欧盟膀胱癌Guidelines(辅助治疗部分,中英文对照)

1、Guidelines onNon-muscle-invasive Bladder Cancer(Ta, T1 and CIS)非肌层浸润性膀胱癌（Ta期和T1期及CIS）指南M. Babjuk (chair), A. Böhle, M. Burger, E. Compérat,E. Kaasinen, J. Palou, B.W.G. van Rhijn, M. Rouprêt,S. Shariat, R. Sylvester, R. Zigeuner© European Association of Urology 2014©欧洲泌尿外科学会

2、2014版权所有European Association of Urology欧洲泌尿外科学会8.ADJUVANT TREATMENT辅助治疗8.1Intravesical chemotherapy膀胱内化疗Although state-of-the-art TURB by itself can eradicate a Ta, T1 tumour completely, these tumours commonly recur and can progress to MIBC. The high variability in the 3-month recurrence rate indica

3、tes that TURB is incomplete or provokes recurrences in a high percentage of patients (90). It is therefore necessary to consider adjuvant therapy in all patients.尽管最先进的TURB本身能够根除Ta期和T1期肿瘤，但是这些肿瘤普遍复发并可能发展为MIBC。3个月复发率的高度变异性表明，TURB并不完备或激发高比例患者复发（90）。因而有必要考虑为所有患者考虑辅助疗法。8.1.1A single, immediate, post-ope

4、rative intravesical instillation of chemotherapy单个的术后即时膀胱灌注化疗Early single instillation has been shown to act by the destruction of circulating tumour cells resulting from TURB, and by an ablative effect (chemoresection) on residual tumour cells at the resection site and on small overlooked tumours (

5、143-146) (LE: 3).早期单个灌注表现为，通过破坏TURB产生的循环肿瘤细胞，通过对切除部位的残余肿瘤细胞、对被忽略的小肿瘤的烧蚀作用（化疗切除术）来起作用（143-146）（LE: 3）。Three large meta-analyses comprising 1476 to 3103 patients have consistently shown that one immediate instillation of chemotherapy after TURB significantly reduced the recurrence rate by 11.7% to 13.

6、0% compared to TURB alone (147-149) (LE: 1a). Although none of the three meta-analyses adequately answered the question concerning which patients benefitted the most from an immediate instillation, some underpowered data from two subgroup analyses (150,151) suggest that immediate instillation is mos

7、t effective in tumour types with the lowest tendency towards recurrence, i.e., in single primary or small tumours. Mitomycin C, epirubicin, and doxorubicin have all shown a beneficial effect; no efficacy comparisons have been made (147-149) (LE: 1a).包含14763103名患者的三个大型荟萃分析一致表明，TURB后作一次即时化疗灌注使复发率降至13.

8、0%，与单独的TURB相比显著降低了11.7%（147-149）（LE: 1a）。尽管三个荟萃分析都没有充分回答哪些患者从即时灌注获得最大益处，但是两个亚组分析（150,151）的某些动力不足的数据显示，即时灌注对于复发倾向性最低的肿瘤类型最有效，即单一原发性肿瘤或小肿瘤。丝裂霉素C、表柔比星和阿霉素已表现出有益效果，未作疗效比较（147-149）（LE: 1a）。There is evidence from one subgroup and one combined analysis that immediate instillation might have an impact on re

9、currence, even when further adjuvant instillations are given (152,153) (LE: 2a). In contrast, a sufficient number of delayed repeat chemotherapy instillations can also reduce recurrence stemming from tumour implantation (145,152,153). Nevertheless, it is likely that immediate instillation is more ef

10、fective in preventing recurrence than any of the individual instillations that follow the immediate instillation (145,154) (LE: 3). Clearly, more studies comparing immediate and delayed-start regimens are needed.一个亚组和一个组合分析的证据证明即时灌注可能对复发有影响，甚至在给予进一步的辅助性灌注时亦有影响（152,153）（LE: 2a）。相比之下，足够数量的经延迟重复性化疗灌注亦可

