袁傳威，陳友根，蘭曉鵬，盧國良，毛少為，于 江，夏慶華

(山東大學(xué)附屬省立醫(yī)院 泌尿微創(chuàng)中心，山東濟(jì)南 250021)

·爭鳴園地·

上尿路尿路上皮腫瘤患者術(shù)后應(yīng)早期預(yù)防性膀胱灌注

袁傳威，陳友根，蘭曉鵬，盧國良，毛少為，于 江，夏慶華

(山東大學(xué)附屬省立醫(yī)院 泌尿微創(chuàng)中心，山東濟(jì)南 250021)

根治性腎、輸尿管切除及膀胱袖狀切除術(shù)是上尿路尿路上皮腫瘤(UTUC)的標(biāo)準(zhǔn)術(shù)式?？赡苁且?yàn)榱黾?xì)胞種植和區(qū)域化癌變的緣故，約22%～47%的患者術(shù)后繼發(fā)膀胱腫瘤。為闡明預(yù)防性膀胱灌注化療在預(yù)防膀胱腫瘤復(fù)發(fā)中的作用，實(shí)施了多個(gè)前瞻性隨機(jī)臨床試驗(yàn)，發(fā)現(xiàn)術(shù)后THP或MMC膀胱灌注可顯著降低其復(fù)發(fā)率，術(shù)后早期應(yīng)用且安全可行。因此，我們建議UTUC術(shù)后應(yīng)預(yù)防性膀胱灌注，但最佳方案尚需研究。

膀胱復(fù)發(fā)；膀胱灌注；腎、輸尿管切除術(shù)；上尿路尿路上皮腫瘤

上尿路尿路上皮腫瘤(upper tract urothelial carcinoma, UTUC)是指起源于腎盂或輸尿管上皮的腫瘤，約占全部尿路上皮腫瘤的5%～10%[1-2]。相對(duì)膀胱腫瘤而言，上尿路上皮腫瘤發(fā)病年齡較大，多介于65～79歲。UTUC具有高度復(fù)發(fā)及進(jìn)展風(fēng)險(xiǎn)，但雙側(cè)上尿路發(fā)生腫瘤的幾率約為1.6%，這使得根治性腎輸尿管切除及膀胱袖狀切除術(shù)成為其標(biāo)準(zhǔn)術(shù)式。

然而，UTUC術(shù)后有22%～47%的患者會(huì)發(fā)生膀胱復(fù)發(fā)[3-5]，而在對(duì)側(cè)腎盂、輸尿管復(fù)發(fā)的比率約為2%～6%[6-8]。因此很自然推測膀胱腫瘤很可能是尿路上皮腫瘤多中心性或上尿路脫落瘤細(xì)胞種植引起的，而這也得到了分子標(biāo)記和DNA測序等多個(gè)試驗(yàn)的證實(shí)[9-10]。在膀胱腫瘤的術(shù)后預(yù)防性治療中，化療藥物膀胱灌注已應(yīng)用了超過40年，其延遲和預(yù)防膀胱腫瘤復(fù)發(fā)和進(jìn)展的效果已獲公認(rèn)[11]。因UTUC發(fā)病率較低，缺乏大樣本前瞻隨機(jī)對(duì)照臨床研究，目前術(shù)后化學(xué)藥物膀胱灌注方案多參照膀胱腫瘤，是否應(yīng)用以及具體方案尚無規(guī)范，本文將就此進(jìn)行探討。

1 UTUC術(shù)后的膀胱復(fù)發(fā)假說

UTUC的膀胱腫瘤復(fù)發(fā)多發(fā)生在術(shù)后2年內(nèi)，其中一個(gè)高峰時(shí)間約為術(shù)后6個(gè)月，這和膀胱腫瘤術(shù)后復(fù)發(fā)時(shí)間較為相似。到目前為止，解釋UTUC術(shù)后復(fù)發(fā)的假說包括腔內(nèi)種植[12]和區(qū)域化癌變[13]兩種。

