Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer

  • Review
  • Intervention

Authors


Abstract

Background

Tumour recurrence following transurethral resection (TUR) for Ta and T1 bladder cancer is a major clinical problem. Intravesical administration of mitomycin C (MMC) or bacillus Calmette-Guérin (BCG) has proven prophylactic activity but both are associated with local and systemic side effects. A systematic review was carried out to compare the efficacy of these two agents.

Objectives

To undertake a systematic review and meta-analysis comparing intravesical mitomycin C and Bacillus Calmette-Guérin in terms of tumour recurrence, disease progression and overall survival in Ta and T1 bladder cancer. Treatment-related toxicities would also be evaluated.

Search methods

A comprehensive search of MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register, Cancerlit, and DARE was performed, and hand searching of relevant journals undertaken.

Selection criteria

Trials in any language were included in the meta-analysis if they were properly randomised, included medium to high risk patients with Ta or T1 bladder cancer and compared intravesical MMC versus BCG.

Data collection and analysis

Trial eligibility, methodological quality and data extraction were assessed independently by two reviewers. Time-to-event analysis was evaluated using log hazard ratios, with a sensitivity analysis for subgroups according to patient's risk of recurrence.

Main results

Twenty-five articles were identified but only seven were considered eligible. This represented 1901 evaluable patients in total, 820 randomised to MMC and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin arm and 834 in the BCG arm. The weighted mean log hazard ratio (variance) for tumour recurrence for the six trials was - 0.022 (0.005). This indicated no significant difference between MMC and BCG (P = 0.76). However, the meta-analysis indicated evidence of significant heterogeneity between trials (P = 0.001). A subgroup analysis of three trials that included only high risk Ta and T1 patients indicated no heterogeneity (P = 0.25) and a log hazard ratio (variance) for recurrence of -0.371 (0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, is highly significant (P = 0.0008). The seventh trial, in abstract form only, used BCG in low doses for two arms of the trial (27 mg and 13.5 mg) compared to a standard dose of mitomycin C (30 mg), and reported a significantly reduced recurrent rate with BCG (27 mg) compared to mitomycin C (P = 0.001). Only two trials included sufficient data to analyse disease progression and survival, representing a total of 681 patients; 338 randomised to BCG and 343 to MMC. There was no significant difference between MMC and BCG for disease progression (log hazard ratio + variance: 0.044 + 0.04, P = 0.16) or survival (-0.112 + 0.03, P = 0.50). Local toxicities (dysuria, cystitis, frequency, and haematuria) were associated with both MMC (30%) and BCG (44%). Systemic toxicities, such as chills, fever and malaise, were observed with both MMC and BCG (12% and 19%, respectively) although skin rash was more common with MMC.

Authors' conclusions

The data from the present meta-analysis indicate that tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

摘要

背景

膀胱內Bacillus CalmetteGuerin與Mitomycin C用於Ta及T1膀胱癌之比較

Ta及T1期之膀胱癌經尿道切除後之腫瘤復發,是重要之臨床問題。膀胱內投予mitomycin C (MMC)或bacillus CalmetteGuerin (BCG) 已證實具有預防的效果,但兩者都會帶來局部或全身的不良反應。本文即是對這兩種藥物的功效,進行系統性的回顧。

目標

對於Ta及T1膀胱癌之腫瘤復發、疾病惡化及總存活率,作一系統性之回顧及metaanalysis,以比較膀胱內灌注MMC及BCG之效果。治療造成的毒性反應也一起分析。

搜尋策略

對MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register、Cancerlit、及DARE進行廣泛搜尋,並且手動搜尋相關期刊。

選擇標準

只要是適當地隨機分派,包含中至高危險群膀胱癌,並且比較膀胱內MMC及BCG之試驗,不論任何語言,皆納入此統合分析。

資料收集與分析

試驗的妥適性、方法學品質及資料採擷由兩位回顧者獨立評估。使用log hazard ratio進行timetoevent analysis,並依病人的復發風險,進行敏感度分析。

主要結論

有25篇文章被搜尋到,但只有7篇堪稱可用。總共有1,901名病患可評估,其中820名被分派至MMC,而1,081名至BCG。共6個試驗具有足夠的資料進行統合分析,包含1,527名病患,其中693名被分派至MMC,而834名至BCG組。6個試驗中,腫瘤復發的加權後平均log hazard ratio (變異數) 是0.022 (0.005) ,亦即MMC及BCG之間並無顯著差異(p = 0.76)。然而,統合分析指出各試驗之間存有顯著的差異 (p = 0.001)。3個僅包含高危險Ta及T1病患試驗的次群體分析指出,彼此試驗設計上差異不大 (p = 0.25),因此統合分析可看出復發的log hazard ratio (變異數)是 −0.371 (0.012)。若以MMC為對照,負值的比率表示BCG組較優,而且十分顯著 (p = 0.0008)。第7個試驗,僅為摘要形式,使用兩組低劑量BCG (27 mg及13.5 mg),與標準劑量之MMC (30 mg)比較,發現使用BCG (27 mg) 比起MMC,復發率顯著降低 (p = 0.001)。只有2個試驗包含足以分析疾病進展及存活的資料,總共681名病患,338名隨機分派至BCG,343名至MMC組。MMC與BCG之間,對疾病進展 (log hazard ratio + 變異數: 0.044 + 0.04, p = 0.16) 及存活期 (log hazard ratio + 變異數: −0.112 + 0.03, p = 0.50) 皆無顯著差異。膀胱局部毒性(解尿疼痛、膀胱炎、頻尿、及血尿)在MMC (30%) 及BCG (44%) 皆可看到。全身性毒性,如寒顫、發燒及疲倦,在MMC及BCG皆有發現(各為12%及19%),然而皮疹較常見於MMC。

作者結論

本統合分析指出,膀胱內BCG比起MMC,僅對腫瘤復發高危險群的病患,顯著降低腫瘤復發。然而,疾病進展或存活期,2組並沒有差異,因此要決定使用何種藥品,也許可以根據不良反應或價格而定。

翻譯人

本摘要由臺灣大學附設醫院沈恆立翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

無結論

Plain language summary

Men and women with Ta and T1 bladder cancer were given two prophylactic treatments of BCG and Mitomycin C and compared.

Men and women who have initially been treated with surgical removal the bladder lining containing cancer (transurethral resection of the bladder) for Ta (cancer that is contained within the tissue lining of the bladder) and T1 (more invasive but not into the musculature) bladder cancer were subsequently treated with one of two additional treatments to prevent tumour recurrence (prophylactic treatment): Bacillus Calmette-Guerin, which is an weakened tubercular vaccine; and mitomycin C, a naturally occurring chemotherapeutic compound. Both agents were instilled into the bladder to treat the tumour. We assessed the comparative effectiveness of these two treatments by conducting a systematic review of the literature and quantitative meta-analysis of the results. In the meta-analysis we found no significant difference between the two treatments, despite heterogeneity, in tumour recurrence. However, BCG was more effective in patients who were at high risk of tumour recurrence. In two trials there was no significant difference in comparisons of disease progression and survival.

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