上尿路尿路上皮肿瘤患者术后应早期预防性膀胱灌注

袁传威，陈友根，兰晓鹏，卢国良，毛少为，于 江，夏庆华

(山东大学附属省立医院 泌尿微创中心，山东济南 250021)

·争鸣园地·

上尿路尿路上皮肿瘤患者术后应早期预防性膀胱灌注

袁传威，陈友根，兰晓鹏，卢国良，毛少为，于 江，夏庆华

(山东大学附属省立医院 泌尿微创中心，山东济南 250021)

根治性肾、输尿管切除及膀胱袖状切除术是上尿路尿路上皮肿瘤(UTUC)的标准术式。可能是因为瘤细胞种植和区域化癌变的缘故，约22%～47%的患者术后继发膀胱肿瘤。为阐明预防性膀胱灌注化疗在预防膀胱肿瘤复发中的作用，实施了多个前瞻性随机临床试验，发现术后THP或MMC膀胱灌注可显著降低其复发率，术后早期应用且安全可行。因此，我们建议UTUC术后应预防性膀胱灌注，但最佳方案尚需研究。

膀胱复发；膀胱灌注；肾、输尿管切除术；上尿路尿路上皮肿瘤

上尿路尿路上皮肿瘤(upper tract urothelial carcinoma, UTUC)是指起源于肾盂或输尿管上皮的肿瘤，约占全部尿路上皮肿瘤的5%～10%[1-2]。相对膀胱肿瘤而言，上尿路上皮肿瘤发病年龄较大，多介于65～79岁。UTUC具有高度复发及进展风险，但双侧上尿路发生肿瘤的几率约为1.6%，这使得根治性肾输尿管切除及膀胱袖状切除术成为其标准术式。

然而，UTUC术后有22%～47%的患者会发生膀胱复发[3-5]，而在对侧肾盂、输尿管复发的比率约为2%～6%[6-8]。因此很自然推测膀胱肿瘤很可能是尿路上皮肿瘤多中心性或上尿路脱落瘤细胞种植引起的，而这也得到了分子标记和DNA测序等多个试验的证实[9-10]。在膀胱肿瘤的术后预防性治疗中，化疗药物膀胱灌注已应用了超过40年，其延迟和预防膀胱肿瘤复发和进展的效果已获公认[11]。因UTUC发病率较低，缺乏大样本前瞻随机对照临床研究，目前术后化学药物膀胱灌注方案多参照膀胱肿瘤，是否应用以及具体方案尚无规范，本文将就此进行探讨。

1 UTUC术后的膀胱复发假说

UTUC的膀胱肿瘤复发多发生在术后2年内，其中一个高峰时间约为术后6个月，这和膀胱肿瘤术后复发时间较为相似。到目前为止，解释UTUC术后复发的假说包括腔内种植[12]和区域化癌变[13]两种。

UTUC起源于肾盏、肾盂及输尿管上皮，肿瘤细胞容易脱落，特别是手术操作过程中，对肿瘤及周围组织的牵拉、挤压使瘤细胞更容易脱落，顺尿流方向发生多器官种植性生长，膀胱黏膜的损伤使瘤细胞粘附、种植变得更加容易，而围手术期患者免疫低下，也增加瘤细胞种植成功几率。

围绕腔内种植和区域化癌变两种假说，很多危险因素被证明和复发相关，如分期、分级、肿瘤多发、位置以及手术方式、尿细胞学检查阳性等[8,14-17]，其中肿瘤分期最为重要。如没有完整切除整段输尿管，输尿管残端发生移行细胞肿瘤的风险为12%～75%，并增加膀胱肿瘤复发及远处转移的几率[18]。早期曾有腹腔镜手术增加术后膀胱肿瘤复发几率的报道，担忧较长的手术时间及气腹高压有利于肿瘤细胞的脱落并增加暴露时间，但这些研究多是刚开始使用腹腔镜手术阶段，随着腹腔镜技术的成熟以及样本量的增加，只要完整切除输尿管，两种术式对膀胱肿瘤复发并无明显差异[19-20]。

