物由比卡魯胺更換為氟他胺后,PSA反應(yīng)率達(dá)87.5%。本研究中單純內(nèi)分泌治療相對(duì)于內(nèi)分泌治療聯(lián)合化療死亡風(fēng)險(xiǎn)增加了3.9倍。

骨是前列腺癌最常見(jiàn)轉(zhuǎn)移部位,90%以上的CRPC患者會(huì)出現(xiàn)骨轉(zhuǎn)移[6,16],一部分患者在內(nèi)分泌治療之前即出現(xiàn)骨轉(zhuǎn)移。前列腺癌骨轉(zhuǎn)移引起成骨與破骨活性紊亂,造成血清ALP升高。本研究認(rèn)為Gleason評(píng)分、ALP水平、治療前有無(wú)合并SRE、經(jīng)內(nèi)分泌治療后PSA達(dá)到的最低值均與患者生存時(shí)間相關(guān),但僅是否聯(lián)合化療及激素敏感持續(xù)時(shí)間是與OS相關(guān)的獨(dú)立預(yù)后因素。Fizazi等[3]對(duì)1 901例mCRPC患者進(jìn)行分析,結(jié)果顯示ALP、骨特異性堿性磷酸酶(BSAP)、有無(wú)疼痛、既往SRE、首次骨轉(zhuǎn)移出現(xiàn)時(shí)間與生存時(shí)間相關(guān)。對(duì)于mCRPC患者化療后生存相關(guān)因素的多因素分析中,化療前ALP濃度、Hb濃度、激素敏感時(shí)間及化療周期是與生存相關(guān)的獨(dú)立預(yù)后因素[17]。有研究顯示內(nèi)分泌治療后PSA最低值是轉(zhuǎn)移性前列腺癌預(yù)后獨(dú)立因素[18]。

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(2015-05-07收稿)

(2015-07-13修回)

(編輯:楊紅欣)

Analysis of prognostic factors associated with survival in men with prostate cancer accompanied by spinal metastases at first diagnosis

Luling SHAN,Xiuxin HAN,Chao ZHANG,Zhiwu REN,Shoulei LIANG,Guowen WANG


Department of Bone and Soft Tissue Oncology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin 300060,China

Objective:Prostate cancer frequently metastasizes to the spine.In this study,we investigate the prognostic factors associated with survival in patients with prostate cancer accompanied by spinal metastases at their preliminary diagnosis.Methods:Clinical data of 49 patients who were diagnosed with spinal metastasis from prostate cancer between January 2005 and December 2010 were analyzed.Variables including alkaline phosphatase(ALP),previous skeletal-related event,Gleason score,prostate-specific antigen(PSA)nadir,and time to castration resistance were obtained.Moreover,the relationship between these variables and overall survival(OS)was analyzed.Survival analysis was performed by using Kaplan-Meier curves.Furthermore,the differences among the OS rates were assessed by using the log rank test.The variables were statistically significant in the univariate analysis(P<0.05)and were included in the multivariate model.Results:The average follow-up time was 64.1 months among the 49 patients.By the end of the follow-up,41 of these patients were dead;the mean survival was 27 months.The 1-,3-,and 5-year survival rate was 81.6%,40.8%, and 20.4%,respectively.Univariate analysis identified that 6 variables were statistically significant prognostic factors of OS:with or without chemotherapy,ALP,previous skeletal-related event,Gleason score,PSA nadir,and time to castration resistance.The multivariate analysis showed that the time to castration resistance of≥19 months and the addition of chemotherapy after disease progression are independent prognostic factors for a high OS.Conclusion:With or without chemotherapy and the time to castration resistance are the independent prognostic factors associated with survival in patients with prostate cancer accompanied by spinal metastases at first diagnosis.

prostate cancer,spinal metastasis,chemotherapy,endocrine therapy,prognosis

10.3969/j.issn.1000-8179.2015.17.515

天津醫(yī)科大學(xué)腫瘤醫(yī)院骨與軟組織腫瘤科,國(guó)家腫瘤臨床醫(yī)學(xué)研究中心,天津市腫瘤防治重點(diǎn)實(shí)驗(yàn)室(天津市300060)

王國(guó)文 wgwhrb@163.com

單露玲 專(zhuān)業(yè)方向?yàn)楣桥c軟組織腫瘤臨床治療與基礎(chǔ)研究。

E-mail:945490577@qq.com

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