11、降低源于肿瘤植入的复发率（145,152,153）。尽管如此，即时灌注很有可能比即时灌注之后的任何单个灌注在防止复发方面更有效（145,154）（LE: 3）。很明显，需要开展更多研究，比较即时灌注方案和延迟启动方案。The prevention of tumour cell implantation should be initiated within the first hours after cell seeding. Within a few hours, the cells are implanted firmly and are covered by extracellular m

12、atrix (144,155-157) (LE: 3). In all single-instillation studies, the instillation was administered within 24 hours. To maximize the efficacy of immediate instillation, one should devise flexible practices that allow the instillation to be given as early as possible, which is in the recovery room or

13、even in the operating theatre.肿瘤细胞植入的预防应在细胞接种后前几个小时内开始。在几个小时内，细胞稳定植入并由细胞外基质覆盖（144,155-157）（LE: 3）。所有单一灌注研究，都在24小时内给予灌注。为了使即时灌注疗效最大化，应设计灵活的做法，允许在恢复室甚至是手术室尽早地给予灌注。Immediate instillation of post-operative chemotherapy should be omitted in any case of overt or suspected intra- or extra-peritoneal perfor

14、ation, which is most likely to appear in extensive TURB procedures, and in situations with bleeding that require bladder irrigation. Clear instructions should be given to the nursing staff to control the free flow of the bladder catheter at the end of the instillation. Severe complications have been

15、 reported in patients with drug extravasation (158).有明显或疑似腹膜内或腹膜外穿孔（最可能出现在广泛的TURB程序中），以及出现需要膀胱冲洗的出血病情时，应忽略术后化疗即时灌注。应向护理人员作出清楚说明，要在灌注结束时控制膀胱导管的自流。据报告，药物外渗的患者出现严重的并发症（158）。8.1.2Additional adjuvant intravesical chemotherapy instillations额外的辅助性膀胱内化疗灌注The need for further adjuvant intravesical therapy de

16、pends on prognosis. In low-risk patients (Tables 7 and 8), a single immediate instillation reduces the risk of recurrence and is considered to be the standard treatment (147) (LE: 1a). No further treatment should be given in these patients before subsequent recurrence. For other patients, however, a

17、 single immediate instillation remains an incomplete treatment because of the considerable likelihood of recurrence and/or progression (Tables 7 and 8).对进一步的辅助性膀胱灌注疗法的需求取决于预后情况。对于低风险患者（表7和表8），单一的即时灌注降低复发风险，被认为是标准治疗（147）（LE: 1a）。在随后复发出现之前，不应给予这些患者进一步治疗。而对于其他患者，由于很可能出现复发和/或进展（表7和表8），故单一的即时灌注仍为不完全治疗。A

18、large meta-analysis of 3703 patients from 11 randomized trials showed a highly significant 44% reduction in the odds of recurrence at one year in favour of chemotherapy over TURB alone (159). This corresponds to an absolute difference of 13-14% in the number of patients with recurrence. Contrary to

19、chemotherapy, two meta-analyses have demonstrated that BCG therapy may reduce the risk of tumour progression (160,161) (LE: 1a) (see Section 8.2.1). Moreover, BCG maintenance therapy appears to be significantly better in preventing recurrences than regimens with mitomycin C (MMC) or epirubicin (162-

20、164) (see Section 8.2.1) (LE: 1a). However, BCG causes significantly more side effects than does chemotherapy (164) (LE: 1a).对来自11个随机试验的3703名患者的大型荟萃分析表明，化疗1年复发几率比单独的TURB降低44%，下降极其显著（159）。与此对应的是复发患者数量上13-14%的绝对差异。与化疗相反，两个荟萃分析已证明，BCG疗法可能会降低肿瘤进展的风险（160,161）（LE: 1a）（见第8.2.1节）。此外，BCG维持疗法预防复发的效果明显似乎比丝裂霉素C