膀胱袖状切除术中黏膜直接暴露，留置尿管也增加了黏膜损伤的几率。相对于完整的尿路上皮，受损的黏膜更易于肿瘤细胞粘附并种植。从复发肿瘤位置看,ITO等[21]报道大部分肿瘤发生于患侧输尿管口附近膀胱壁(含三角区)或膀胱颈，这也验证了肿瘤细胞更容易种植于受损的尿路上皮。

综合以上分析，UTUC术后膀胱复发可以用腔内种植和区域化癌变两种假说解释。在行根治性切除术后，如何有效降低术后肿瘤细胞脱落、种植成为预防复发的重点。

最近有一项包含有5组研究共计614例行根治术的UTUC患者的荟萃分析证实，术后给予膀胱灌注组膀胱肿瘤复发率(20.5%)明显低于无灌注化疗组(36.7%)[22]。近年来亦有前瞻性随机对照试验表明，根治性肾输尿管全切及膀胱袖状切除术后早期应用丝裂霉素C或吡柔比星行膀胱灌注，可明显降低膀胱肿瘤复发的风险[21,23]。然而，WU等[24]的研究表明，UTUC术后预防性膀胱灌注抗肿瘤药物或卡介苗(bacillus calmette-guérin，BCG)时，虽明显降低膀胱肿瘤复发风险，但其效益却仅局限于预防早期膀胱肿瘤复发，而不能起到长期预防的作用，且同时发现其与术后肿瘤特异性生存率亦无明显统计学意义。

因此，尽管UTUC根治术后是否应常规预防性膀胱灌注化疗以降低膀胱肿瘤复发仍未达成共识，但预防性膀胱灌注化疗可能是预防UTUC根治术后膀胱肿瘤复发的重要预防措施。

2 UTUC术后膀胱灌注化疗药物的选择

丝裂霉素C(Mitomycin C)、表柔比星(Epirubicin)以及吡柔比星(THP)等是预防浅表性膀胱肿瘤患者术后肿瘤复发的常用药物，也是目前常用于UTUC患者术后膀胱灌注化疗的药物。WU等[24]分别应用10 mg丝裂霉素C溶于20 mL生理盐水以及20 mg表柔比星溶于20 mL生理盐水对UTUC术后患者行膀胱灌注，结果表明肿瘤复发率灌注丝裂霉素C组为25.9%，灌注表柔比星组为29.0%，无灌注治疗的对照组为41.3%，灌注组与对照组相比明显减低，但其差别无统计学意义(P=0.188)。ITO等[21]的前瞻性随机对照Ⅱ期临床研究表明，术后48 h内以30 mg吡柔比星溶于30 mL生理盐水行单次膀胱灌注，患者2年肿瘤复发率为16.9%，明显低于无灌注治疗对照组2年复发率(42.2%)(P=0.025)。O'BRIEN[23]等在英国进行了一项多中心前瞻性随机对照临床试验，纳入284名因UTUC行根治性肾输尿管切除术的患者，术后拔除尿管时单剂应用40 mg丝裂霉素C进行膀胱灌注，随访1年(术后3、6、12个月时行膀胱镜检查)，发现膀胱灌注丝裂霉素C治疗能将术后1年膀胱肿瘤复发绝对风险降低11%，相对风险降低40%，且没有严重不良反应，这是目前样本量最大的随机对照试验。

卡介苗虽然推荐用于高危非肌层浸润性膀胱肿瘤的治疗，但不能改变低危非肌层浸润性膀胱肿瘤的病程，且副作用发生率较高。用于UTUC术后的报道只少量见于肾盂、输尿管原位肿瘤的治疗性灌注。术后膀胱有开放创面，即可灌注易引起严重的副作用，将BCG用于UTUC术后即刻膀胱灌注尚缺乏经验。

3 UTUC术后膀胱灌注化疗时机

为避免灌注的相关副作用，大部分化学药物膀胱灌注时间均较晚。两项独立的随机试验表明UTUC术后单次应用MMC或THP进行膀胱灌注均能降低膀胱尿路上皮肿瘤发生几率，出于化学药物渗漏等安全考虑，用药时间为术后2 d到1周以后。O’BRIEN的Ⅲ期试验中，在拔除尿管时进行膀胱灌注[23]，因丝裂霉素C灌注时间较晚(通常为术后1周或更长)，其机制可能是阻碍已经种植的细胞形成新的肿瘤。和膀胱肿瘤术后单次灌注相比，疗效相仿(相对风险降低约40%)；ITO等[21]报道随机临床Ⅱ期试验中，术后48 h内单剂应用30 mg吡柔比星，明显减低术后1年和2年复发率的同时，并未引起明显副作用。

