Seminar article
Management of the first recurrence of T1G3 bladder cancer: Does intravesical chemotherapy deserve a chance?

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Abstract

Objective

Is there a role for intravesical chemotherapy in a patient who has a first recurrence of a T1G3 bladder cancer?

Materials and Methods

American and European guidelines are checked for their advise, and recent literature on this topic is reviewed to critically test the advice and look for potential alternative strategies in this particular case.

Results

Guidelines indicate that a patient with a pT1G3 tumor should initially receive BCG intravescial therapy, although cystectomy can be considered. In case of a recurrence, cystectomy is the treatment of choice. Although several new drugs and strategies are under development and in clinical research, there is only experience to some degree in BCG failing patients with thermochemotherapy, with promising results.

Conclusions

In a patient with a recurrence of T1G3 bladder cancer after BCG therapy, progression and subsequent cancer death is the threat. Guideline standard is radical surgery. Alternative possibilities are still limited.

Introduction

Guideline advice in a first recurrence of a T1G3 bladder cancer.

What can we learn from the 2007 AUA guideline on bladder cancer [1]. T1G3 bladder cancer is considered at high risk for recurrence and progression. The therapeutic advice for these patients is induction and maintenance intravesical BCG. Cystectomy should be considered in selected patients. Radical cystectomy is treatment of choice in those patients failing on intravesical BCG, although in selected patients, a 2nd induction course with BCG could be given. The 2008 EAU guideline on TaT1 bladder cancer is quite similar [2]. Again, a patient with a T1G3 tumor is clearly considered at high risk, and therapy includes at least 1 year of intravesical BCG, whereas a radical cystectomy is optional. Also in this guideline, radical cystectomy is considered the treatment of choice in cases where there is no response to intravesical BCG.

The reasons to chose for BCG in the first place seem obvious. Although BCG is more toxic, it is more effective than intravesical chemotherapy and it even lowers the change of progression to muscle-invasive disease. In the largest meta-analysis on this subject, there was a documented 27% reduction in progression with intravesical BCG compared with intravesical chemotherapy (an absolute reduction from 13.8% to 9.8%), which was even 37% when only maintenance BCG was considered [3]. In a subsequent meta-analysis, where only intravesical mitomycin-C (MMC) was compared with BCG, Böhle et al. came to similar conclusions [4]. They reported a 23% reduction in progression rates (34% with maintenance BCG), which was an absolute reduction from 9.4% to 7.7%. Although the optimal period of maintenance BCG therapy is still unknown, BCG should not be given for too long; for example, until there is documented progression to muscle invasive disease? The fate of patients that have progression from non-muscle-invasive to muscle-invasive disease shows that the window of opportunity is limited [3], [5], [6]. Schrier et al., for example, found a 3-year cancer-specific survival rate of >90% for all non-muscle-invasive tumors, approximately 65% for patients presenting primarily with an invasive bladder tumor, and less than 40% for patients with invasive tumors matched for stage with the group of primary invasive tumours, but with the history of a non-muscle-invasive bladder tumor and subsequent progression [5].

The first conclusion is that the guidelines are clear and correct in their advise: in case of a recurrence after a T1G3 bladder tumor which, according to the guideline, should have been treated with BCG, one should discuss a cystectomy.

Section snippets

Alternative intravesical chemotherapy

However, there are some potential exceptions. Additional BCG could be considered if there is a low grade and low stage recurrence during or within 1 year after BCG therapy. Additional BCG could also be considered in case of a late (>1 year after BCG) high grade or high stage recurrence.

Intravesical chemotherapy could be used in patients where BCG was not administered properly. This is usually due to toxicity, seen in approximately 20% of patients, and usually during the first 6 months [7].

Device assisted instillation therapy

An interesting new development is to increase the efficacy of intravesical chemotherapy with a device. The first example is electromotive drug administration (EMDA), where the efficacy (penetration) of intravesical MMC is increased with an electrical gradient between the bladder contents (the catheter) and the bladder wall (the patient). Di Stasi et al. published long-term results of a randomized trial in which they compared intravesical BCG in one arm vs. sequential BCG and EMDA with MMC in

Summary

In a patient with a recurrence of T1G3 bladder cancer after BCG therapy, progression and subsequent cancer death is the problem. In exceptional cases BCG can be tried again, such as after inadequate BCG therapy, a long interval, or a low risk recurrence. Standard therapy according to guidelines is radical surgery. Does intravesical chemotherapy deserve a chance? Conventional and newer drugs probably not or not yet. EMDA, although very promising, has not been tested in BCG failures.

References (18)

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Cited by (5)

  • The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: External validation of the EORTC risk tables

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    Five meta-analyses have demonstrated that BCG is more effective than intravesical chemotherapy for recurrence, mainly when BCG is administered using some form of maintenance [15–19]. Likewise, although the ability of BCG to prevent disease progression remains controversial [14], various meta-analyses have shown that BCG lowers the chance of progression to muscle-invasive disease [20–22]. Probably if a second-look TUR had been done and if BCG had been given for >6 mo, the recurrence and progression rates might have been even lower than those observed in this study.

  • Variations in treatment policies and outcome for bladder cancer in the Netherlands

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    Patients in high-volume centers exhibited lower mortality rates than in low-volume centers. American and European guidelines indicate that a patient with a pT1G3 tumor should initially receive BCG intravesical therapy, although cystectomy can be considered.4,12,13 The majority (90%) of patients with the high grade T1-tumours in our study received initially local therapy only (TUR-BT with BCG-instillations).

  • Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium

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    T1 bladder tumors are subject to many investigations and debates. Although T1G3 lesions represent a small group (<10% of all tumors), the clinical management remains a dynamic process, and despite the implementation of several known risk factors including multifocality, associated CIS, the presence of multifocal T1 disease, the presence of residual tumor at restaging transurethral resection (TUR), and prior history of bacillus Calmette-Guérin (BCG) treatment, definite guidelines for selecting patients' initial treatment are pending [132–146]. In addition, T1G3 lesions remain enigmatic in terms of both their natural history and their molecular profile: some tumors destined to be muscle invasive will be sampled on their journey towards muscle and thus fall into the T1 classification, when in molecular terms they are fully fledged invasive tumors.

  • p53 immunohistochemistry in bladder cancer-a new approach to an old question

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    Thus, T1 lesions are subject to many investigations and debates. Despite the fact that these tumors represent only a small group (<10% of all bladder tumors), the clinical management remains a dynamic process and despite the implementation of several known clinical risk factors including multifocality, associated CIS, the presence of residual tumor at rebiopsy, and previous treatment with bacillus Calmette-Guérin (BCG) treatment, definite guidelines for selecting patients' initial treatment are pending [53–60]. In addition, T1G3 lesions remain enigmatic in terms of both their natural history and their molecular profile: some tumors destined to be muscle-invasive will be sampled on their journey towards muscle and thus fall into the T1 classification, when in molecular terms they are fully fledged invasive tumors.

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