21、（MMC）或表柔比星更好（162-164）（见第8.2.1节）（LE: 1a）。然而，与化疗相比，BCG的副作用显著增加了（164）（LE: 1a）。The length and frequency of chemotherapy instillations is still controversial. A systematic review of RCTs, comparing different schedules of intravesical chemotherapy instillations, concluded that the ideal duration and inten

22、sity of the schedule remains undefined because of conflicting data (165). The available evidence does not support any treatment longer than one year (LE: 3).化疗灌注的时长和频率仍具有争议。对RCT的系统评价，比较了不同的膀胱内化疗灌注计划，结论是由于数据冲突，仍无法确定用药计划理想的持续时间和强度（165）。可用的证据并不支持任何超过一年的治疗（LE: 3）。8.1.3Options for improving efficacy of i

23、ntravesical chemotherapy提高膀胱内化疗疗效的方案Some promising data have been presented about enhancing the efficacy of MMC using microwave-induced hyperthermia (Synergo) or electromotive drug administration (EMDA) in patients with high-risk tumours. The current evidence, however, is limited. The number of pati

24、ents in the prospective series using microwave-induced hyperthermia was small with inconclusive data on progression. In one study of 212 patients comparing BCG with sequential BCG and electromotive MMC, a significant benefit was found in favour of the electromotive arm, regarding recurrence and prog

25、ression (166,167) (LE: 2b). Still, both treatment modalities are considered to be experimental.对高风险肿瘤患者，利用微波诱导的高热（Synergo）或电化学灌注治疗（EMDA）来提高MMC疗效，已得出一些很有希望的数据。然而，现有证据是有限的。利用微波诱导的高热所作的前瞻性系列中，患者数量较小，进展数据没有定论。一项对212名患者的研究，BCG与顺序BCG和电动MMC之间作了比较，发现在复发和进展方面，电动臂具有显著的益处（166,167）（LE: 2b）。然而，两种治疗方式都被认为是试验性的。On

26、e RCT using MMC has demonstrated that adapting urinary pH, decreasing urinary excretion, and buffering the intravesical solution reduced the recurrence rate (168) (LE: 1b). Another trial reported that a 1-hour instillation of MMC was more effective than 30 minutes instillation, but no efficacy compa

27、risons are available for 1- and 2-hour instillations (169) (LE: 3).利用MMC的一项RCT已证明，调节尿液pH、减少排尿和缓冲膀胱内液降低了复发率（168）（LE: 1b）。据另一项试验报告，灌注MMC1小时比30分钟更有效，但没有1小时和2小时灌注的疗效对比可以利用（169）（LE: 3）。Another RCT using epirubicin has documented that concentration is more important than treatment duration (170) (LE: 1b).

28、 In view of these data, which need confirmation, it seems advisable to ask the patient not to drink on the morning before instillation, and to dissolve the drug in a buffered solution at optimal pH.另一项利用表柔比星的RCT已有记录表明，浓度比治疗持续时间更重要（170）（LE: 1b）。鉴于这些需要确认的数据，似乎可取的做法是要求患者在灌注前的早上不要喝水，而是在把药物溶解达到最佳pH的缓冲液中。

29、8.2Intravesical bacillus Calmette-Guérin (BCG) immunotherapy膀胱内卡介苗（BCG）免疫疗法8.2.1Efficacy of BCGBCG疗效Five meta-analyses have confirmed that BCG after TURB is superior to TURB alone or TURB + chemotherapy for preventing the recurrence of non-muscle-invasive tumours (162,171-174) (LE: 1a). Three r

30、ecent RCTs of intermediate- and high-risk tumours have been conducted. BCG was compared with epirubicin + interferon (175), MMC (176), or epirubicin alone (163). All of these studies have confirmed the superiority of BCG for prevention of tumour recurrence (LE: 1a). The effect is long lasting (163,1

