1: J Urol. 2004 Feb;171(2 Pt 1):561-9.
Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a
systematic review and meta-analysis.
Winquist E, Kirchner TS, Segal R, Chin J, Lukka H; Genitourinary Cancer Disease
Site Group, Cancer Care Ontario Program in Evidence-based Care Practice
Guidelines Initiative.
London Regional Cancer Centre, Ontario, Canada. eric.winquist@lrcc.on.ca
PURPOSE: Despite local therapy most patients with muscle invasive transitional
cell carcinoma (TCC) of the bladder die of systemic relapse, indicating a need
for effective adjunctive systemic treatment. We determined whether neoadjuvant
chemotherapy improved overall survival. MATERIALS AND METHODS: A systematic
review and meta-analysis were performed of all known randomized controlled
trials (RCTs) of neoadjuvant chemotherapy for stages II and III TCC conducted
between 1984 and 2002. RESULTS: A total of 16 eligible RCTs (3,315 patients)
were identified. Of these trials 11 (2,605 patients) provided data suitable for
a meta-analysis of overall survival and the pooled HR was 0.90 (95% CI 0.82 to
0.99, p = 0.02). Eight trials used cisplatin based combination chemotherapy and
the pooled HR was 0.87 (95% CI 0.78 to 0.96, p = 0.006), consistent with an
absolute overall survival benefit of 6.5% (95% CI 2 to 11%) from 50% to 56.5%.
Reported progression-free survival data were insufficient for meta-analysis but
they appeared concordant with overall survival results. Mortality due to
combination chemotherapy was 1.1%. A major pathological response was associated
with improved overall survival in 4 trials.CONCLUSIONS Neoadjuvant cisplatin
based chemotherapy improves overall survival in muscle invasive TCC. The size of
the effect is modest and combination chemotherapy can be administered safely
without adverse outcomes resulting in delayed local therapy. An optimal
chemotherapy regimen was not identified and newer regimens have not been tested
in RCTs in this setting. Further efforts to identify the patients most likely to
benefit from neoadjuvant therapy are necessary to optimize its use.
Publication Types:
Meta-Analysis
Review
Review, Academic
PMID: 14713760 [PubMed]
2: Am J Clin Oncol. 2003 Aug;26(4):402-7.
Impact of intravesical chemotherapy versus BCG immunotherapy on recurrence of
superficial transitional cell carcinoma of the bladder: metaanalytic
reevaluation.
Huncharek M, Kupelnick B.
Division of Radiation Oncology, Department of Clinical Oncology, Marshfield
Clinic Cancer Center, Wisconsin, USA.
Bacille Calmette-Guerin (BCG) immunotherapy is currently considered the most
effective agent in the management of superficial bladder cancer. Prior work
suggests that the efficacy of intravesical chemotherapy in preventing tumor
recurrence may be greater than previously suggested. This latter finding,
therefore, brings into question the currently perceived superiority of BCG
treatment for this disease. A metaanalysis was performed to rigorously examine
existing data relevant to this relationship and to quantify the relative
efficacy of both treatment modalities on tumor recurrence. A prospective
protocol outlining the above-noted metaanalysis was initially developed followed
by a thorough search of the existing published literature using strict
eligibility criteria. Nine randomized trials were found that met protocol
specifications. These reports contained data on 2,261 patients that were
statistically combined using a fixed effects model (Peto). The outcome of
interest was the proportion of patients with recurrence at 1, 2, and 3 years
following intravesical therapy (i.e., a summary odds ratio, ORp). Combining all
nine trials using 1-year recurrence as the endpoint demonstrated significant
statistical heterogeneity, although the ORp favored BCG over intravesical
chemotherapy (0.89 [0.74-1.07]). This precluded statistical pooling of the data
and sensitivity analyses were performed to determine the source of
heterogeneity. These tests showed that the prior chemotherapy treatment in a
large number of the randomized trials biased study results in favor of the BCG
arms. Once the data were stratified on presence or absence of prior drug
treatment, intravesical chemotherapy reduced 1-, 2-, and 3-year recurrence by
21% to 82% versus BCG, depending on the endpoint of interest. The available data
suggest that clinical trials directly comparing intravesical BCG to intravesical
chemotherapy must stratify on the presence or absence of prior chemotherapy.
