袁傳威，陳友根，蘭曉鵬，盧國良，毛少為，于 江，夏慶華

(山東大學附屬省立醫(yī)院 泌尿微創(chuàng)中心，山東濟南 250021)

·爭鳴園地·

上尿路尿路上皮腫瘤患者術(shù)后應早期預防性膀胱灌注

袁傳威，陳友根，蘭曉鵬，盧國良，毛少為，于 江，夏慶華

(山東大學附屬省立醫(yī)院 泌尿微創(chuàng)中心，山東濟南 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)的標準術(shù)式?？赡苁且驗榱黾毎N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。為闡明預防性膀胱灌注化療在預防膀胱腫瘤復發(fā)中的作用，實施了多個前瞻性隨機臨床試驗，發(fā)現(xiàn)術(shù)后THP或MMC膀胱灌注可顯著降低其復發(fā)率，術(shù)后早期應用且安全可行。因此，我們建議UTUC術(shù)后應預防性膀胱灌注，但最佳方案尚需研究。

膀胱復發(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具有高度復發(fā)及進展風險，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)成為其標準術(shù)式。

然而，UTUC術(shù)后有22%～47%的患者會發(fā)生膀胱復發(fā)[3-5]，而在對側(cè)腎盂、輸尿管復發(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胞種植引起的，而這也得到了分子標記和DNA測序等多個試驗的證實[9-10]。在膀胱腫瘤的術(shù)后預防性治療中，化療藥物膀胱灌注已應用了超過40年，其延遲和預防膀胱腫瘤復發(fā)和進展的效果已獲公認[11]。因UTUC發(fā)病率較低，缺乏大樣本前瞻隨機對照臨床研究，目前術(shù)后化學藥物膀胱灌注方案多參照膀胱腫瘤，是否應用以及具體方案尚無規(guī)范，本文將就此進行探討。

1 UTUC術(shù)后的膀胱復發(fā)假說

UTUC的膀胱腫瘤復發(fā)多發(fā)生在術(shù)后2年內(nèi)，其中一個高峰時間約為術(shù)后6個月，這和膀胱腫瘤術(shù)后復發(fā)時間較為相似。到目前為止，解釋UTUC術(shù)后復發(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，腫瘤細胞容易脫落，特別是手術(shù)操作過程中，對腫瘤及周圍組織的牽拉、擠壓使瘤細胞更容易脫落，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，很多危險因素被證明和復發(fā)相關，如分期、分級、腫瘤多發(fā)、位置以及手術(shù)方式、尿細胞學檢查陽性等[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)生移行細胞腫瘤的風險為12%～75%，并增加膀胱腫瘤復發(fā)及遠處轉(zhuǎn)移的幾率[18]。早期曾有腹腔鏡手術(shù)增加術(shù)后膀胱腫瘤復發(fā)幾率的報道，擔憂較長的手術(shù)時間及氣腹高壓有利于腫瘤細胞的脫落并增加暴露時間，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)式對膀胱腫瘤復發(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。相對于完整的尿路上皮，受損的黏膜更易于腫瘤細胞粘附并種植。從復發(fā)腫瘤位置看,ITO等[21]報道大部分腫瘤發(fā)生于患側(cè)輸尿管口附近膀胱壁(含三角區(qū))或膀胱頸，這也驗證了腫瘤細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)后腫瘤細胞脫落、種植成為預防復發(fā)的重點。

最近有一項包含有5組研究共計614例行根治術(shù)的UTUC患者的薈萃分析證實，術(shù)后給予膀胱灌注組膀胱腫瘤復發(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對照試驗表明，根治性腎輸尿管全切及膀胱袖狀切除術(shù)后早期應用絲裂霉素C或吡柔比星行膀胱灌注，可明顯降低膀胱腫瘤復發(fā)的風險[21,23]。然而，WU等[24]的研究表明，UTUC術(shù)后預防性膀胱灌注抗腫瘤藥物或卡介苗(bacillus calmette-guérin，BCG)時，雖明顯降低膀胱腫瘤復發(fā)風險，但其效益卻僅局限于預防早期膀胱腫瘤復發(fā)，而不能起到長期預防的作用，且同時發(fā)現(xiàn)其與術(shù)后腫瘤特異性生存率亦無明顯統(tǒng)計學意義。

因此，盡管UTUC根治術(shù)后是否應常規(guī)預防性膀胱灌注化療以降低膀胱腫瘤復發(fā)仍未達成共識，但預防性膀胱灌注化療可能是預防UTUC根治術(shù)后膀胱腫瘤復發(fā)的重要預防措施。