31、76) and was also observed in a separate analysis of patients with intermediate-risk tumours (163).五项荟萃分析已确认，在预防非肌层浸润性肿瘤方面，TURB之后使用BCG优于单独的TURB或TURB+化疗方案（162,171-174）（LE: 1a）。中、高风险肿瘤三项最近的RCT已实施。BCG与表柔比星+干扰素（175）、MMC（176）或单独的表柔比星（163）之间作了比较。所有这些研究已确认BCG在肿瘤复发预防上的优越性（LE: 1a）。效果持久（163,176），而且在中风险肿瘤患者的单独分

32、析中亦获得该效果（163）。One meta-analysis (162) has evaluated the individual data from 2820 patients enrolled in nine RCTs that have compared MMC versus BCG. In the trials with BCG maintenance, there was a 32% reduction in the risk of recurrence for BCG compared to MMC (p < 0.0001) compared to a 28% increa

33、se in the risk of recurrence (p = 0.006) for patients treated with BCG in the trials without BCG maintenance.一项荟萃分析（162）分析了2820名患者的个体数据，这些患者参与了九项比较MMC与BCG的RCT。在有BCG维持的这些试验中，用BCG的复发风险比MMC低32%（p< 0.0001）；相比之下，试验中用BCG治疗而无BCG维持的患者，复发风险增加28%（p=0.006）。Two meta-analyses have demonstrated that BCG therap

34、y prevents, or at least delays, the risk of tumour progression (160,161) (LE: 1a). A meta-analysis carried out by the EORTC-GUCG has evaluated data from 4863 patients (81.6% with papillary tumours and 18.4% with primary or concurrent CIS) enrolled in 24 RCTs. Five different BCG strains were used, an

35、d in 20 of the trials, some form of BCG maintenance was used. Based on a median follow-up of 2.5 years, in 260 out of 2658 patients (9.8%) treated with BCG, tumours progressed compared to 304 out of 2205 (13.8%) in the control groups (TURB alone, TURB + intravesical chemotherapy, or TUR + other immu

36、notherapy). This shows a reduction of 27% in the odds of progression with BCG maintenance treatment (p = 0.0001). The size of the reduction was similar in patients with Ta, T1 papillary tumours and in those with CIS (161). A recent RCT with long-term observation has demonstrated significantly fewer

37、distant metastases and better overall- and disease-specific survival in patients treated with BCG compared to epirubicin (163) (LE: 1b). On the contrary, a meta-analysis of individual patient data was not able to confirm any statistically significant difference between MMC and BCG for progression, s

38、urvival and cause of death (162).两项荟萃分析已证明，BCG疗法能预防，或者至少延迟肿瘤进展的风险（160,161）（LE: 1a）。EORTC-GUCG实施的一项荟萃分析分析了24项RCT中4863名患者（81.6%有乳头状肿瘤，18.4%有原发性或并发性CIS）的数据。采用了五个不同的BCG品系，其中有20个试验，使用了某种形式的BCG维持。根据一项中位数时间为两年半年的随访，用BCG治疗的2658名患者中有260名（9.8%）的肿瘤有所进展，而对照组（单独的TURB、TURB+膀胱内化疗或TUR+其他免疫疗法）的2205名患者中有304名（13.8%）出现

39、这一情况。这表明，BCG维持治疗的进展几率下降了27%（p=0.0001）。Ta期和T1期乳头状肿瘤患者和CIS患者具有类似的下降幅度（161）。最近一项经长期观察的RCT已证明，与表柔比星相比，用BCG治疗的患者的远处转移显著减少，总体生存率和疾病特异性生存率更高（163）（LE: 1b）。相反地，个体患者数据的荟萃分析无法确认MMC与BCG在进展、生存率和死亡原因方面任何显著的统计差异（162）。The conflicting results in the outcomes of the studies can be explained by different patient chara