UTUC起源于腎盞、腎盂及輸尿管上皮，腫瘤細(xì)胞容易脫落，特別是手術(shù)操作過程中，對(duì)腫瘤及周圍組織的牽拉、擠壓使瘤細(xì)胞更容易脫落，順尿流方向發(fā)生多器官種植性生長，膀胱黏膜的損傷使瘤細(xì)胞粘附、種植變得更加容易，而圍手術(shù)期患者免疫低下，也增加瘤細(xì)胞種植成功幾率。

圍繞腔內(nèi)種植和區(qū)域化癌變兩種假說，很多危險(xiǎn)因素被證明和復(fù)發(fā)相關(guān)，如分期、分級(jí)、腫瘤多發(fā)、位置以及手術(shù)方式、尿細(xì)胞學(xué)檢查陽性等[8,14-17]，其中腫瘤分期最為重要。如沒有完整切除整段輸尿管，輸尿管殘端發(fā)生移行細(xì)胞腫瘤的風(fēng)險(xiǎn)為12%～75%，并增加膀胱腫瘤復(fù)發(fā)及遠(yuǎn)處轉(zhuǎn)移的幾率[18]。早期曾有腹腔鏡手術(shù)增加術(shù)后膀胱腫瘤復(fù)發(fā)幾率的報(bào)道，擔(dān)憂較長的手術(shù)時(shí)間及氣腹高壓有利于腫瘤細(xì)胞的脫落并增加暴露時(shí)間，但這些研究多是剛開始使用腹腔鏡手術(shù)階段，隨著腹腔鏡技術(shù)的成熟以及樣本量的增加，只要完整切除輸尿管，兩種術(shù)式對(duì)膀胱腫瘤復(fù)發(fā)并無明顯差異[19-20]。

膀胱袖狀切除術(shù)中黏膜直接暴露，留置尿管也增加了黏膜損傷的幾率。相對(duì)于完整的尿路上皮，受損的黏膜更易于腫瘤細(xì)胞粘附并種植。從復(fù)發(fā)腫瘤位置看,ITO等[21]報(bào)道大部分腫瘤發(fā)生于患側(cè)輸尿管口附近膀胱壁(含三角區(qū))或膀胱頸，這也驗(yàn)證了腫瘤細(xì)胞更容易種植于受損的尿路上皮。

綜合以上分析，UTUC術(shù)后膀胱復(fù)發(fā)可以用腔內(nèi)種植和區(qū)域化癌變兩種假說解釋。在行根治性切除術(shù)后，如何有效降低術(shù)后腫瘤細(xì)胞脫落、種植成為預(yù)防復(fù)發(fā)的重點(diǎn)。

最近有一項(xiàng)包含有5組研究共計(jì)614例行根治術(shù)的UTUC患者的薈萃分析證實(shí)，術(shù)后給予膀胱灌注組膀胱腫瘤復(fù)發(fā)率(20.5%)明顯低于無灌注化療組(36.7%)[22]。近年來亦有前瞻性隨機(jī)對(duì)照試驗(yàn)表明，根治性腎輸尿管全切及膀胱袖狀切除術(shù)后早期應(yīng)用絲裂霉素C或吡柔比星行膀胱灌注，可明顯降低膀胱腫瘤復(fù)發(fā)的風(fēng)險(xiǎn)[21,23]。然而，WU等[24]的研究表明，UTUC術(shù)后預(yù)防性膀胱灌注抗腫瘤藥物或卡介苗(bacillus calmette-guérin，BCG)時(shí)，雖明顯降低膀胱腫瘤復(fù)發(fā)風(fēng)險(xiǎn)，但其效益卻僅局限于預(yù)防早期膀胱腫瘤復(fù)發(fā)，而不能起到長期預(yù)防的作用，且同時(shí)發(fā)現(xiàn)其與術(shù)后腫瘤特異性生存率亦無明顯統(tǒng)計(jì)學(xué)意義。