但MORIARTY等[25]报道超过10年的应用经验也表明，术中即刻用丝裂霉素C进行膀胱灌注安全可行，无明显严重并发症，虽然这个报道样本量较小，但应用时间较长，较为可信，当然这需要多中心试验加以验证。

研究显示术前尿细胞学检查阳性的UTUC患者术后更易发生膀胱肿瘤[26-27]，因为膀胱黏膜可能持续暴露于脱落的肿瘤细胞，但随后的临床发现对这类患者术后THP即刻膀胱灌注可显著减低这一类患者的膀胱肿瘤复发率，表明肿瘤细胞种植更可能是发生在术后，尽早杀灭尚未粘附或种植的瘤细胞很可能进一步降低其复发率。

对于化疗药物灌注时机的选择，膀胱肿瘤术后是倾向于尽早使用，推荐术后6 h内。参考膀胱肿瘤的研究，术后6 h内灌注可降低其复发率，但超过24 h后则无明显效果[28-29]，另一项随机对照则表明TURBT术前应用MMC膀胱灌注效果优于术后应用[30]。出于膀胱肿瘤复发机制的考虑，目前膀胱肿瘤术后普遍倾向于尽早应用，以防止肿瘤细胞种植。借鉴膀胱肿瘤的经验，目前倾向于UTUC术后尽早进行膀胱灌注。

4 UTUC术后膀胱灌注化疗的对象选择

先前已有报道称UTUC根治术后膀胱肿瘤复发风险受到包括患者本身、肿瘤及治疗特性的影响[14,31]。AZéMAR等[32]发现既往膀胱肿瘤病史及多病灶的原发性肿瘤是最常见的与膀胱肿瘤复发的两个相关因素。O’BRIEN等[23]认为分化良好的UTUC患者术后膀胱肿瘤的复发较罕见(18例中有1例，6%)，故认为除非原发肿瘤呈多灶性，否则不推荐给予病理分级为I级患者术后常规行膀胱灌注化疗药物。然而，本研究对象中未包括行根治术前有膀胱肿瘤病史患者，而临床许多行根治术的UTUC患者术前有膀胱肿瘤病史，所以此研究无法指导这部分患者术后是否应接受膀胱灌注。

为评估UTUC行根治性肾输尿管切除术后膀胱肿瘤复发的有效预测因子，近期国外开展了一项荟萃分析[34]，总计18个回顾性研究共8 275例患者，其中2 402例(29%)被诊断为膀胱肿瘤复发的中位时间为22.2个月(范围 6.7～56.5月)。男性、术前膀胱肿瘤病史以及术前慢性肾脏疾病病史被认为是患者特异性预测因素；而术前尿液脱落细胞学检查阳性、输尿管下段肿瘤、原发肿瘤多灶性、病理证实为浸润性肿瘤、肿瘤出现坏死等则被认为是肿瘤特异性预测因素。腹腔镜手术、输尿管末端膀胱袖状切除和手术切缘阳性等治疗特异性因素也被认为与肿瘤复发密切相关。国内亦有一项包含有727名患者的研究，得出了相似的结果[35]。因此认为，从患者本身、肿瘤及治疗因素三方面对UTUC术后膀胱肿瘤复率进行系统评估，可以指导优化膀胱灌注化疗方案及筛选适合膀胱灌注化疗的对象。

综上所述，UTUC行根治性肾、输尿管全切术后，膀胱肿瘤复发率非常高，而化疗药物膀胱灌注可明显降低其复发率。因此，UTUC行肾、输尿管切除术后，进行膀胱灌注是必要的。但具体灌注方案如药物选择以及灌注时间尚存争议，需针对不同危险因素设计样本量更大的对照试验加以规范。

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(编辑 王 玮)

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

山东省医药卫生科技发展计划(No.2014WS0351)

夏庆华, 主任医师.E-mail: xqhgege@hotmail.com

袁传威(1988-)，男(达斡尔族)，医师，硕士.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