40、cteristics, duration of follow-up, methodology and statistical power. However, most studies showed a reduction in the risk of progression in high- and intermediate-risk tumours if BCG was applied including a maintenance schedule.研究结果出现矛盾可由以下原因来解释：不同的患者特征、随访持续时间、方法和统计功效。然而多数研究表明，若应用BCG时含有维持计划，则高、中风险肿

41、瘤的进展风险会降低。Two other meta-analyses have suggested a possible bias in favour of BCG arising from the inclusion of patients previously treated with intravesical chemotherapy (177,178). In the most recent meta-analysis, however, BCG maintenance was more effective than MMC in patients previously treated

42、with chemotherapy (162) (LE: 1a).另外两项荟萃分析已表明，由于先前采用膀胱内化疗治疗的患者也包含在内，因此可能存在偏向BCG的情况（177,178）。然而，在大多数最近的荟萃分析中，对于先前用膀胱内化疗的患者而言，BCG维持比MMC更有效（162）（LE: 1a）。8.2.2Optimal BCG schedule最佳BCG用药计划Induction BCG instillations are classically given according to the empirical 6-weekly schedule introduced by Morales

43、in 1976 (179). For optimal efficacy, BCG must be given in a maintenance schedule (160-162,174) (LE: 1a). In the EORTC-GU group meta-analysis, only patients who received maintenance BCG benefitted. Many different maintenance schedules have been used, ranging from a total of 10 instillations given in

44、18 weeks to 27 over 3 years (180). The meta-analysis was unable to determine which BCG maintenance schedule was the most effective (161). In their meta-analysis, Böhle et al. concluded that at least one year of maintenance BCG is required to obtain superiority of BCG over MMC for prevention of

45、recurrence or progression (160,174) (LE: 1a).根据Morales1976年提出的经验性6周计划，按照经典的方式给予诱导式BCG灌注（179）。为达到最佳疗效，必须在维持计划给出BCG（160-162,174）（LE: 1a）。在EORTC-GU小组荟萃分析中，仅接受过BCG维持治疗的患者获益。已采用诸多不同的维持计划，在3年内总共10次灌注的时间从18周到27周不等（180）。荟萃分析无法确定哪个BCG维持计划最有效（161）。Böhle等人的荟萃分析的结论是，要获得BCG在复发或进展方面对于MMC的优越性，至少需要一年的BCG维持治疗（1

46、60,174）（LE: 1a）。The optimal number of induction instillations and optimal frequency and duration of maintenance instillations remain unknown (181). However, in an RCT of 1355 patients, the EORTC has shown that when BCG is given at full dose, 3 years maintenance reduces the recurrence rate compared t

47、o one year in high- but not in intermediate-risk patients. There were no differences in progression or overall survival (178) (LE: 1b). The benefit of the two additional years of maintenance in the high-risk patients should be weighed against its added costs and inconveniences.诱导灌注的最佳数量和维持灌注的最佳频率和持续

48、时间依然不明（181）。然而，在一项有1355名患者的RCT中，EORTC已表明，当全剂量给予BCG时，与高风险患者一年维持相比，3年维持降低了复发率，但对于中风险患者并非如此。进展率或总体生存率没有差异（178）（LE: 1b）。高风险患者额外两年的维持治疗所获得的益处应与增加的成本和不便作对比，权衡利弊。8.2.3BCG toxicityBCG毒性BCG intravesical treatment is associated with more side effects compared to intravesical chemotherapy (164) (LE: 1a). Howev

49、er, serious side effects are encountered in < 5% of patients and can be treated effectively in almost all cases (182) (LE: 1b). It has been shown that maintenance schedule is not associated with an increased risk of side effects comparing to an induction course (182). Side effects requiring treat