因此，盡管UTUC根治術(shù)后是否應(yīng)常規(guī)預(yù)防性膀胱灌注化療以降低膀胱腫瘤復(fù)發(fā)仍未達(dá)成共識(shí)，但預(yù)防性膀胱灌注化療可能是預(yù)防UTUC根治術(shù)后膀胱腫瘤復(fù)發(fā)的重要預(yù)防措施。

2 UTUC術(shù)后膀胱灌注化療藥物的選擇

絲裂霉素C(Mitomycin C)、表柔比星(Epirubicin)以及吡柔比星(THP)等是預(yù)防淺表性膀胱腫瘤患者術(shù)后腫瘤復(fù)發(fā)的常用藥物，也是目前常用于UTUC患者術(shù)后膀胱灌注化療的藥物。WU等[24]分別應(yīng)用10 mg絲裂霉素C溶于20 mL生理鹽水以及20 mg表柔比星溶于20 mL生理鹽水對(duì)UTUC術(shù)后患者行膀胱灌注，結(jié)果表明腫瘤復(fù)發(fā)率灌注絲裂霉素C組為25.9%，灌注表柔比星組為29.0%，無灌注治療的對(duì)照組為41.3%，灌注組與對(duì)照組相比明顯減低，但其差別無統(tǒng)計(jì)學(xué)意義(P=0.188)。ITO等[21]的前瞻性隨機(jī)對(duì)照Ⅱ期臨床研究表明，術(shù)后48 h內(nèi)以30 mg吡柔比星溶于30 mL生理鹽水行單次膀胱灌注，患者2年腫瘤復(fù)發(fā)率為16.9%，明顯低于無灌注治療對(duì)照組2年復(fù)發(fā)率(42.2%)(P=0.025)。O'BRIEN[23]等在英國進(jìn)行了一項(xiàng)多中心前瞻性隨機(jī)對(duì)照臨床試驗(yàn)，納入284名因UTUC行根治性腎輸尿管切除術(shù)的患者，術(shù)后拔除尿管時(shí)單劑應(yīng)用40 mg絲裂霉素C進(jìn)行膀胱灌注，隨訪1年(術(shù)后3、6、12個(gè)月時(shí)行膀胱鏡檢查)，發(fā)現(xiàn)膀胱灌注絲裂霉素C治療能將術(shù)后1年膀胱腫瘤復(fù)發(fā)絕對(duì)風(fēng)險(xiǎn)降低11%，相對(duì)風(fēng)險(xiǎn)降低40%，且沒有嚴(yán)重不良反應(yīng)，這是目前樣本量最大的隨機(jī)對(duì)照試驗(yàn)。

卡介苗雖然推薦用于高危非肌層浸潤性膀胱腫瘤的治療，但不能改變低危非肌層浸潤性膀胱腫瘤的病程，且副作用發(fā)生率較高。用于UTUC術(shù)后的報(bào)道只少量見于腎盂、輸尿管原位腫瘤的治療性灌注。術(shù)后膀胱有開放創(chuàng)面，即可灌注易引起嚴(yán)重的副作用，將BCG用于UTUC術(shù)后即刻膀胱灌注尚缺乏經(jīng)驗(yàn)。

3 UTUC術(shù)后膀胱灌注化療時(shí)機(jī)

為避免灌注的相關(guān)副作用，大部分化學(xué)藥物膀胱灌注時(shí)間均較晚。兩項(xiàng)獨(dú)立的隨機(jī)試驗(yàn)表明UTUC術(shù)后單次應(yīng)用MMC或THP進(jìn)行膀胱灌注均能降低膀胱尿路上皮腫瘤發(fā)生幾率，出于化學(xué)藥物滲漏等安全考慮，用藥時(shí)間為術(shù)后2 d到1周以后。O’BRIEN的Ⅲ期試驗(yàn)中，在拔除尿管時(shí)進(jìn)行膀胱灌注[23]，因絲裂霉素C灌注時(shí)間較晚(通常為術(shù)后1周或更長)，其機(jī)制可能是阻礙已經(jīng)種植的細(xì)胞形成新的腫瘤。和膀胱腫瘤術(shù)后單次灌注相比，療效相仿(相對(duì)風(fēng)險(xiǎn)降低約40%)；ITO等[21]報(bào)道隨機(jī)臨床Ⅱ期試驗(yàn)中，術(shù)后48 h內(nèi)單劑應(yīng)用30 mg吡柔比星，明顯減低術(shù)后1年和2年復(fù)發(fā)率的同時(shí)，并未引起明顯副作用。

