edited_Witjes_edit_Layout 1 02/10/2009 11:09 Page 40
Bladder Cancer
NMIBC patients using maximally 2,000mg twice weekly two times for they may paradoxically be ideal for treating cancers that arise in an
three weeks, with one week’s rest in between.
12
Gemcitabine was anatomically accessible site such as the bladder. In vitro
well tolerated with minimal bladder irritation and tolerable chemosensitivity data show that depending on the type of human
myelosuppression. Complete response (CR) was seen in 39% of bladder cancer cell line used, the concentration of apaziquone to
patients (seven of 18); partial response (PR) was seen in 22% (four of reach a 50% lethal dose (LD
50
) was six to 78 times lower than the
18). In a phase I trial with 10 patients performed in our hospital, concentration of mitomycin-C (MMC), which makes apaziquone a
patients were maximally treated with gemcitabine 2,000mg. Seven very promising and potent drug.
22
Subsequently, a recent phase II
patients experienced mild transient adverse effects. Gemcitabine marker lesion study of intravesical apaziquone on low- to
intermediate-risk NMIBC patients showed that six instillations of
4mg/40ml of apaziquone achieve 67% (30 of 45) histologically
There is still a role for chemotherapy in proven CR within four weeks after completion of the therapy, while
maintaining an adverse effect profile comparable with other
the treatment of non-muscle-invasive
common chemotherapeutic agents.
23
The long-term results of this
bladder cancer, but it is reserved for study will be published in 2009. The recurrence-free rate at one-
and two-year follow-up was 56.5 and 49.5%, respectively.
24
These
patients with low- and intermediate-risk
long-term results are good in comparison with the results of other
disease and bacillus Calmette-Guerin- ablative studies. In conclusion, apaziquone has some ideal
properties for intravesical treatment, suggesting that it is safe and
refractory disease.
will be effective. Current and future phase III studies will provide
additional information.
plasma levels were immeasurable or low, with peak levels between
30 and 60 minutes. Thus, intravesical gemcitabine in the dose used Taxanes
has minimal and reversible adverse effects, and plasma evaluation The taxanes docetaxel and paclitaxel are known to demonstrate
indicates that its intravesical use is safe.
13
Several other phase I antitumour activity in a wide range of cancers, including bladder
studies also show that gemcitabine 2,000mg is well tolerated cancer.
25
A recent phase I trial of NMIBC patients for whom standard
intravesically with minimal systemic absorption and toxicity.
14,15
The intravesical therapy failed shows that intravesical doxcetaxel has no
efficacy of gemcitabine was shown in several phase II studies. systemic absorption and no grade 3 or 4 dose-limiting toxicities in
Gontero et al. performed a marker lesion study in which the CR was patients.
26
Barlow et al. showed in a retrospective analysis that
56% (22 of 39).
16
Neither systemic nor local adverse effects generally salvage intravesical docetaxel resulted in 61% CR (23 of 33) after six
exceeded grade I toxicity. However, Serrata et al. found less instillations.
27
Grade 1 or 2 toxicity was seen in 36% (12 of 33). More
promising results in a marker lesion study, with a CR of 23% (six of studies are needed to evaluate efficacy. The usage of paclitaxel for
23).
17
Dalbagni et al. performed a phase II study with 30 BCG- intravesical therapy has been limited due to its high lipid solubility and
refractory NMIBC patients.
18
Patients were treated with 2,000mg poor efficiency in intravesical delivery. This difficulty can be solved by
twice weekly two times for three consecutive weeks. CR was 50%, forming paclitaxel-loaded gelatin nanoparticles or paclitaxel-
with one-year recurrence-free survival of 21%. Twelve patients had a incorporated polyglycerols.
28
In vivo studies with mice show that
tumour recurrence with a median recurrence-free survival time of mucoadhesive paclitaxel nanoparticles are more effective in reducing
only 3.6 months. Nevertheless, the authors concluded that orthotope tumour growth than taxol. Nevertheless, paclitaxel in the
gemcitabine has activity in high-risk patients and remains a viable treatment of NMIBC is still very experimental.
option for some patients who refuse cystectomy. In conclusion, also
given the efficacy of systemic gemcitabine in invasive bladder Immunotherapy
cancer, intravesical gemcitabine is safe and its efficacy promising. Sylvester et al. performed a meta-analysis of 24 clinical trials with, in
More trials are under way and awaited. total, 4,863 patients comparing TUR plus intravesical BCG to
resection alone or resection plus a treatment other than BCG.
29
They
Apaziquone found that adjuvant BCG is superior to TUR alone and more effective
Apaziquone belongs to a group of novel anticancer agents known than adjuvant chemotherapeutic drugs with regard to progression-
as bioreductive drugs. These drugs are inactive prodrugs that free survival. After a median follow-up of 2.5 years, progression was
require activation by cellular reductase enzymes in order to seen in 9.8% in the BCG-treated group versus 13.8% in the non-BCG
become toxic to the cell.
19
In the case of apaziquone, the enzyme group (odds ratio [OR] 0.73; p=0.001). This difference was even larger
DT-diaphorase plays a central role in activating the drug. However, when only maintenance trials were used: OR 0.63 (p=0.00004).
under hypoxic conditions, apaziquone is also activated in cells However, the follow-up was relatively short, resulting in a low
lacking expression of DT-diaphorase. Apaziquone has undergone absolute number of patients with progression: 6.4% in patients with
clinical evaluation against a range of tumour types but failed to papillary tumours and 13.9% in patients with CIS. Recently,
demonstrate activity when the drug was administered into the Malmström et al. performed a meta-analysis of nine trials that
bloodstream.
20,21
Based on several studies by Loadman et al. at the included 2,820 patients comparing long-term results of MMC and
University of Bradford, it would appear that the main reason for BCG treatment for NMIBC.
30
The results of this meta-analysis will be
apaziquone’s failure in the clinical setting is poor delivery. The basis published soon in European Urology. In this analysis there was no
for this hypothesis stems from the fact that apaziquone is rapidly difference in the time to first recurrence (p=0.09) between BCG and
removed from the bloodstream (half-life <10 minutes) besides poor MMC. However, in the case of BCG maintenance, a 32% reduction in
penetration through avascular tissue. Although these properties of risk of recurrence with BCG compared with MMC was found
apaziquone are a problem in terms of treating systemic disease, (p<0.0001), and there was a 28% risk increase (p=0.006) for BCG in
40 EUROPEAN UROLOGICAL REVIEW
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92