50、ment stoppage were seen more often in the first year of therapy (183).与膀胱内化疗相比，与BCG膀胱内治疗有关的副作用更多（164）（LE: 1a）。然而，遭遇严重副作用的患者比例<5%，而且在几乎所有的病例中，这些副作用都可以得到有效治疗（182）（LE: 1b）。已有证据表明，维持计划并不与高于诱发疗程的副作用风险有关（182）。需要治疗中断的副作用在治疗的头一年更常见（183）。Major complications can appear after systemic absorption of the drug

51、. Thus, contraindications of BCG intravesical instillation should be respected. BCG should not be administered (absolute contraindications):全身吸收药物后可能出现重大并发症。因而，应当遵守BCG膀胱内灌注的禁忌症。以下情况（绝对禁忌症），不应使用BCG：during the first 2 weeks after TURB;TURB后前2周之内；in patients with macroscopic haematuria;肉眼血尿患者；after tra

52、umatic catheterization;创伤性导管插入术后；in patients with a symptomatic urinary tract infection.症状性泌尿道感染患者。The presence of leukocyturia, microscopic haematuria or asymptomatic bacteriuria is not a contraindication for BCG application, and antibiotic prophylaxis is not necessary in these cases (184-186) (LE:

53、 3).出现白细胞尿、显微镜血尿或无症状细菌尿并非BCG应用的禁忌症，且这些病例中不需要抗生素预防（184-186）（LE: 3）。BCG should be used with caution (relative contraindication) in immunocompromised patients (immunosuppression, human immunodeficiency virus (HIV) infection) (187), although some small studies have shown similar efficacy and no increase

54、 in complications compared to non-immunocompromised patients (188,189) (LE: 3).对于免疫功能低下患者（免疫抑制、人类免疫缺陷（HIV）病毒），应小心使用BCG（相对禁忌症）（187），尽管某些小型研究已表明，与非免疫功能低下患者相比，BCG具有类似疗效且不会增加并发症（188,189）（LE: 3）。The management of side effects after BCG should reflect their type and grade. Recommendations for individual s

55、ituations have been provided by the International Bladder Cancer Group (IBCG) and by a Spanish group (190,191) (Table 9).对BCG后副作用的管理应体现副作用的类型和级别。针对个别情况的推荐已IBCG和西班牙研究组提供（190,191）（表9）。Table 9: Management options for side effects associated with intravesical BCG (190,192,193)表9：膀胱内BCG相关副作用的管理方案（190,192

56、,193）Management options for local side effects (modified from IBCG group)局部副作用的处理方案（依据IBCG小组修改而来）Symptoms of cystitis膀胱炎的症状Phenazopyridine, propantheline bromide, or NSAIDs非那吡啶、溴丙胺太林或非甾体抗炎药If symptoms improve within a few days: continue instillations若在症状在几天内有所改善：继续灌注If symptoms persist or worsen:若症状

57、持续或恶化：a.Postpone the instillations暂停灌注b.Perform a urine culture作尿培养c.Start empirical antibiotic treatment开始经验性抗生素治疗If symptoms persist even with antibiotic treatment:若经抗生素治疗后，症状仍持续：d.With positive culture: antibiotic treatment according to sensitivity.培养阳性：根据灵敏度进行抗生素治疗e.With negative culture: quinol

58、ones and potentially analgesic anti- inflammatory instillations once daily for 5 days (repeat cycle if necessary) (194).培养阴性：喹诺酮类和潜在止痛抗炎灌注，5天每日一次（必要时重复周期）（194）。If symptoms persist: anti-tuberculosis drugs + corticosteroids.若症状持续：抗结核药物+皮质类固醇If no response to treatment and/or contracted bladder: radical cystectomy.若对治疗无反应和/或固缩膀胱：根治性膀胱切除术Haematuria血尿症Perform urine culture to exclude haemorrhagic cystitis, if other symptoms present.若出现其他症状，则作尿培养，排除出血性膀胱炎。If haematuria persists, perform cystoscopy to evaluate presence of bladder tumour.若血尿症持续，则作膀胱镜检查，评估膀胱癌