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)等是預防淺表性膀胱腫瘤患者術(shù)后腫瘤復發(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UTUC術(shù)后患者行膀胱灌注，結(jié)果表明腫瘤復發(fā)率灌注絲裂霉素C組為25.9%，灌注表柔比星組為29.0%，無灌注治療的對照組為41.3%，灌注組與對照組相比明顯減低，但其差別無統(tǒng)計學意義(P=0.188)。ITO等[21]的前瞻性隨機對照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年腫瘤復發(fā)率為16.9%，明顯低于無灌注治療對照組2年復發(fā)率(42.2%)(P=0.025)。O'BRIEN[23]等在英國進行了一項多中心前瞻性隨機對照臨床試驗，納入284名因UTUC行根治性腎輸尿管切除術(shù)的患者，術(shù)后拔除尿管時單劑應用40 mg絲裂霉素C進行膀胱灌注，隨訪1年(術(shù)后3、6、12個月時行膀胱鏡檢查)，發(fā)現(xiàn)膀胱灌注絲裂霉素C治療能將術(shù)后1年膀胱腫瘤復發(fā)絕對風險降低11%，相對風險降低40%，且沒有嚴重不良反應，這是目前樣本量最大的隨機對照試驗。

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。

3 UTUC術(shù)后膀胱灌注化療時機

為避免灌注的相關副作用，大部分化學藥物膀胱灌注時間均較晚。兩項獨立的隨機試驗表明UTUC術(shù)后單次應用MMC或THP進行膀胱灌注均能降低膀胱尿路上皮腫瘤發(fā)生幾率，出于化學藥物滲漏等安全考慮，用藥時間為術(shù)后2 d到1周以后。O’BRIEN的Ⅲ期試驗中，在拔除尿管時進行膀胱灌注[23]，因絲裂霉素C灌注時間較晚(通常為術(shù)后1周或更長)，其機制可能是阻礙已經(jīng)種植的細胞形成新的腫瘤。和膀胱腫瘤術(shù)后單次灌注相比，療效相仿(相對風險降低約40%)；ITO等[21]報道隨機臨床Ⅱ期試驗中，術(shù)后48 h內(nèi)單劑應用30 mg吡柔比星，明顯減低術(shù)后1年和2年復發(fā)率的同時，并未引起明顯副作用。

但MORIARTY等[25]報道超過10年的應用經(jīng)驗也表明，術(shù)中即刻用絲裂霉素C進行膀胱灌注安全可行，無明顯嚴重并發(fā)癥，雖然這個報道樣本量較小，但應用時間較長，較為可信，當然這需要多中心試驗加以驗證。

研究顯示術(shù)前尿細胞學檢查陽性的UTUC患者術(shù)后更易發(fā)生膀胱腫瘤[26-27]，因為膀胱黏膜可能持續(xù)暴露于脫落的腫瘤細胞，但隨后的臨床發(fā)現(xiàn)對這類患者術(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發(fā)率，表明腫瘤細胞種植更可能是發(fā)生在術(shù)后，盡早殺滅尚未粘附或種植的瘤細胞很可能進一步降低其復發(fā)率。

對于化療藥物灌注時機的選擇，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)灌注可降低其復發(fā)率，但超過24 h后則無明顯效果[28-29]，另一項隨機對照則表明TURBT術(shù)前應用MMC膀胱灌注效果優(yōu)于術(shù)后應用[30]。出于膀胱腫瘤復發(fā)機制的考慮，目前膀胱腫瘤術(shù)后普遍傾向于盡早應用，以防止腫瘤細胞種植。借鑒膀胱腫瘤的經(jīng)驗，目前傾向于UTUC術(shù)后盡早進行膀胱灌注。

4 UTUC術(shù)后膀胱灌注化療的對象選擇

先前已有報道稱UTUC根治術(shù)后膀胱腫瘤復發(fā)風險受到包括患者本身、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發(fā)的兩個相關因素。O’BRIEN等[23]認為分化良好的UTUC患者術(shù)后膀胱腫瘤的復發(fā)較罕見(18例中有1例，6%)，故認為除非原發(fā)腫瘤呈多灶性，否則不推薦給予病理分級為I級患者術(shù)后常規(guī)行膀胱灌注化療藥物。然而，本研究對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這部分患者術(shù)后是否應接受膀胱灌注。

為評估UTUC行根治性腎輸尿管切除術(shù)后膀胱腫瘤復發(fā)的有效預測因子，近期國外開展了一項薈萃分析[34]，總計18個回顧性研究共8 275例患者，其中2 402例(29%)被診斷為膀胱腫瘤復發(fā)的中位時間為22.2個月(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為是患者特異性預測因素；而術(shù)前尿液脫落細胞學檢查陽性、輸尿管下段腫瘤、原發(fā)腫瘤多灶性、病理證實為浸潤性腫瘤、腫瘤出現(xiàn)壞死等則被認為是腫瘤特異性預測因素。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為與腫瘤復發(fā)密切相關。國內(nèi)亦有一項包含有727名患者的研究，得出了相似的結(jié)果[35]。因此認為，從患者本身、腫瘤及治療因素三方面對UTUC術(shù)后膀胱腫瘤復率進行系統(tǒng)評估，可以指導優(yōu)化膀胱灌注化療方案及篩選適合膀胱灌注化療的對象。

綜上所述，UTUC行根治性腎、輸尿管全切術(shù)后，膀胱腫瘤復發(fā)率非常高，而化療藥物膀胱灌注可明顯降低其復發(fā)率。因此，UTUC行腎、輸尿管切除術(shù)后，進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間尚存爭議，需針對不同危險因素設計樣本量更大的對照試驗加以規(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)展計劃(No.2014WS0351)

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

袁傳威(1988-)，男(達斡爾族)，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