但MORIARTY等[25]報(bào)道超過10年的應(yīng)用經(jīng)驗(yàn)也表明，術(shù)中即刻用絲裂霉素C進(jìn)行膀胱灌注安全可行，無明顯嚴(yán)重并發(fā)癥，雖然這個(gè)報(bào)道樣本量較小，但應(yīng)用時(shí)間較長，較為可信，當(dāng)然這需要多中心試驗(yàn)加以驗(yàn)證。

研究顯示術(shù)前尿細(xì)胞學(xué)檢查陽性的UTUC患者術(shù)后更易發(fā)生膀胱腫瘤[26-27]，因?yàn)榘螂尊つた赡艹掷m(xù)暴露于脫落的腫瘤細(xì)胞，但隨后的臨床發(fā)現(xiàn)對(duì)這類患者術(shù)后THP即刻膀胱灌注可顯著減低這一類患者的膀胱腫瘤復(fù)發(fā)率，表明腫瘤細(xì)胞種植更可能是發(fā)生在術(shù)后，盡早殺滅尚未粘附或種植的瘤細(xì)胞很可能進(jìn)一步降低其復(fù)發(fā)率。

對(duì)于化療藥物灌注時(shí)機(jī)的選擇，膀胱腫瘤術(shù)后是傾向于盡早使用，推薦術(shù)后6 h內(nèi)。參考膀胱腫瘤的研究，術(shù)后6 h內(nèi)灌注可降低其復(fù)發(fā)率，但超過24 h后則無明顯效果[28-29]，另一項(xiàng)隨機(jī)對(duì)照則表明TURBT術(shù)前應(yīng)用MMC膀胱灌注效果優(yōu)于術(shù)后應(yīng)用[30]。出于膀胱腫瘤復(fù)發(fā)機(jī)制的考慮，目前膀胱腫瘤術(shù)后普遍傾向于盡早應(yīng)用，以防止腫瘤細(xì)胞種植。借鑒膀胱腫瘤的經(jīng)驗(yàn)，目前傾向于UTUC術(shù)后盡早進(jìn)行膀胱灌注。

4 UTUC術(shù)后膀胱灌注化療的對(duì)象選擇

先前已有報(bào)道稱UTUC根治術(shù)后膀胱腫瘤復(fù)發(fā)風(fēng)險(xiǎn)受到包括患者本身、腫瘤及治療特性的影響[14,31]。AZéMAR等[32]發(fā)現(xiàn)既往膀胱腫瘤病史及多病灶的原發(fā)性腫瘤是最常見的與膀胱腫瘤復(fù)發(fā)的兩個(gè)相關(guān)因素。O’BRIEN等[23]認(rèn)為分化良好的UTUC患者術(shù)后膀胱腫瘤的復(fù)發(fā)較罕見(18例中有1例，6%)，故認(rèn)為除非原發(fā)腫瘤呈多灶性，否則不推薦給予病理分級(jí)為I級(jí)患者術(shù)后常規(guī)行膀胱灌注化療藥物。然而，本研究對(duì)象中未包括行根治術(shù)前有膀胱腫瘤病史患者，而臨床許多行根治術(shù)的UTUC患者術(shù)前有膀胱腫瘤病史，所以此研究無法指導(dǎo)這部分患者術(shù)后是否應(yīng)接受膀胱灌注。

