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New Treatments for Non-muscle-invasive Bladder Cancer
the trials without maintenance. In addition, this meta-analysis 40mg has been shown to be more effective in reducing recurrences
showed no statistically significant differences regarding progression, (17 versus 58%) in patients with NMIBC.
38
Gofrit et al. studied patients
overall survival and cancer-specific survival between the two with high-grade NMIBC.
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Patients were treated with either a
treatments. Earlier, Lamm et al. also showed significantly improved prophylactic protocol (MMC 40mg) after radical TUR or with an
recurrence-free survival time in high-risk NMIBC with BCG ablative protocol (MMC 80mg) in cases of a visible tumour or CIS. In
maintenance therapy but found increased adverse effects. Five per the prophylactic protocol (n=24), after a mean follow-up of 35.3
cent of patients had to stop during induction therapy and 20% of months, 15 patients (62.5%) were recurrence-free. The ablative
patients during maintenance therapy.
31,32
There is a need for protocol was administered to 28 patients, with a complete ablation
treatments as effective as BCG but with fewer adverse effects. rate of 75%. After a mean follow-up of 20 months, 80.9% of these
patients were recurrence-free. The authors concluded that this
Mycobacterial Cell Wall–DNA Complex treatment is safe and effective.
Cell wall skeletons isolated from many bacteria have been shown
to possess anticancer activity. The anticancer activities of such Data of 90 intermediate- and high-risk NMIBC patients treated with
preparations have been attributed to the activation of immune thermochemotherapy were published in 2004.
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The overall recurrence
effector cells and not to a direct effect on cancer cell division. rates were 14.3 and 24.6% at one year and two years, respectively. In
Mycobacterial cell wall–DNA complex (MCC) is a new immuno- this study a sub-analysis was performed for BCG treatment failures.
stimulant prepared from Mycobacterium phlei. It has an indirect The recurrences rates were 23 and 41% at one year and two years,
effect via the induction of anticancer cytokines and a direct effect respectively. Recently, the results of thermochemotherapy in patients
by the induction of apoptosis. Morales et al. used MCC to treat 61 with CIS were published (n=51, of whom 34 were BCG failures).
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The
CIS patients with 4mg once weekly for six weeks and then monthly initial cytology- and biopsy-proven CR was 92%. The recurrence rate
for one year. This resulted in recurrence-free survival of 62.5% of after two-year follow-up was 49%. Adverse effects (bladder
patients at 12 weeks, 49.3% at 24 weeks and 41.1% at 60 weeks complaints) were generally mild and transient. More long-term
after therapy and with minimal toxicity.
33
analysis is needed to confirm these promising results.
MCC is also studied in patients with CIS for whom BCG treatment is Electromotive Drug Administration
failing. Patients received six weekly instillations of MCC 4mg (n=25) or Electromotive drug administration (EMDA) is another method to
8mg (n=30) followed by three weekly instillations at weeks 12 and 24. enhance drug delivery through the bladder urothelium by creating
The 4mg group had 27.3% CR at 26 weeks, and the 8mg group had an electrical gradient between chemotherapeutic agent and bladder
46.4% CR at the same point. MCC was well tolerated by both dose wall. In laboratory studies, EMDA using MMC demonstrated
groups.
34
These results make MCC very promising in patients with CIS markedly increased transport rates compared with passive
for whom BCG treatment is failing. transport. Di Stasi et al. performed a prospective, randomised study
with high-risk NMIBC patients comparing passive MMC,
Lactobacillus casei electromotive-enhanced MMC and BCG treatment.
42
The CR at six
Orally administered Lactobacillus casei (LC) has been shown to have months was 31% for passive MMC, 58% for electromotive MMC and
antitumour effects
35,36
in vitro and in vivo. In the prospective, 64% for BCG. The median time to recurrence was 20, 35 and 26
randomised, controlled study by Naito et al., patients with NMIBC months, respectively. Peak plasma MMC was significantly higher
were treated with TUR followed by an immediate epirubicin following electromotive MMC than after passive MMC (43 versus
instillation. Afterwards, patients were treated either with solely 8ng/ml). Thus, this study shows that intravesical electromotive
intravesical epirubicin (30mg/ml) or with epirubicin and oral LC for administration increases bladder uptake of MMC, resulting in an
one year. The epirubicin plus LC group had a significantly higher three- improved response rate. In addition, adverse effects were more
year recurrence-free survival rate compared with the solely epirubicin common in the EMDA group compared with the MMC group but
group (74.6 versus 59.9%), with no significant difference in adverse were still significantly less than the BCG group.
effects. This combination seems to be effective, and costs are low.
Di Stasi et al. also studied sequential BCG and electromotive MMC
Interferon-α versus BCG monotherapy in a randomised, controlled trial.
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Patients
Another effective combination is BCG and interferon-α (IFN-α). This were treated either with six weekly BCG instillations (n=105) or
combination was studied in a large multicentre phase II trial.
37
In total, with two weekly BCG instillations followed by three weekly
467 patients in whom BCG failed were treated with low-dose BCG plus electromotive-enhanced MMC instillations (n=107). Complete
IFN-α. With a median follow-up of 24 months, 45% remained free of responders underwent maintenance treatment for up to one year.
tumour compared with 59% in the BCG-naïve group (n=536). The Patients treated with the combination therapy had a higher disease-
authors concluded that combination therapy was effective in BCG- free interval (69 versus 21 months; p=0.0012), lower recurrence rate
naive patients and those for whom BCG therapy was failing. (41.9 versus 57.9%; p=0.0012) and lower progression rate (9.3 versus
21.9%; p=0.004) than patients treated solely with BCG. The authors
New Agent Delivery presumed that BCG-induced inflammation might increase the
Microwave-induced Thermochemotherapy permeability of the bladder for MMC and exert its effect.
Another option to increase efficacy of NIMBC treatments is to
increase the dose of the therapeutic agent to the urothelium. An Photodynamic Therapy
effective way to achieve this is to use intravesical microwave-induced Intravesical photodynamic therapy (PDT) is an approach using
thermotherapy to enhance drug effectiveness. In a multicentre trial, photosensitisers that selectively bind to bladder tumours and
intravesical thermotherapy (40 minutes; 42ºC) combined with MMC cause tumour ablation applying intravesical light. Waidelich et al.
EUROPEAN UROLOGICAL REVIEW 41