為評(píng)估UTUC行根治性腎輸尿管切除術(shù)后膀胱腫瘤復(fù)發(fā)的有效預(yù)測因子，近期國外開展了一項(xiàng)薈萃分析[34]，總計(jì)18個(gè)回顧性研究共8 275例患者，其中2 402例(29%)被診斷為膀胱腫瘤復(fù)發(fā)的中位時(shí)間為22.2個(gè)月(范圍 6.7～56.5月)。男性、術(shù)前膀胱腫瘤病史以及術(shù)前慢性腎臟疾病病史被認(rèn)為是患者特異性預(yù)測因素；而術(shù)前尿液脫落細(xì)胞學(xué)檢查陽性、輸尿管下段腫瘤、原發(fā)腫瘤多灶性、病理證實(shí)為浸潤性腫瘤、腫瘤出現(xiàn)壞死等則被認(rèn)為是腫瘤特異性預(yù)測因素。腹腔鏡手術(shù)、輸尿管末端膀胱袖狀切除和手術(shù)切緣陽性等治療特異性因素也被認(rèn)為與腫瘤復(fù)發(fā)密切相關(guān)。國內(nèi)亦有一項(xiàng)包含有727名患者的研究，得出了相似的結(jié)果[35]。因此認(rèn)為，從患者本身、腫瘤及治療因素三方面對(duì)UTUC術(shù)后膀胱腫瘤復(fù)率進(jìn)行系統(tǒng)評(píng)估，可以指導(dǎo)優(yōu)化膀胱灌注化療方案及篩選適合膀胱灌注化療的對(duì)象。

綜上所述，UTUC行根治性腎、輸尿管全切術(shù)后，膀胱腫瘤復(fù)發(fā)率非常高，而化療藥物膀胱灌注可明顯降低其復(fù)發(fā)率。因此，UTUC行腎、輸尿管切除術(shù)后，進(jìn)行膀胱灌注是必要的。但具體灌注方案如藥物選擇以及灌注時(shí)間尚存爭議，需針對(duì)不同危險(xiǎn)因素設(shè)計(jì)樣本量更大的對(duì)照試驗(yàn)加以規(guī)范。

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(編輯 王 瑋)

Patients with upper tract urothelial carcinoma should receive early prophylactic intravesical chemotherapy after nephroureterectomy

YUAN Chuan-wei，CHEN You-gen，LAN Xiao-peng，LU Guo-liang，MAO Shao-wei，Yu Jiang，XIA Qing-hua

(Department of Minimally Invasive Urology, Provincial Hospital Affiliated to Shandong University, Jinan 250021)

The standard management of upper tract urothelial carcinoma (UTUC) was radical nephroureterectomy with bladder cuff excision, however, approximately 22%-47% of them develop subsequent bladder tumour recurrence, potentially because of the implantation of cancer cells and field cancerization. To elucidate the effect of prophylactic intravesical chemotherapy in preventting bladder recurrence, several prospective randomized phase II studies were conducted.A significant decrease in bladder recurrence after surgery was observed in the intravesical instillation by THP or MMC. Early prophylactic intravesical chemotherapy is also effective and safe for the prevention of bladder recurrence after radical nephroureterectomy. Therefore, we suggest that prophylactic intravesical chemotherapy should be performed in patients with UTUC after radical nephroureterectomy, but the optimal regimen should be explored in future.

bladder recurrence; intravesical chemotherapy;radical nephroureterectomy; upper tract urothelial carcinoma

2015-06-30

2015-07-18

山東省醫(yī)藥衛(wèi)生科技發(fā)展計(jì)劃(No.2014WS0351)

夏慶華, 主任醫(yī)師.E-mail: xqhgege@hotmail.com

袁傳威(1988-)，男(達(dá)斡爾族)，醫(yī)師，碩士.研究方向：泌尿系上尿路疾病.E-mail:yuan19361212@163.com

R737.4

A

10.3969/j.issn.1009-8291.2015.08.019