Recurrences following prior intravesical chemotherapy appear less responsive to
drug therapy than those in chemotherapy-naive patients. The currently perceived
superiority of BCG therapy may therefore be an artifact of this phenomenon,
since most randomized trials include chemotherapy failures in their chemotherapy
treatment arms.
Publication Types:
Meta-Analysis
PMID: 12902895 [PubMed]
3: Lancet. 2003 Jun 7;361(9373):1927-34.
Comment in:
Lancet. 2003 Jun 7;361(9373):1922-3.
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and
meta-analysis.
Advanced Bladder Cancer Meta-analysis Collaboration.
BACKGROUND: Controversy exists as to whether neoadjuvant chemotherapy improves
survival in patients with invasive bladder cancer, despite randomised controlled
trials of more than 3000 patients. We undertook a systematic review and
meta-analysis to assess the effect of such treatment on survival in patients
with this disease. METHODS: We analysed updated data for 2688 individual
patients from ten available randomised trials. FINDINGS: Platinum-based
combination chemotherapy showed a significant benefit to overall survival
(combined hazard ratio [HR] 0.87 [95% CI 0.78-0.98, p=0.016]; 13% reduction in
risk of death; 5% absolute benefit at 5 years [1-7]; overall survival increased
from 45% to 50%). This effect was observed irrespective of the type of local
treatment, and did not vary between subgroups of patients. The HR for all
trials, including those using single-agent cisplatin, tended to favour
neoadjuvant chemotherapy (HR=0.91, 95% CI 0.83-1.01) although this tendency was
not significant (p=0.084). Although platinum based combination chemotherapy was
beneficial, there was no evidence to support the use of single-agent platinum;
indeed, there was a significant difference in the effect between these groups of
trials (p=0.044). INTERPRETATION: This improvement in survival encourages the
use of platinum-based combination chemotherapy for patients with invasive
bladder cancer.
Publication Types:
Meta-Analysis
Review
Review, Academic
PMID: 12801735 [PubMed]
4: J Urol. 2003 Jun;169(6):1975-82.
Tumor markers in the diagnosis of primary bladder cancer. A systematic review.
Glas AS, Roos D, Deutekom M, Zwinderman AH, Bossuyt PM, Kurth KH.
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center,
OLVG, Amsterdam, The Netherlands.
PURPOSE: We systematically reviewed the available evidence, and obtained and
compared summary estimates of the sensitivity and specificity of cytology and
the urine based markers bladder tumor antigen, BTA stat (Polymedco, Redmond,
Washington), BTA TRAK (Polymedco), NMP22 (Matritech, Cambridge, Massachusetts),
telomerase and fibrin degradation product in detecting primary bladder cancer.
MATERIALS AND METHODS: Studies on the diagnosis of primary bladder cancer
published from 1990 through November 2001 in English and German were retrieved
from MEDLINE and EMBASE data bases. In our research we included studies that
evaluated 1 or more of the markers, used cystoscopy as the reference standard
and allowed the construction of a 2 x 2 contingency table for a per patient
analysis. The data plus items on study and clinical characteristics were
extracted by 2 observers. Sensitivity and specificity for each marker were
estimated using a bivariate random effect meta-analysis. A multivariable
analysis was performed to explain study variation. RESULTS: A total of 42
studies were included in our review. Only 2 studies were available on fibrin
degradation product, hence a meta-analysis was not possible. Cytology had the
best specificity at 94% (95% CI: 90% to 96%). This figure was significantly
better than that of the other markers except for telomerase (specificity 86%
[71% to 94%]). Telomerase had the best sensitivity (75% [71% to 79%]) but it was
not significantly better than that of BTA stat (70% [66% to 74%]). Case control
designs yielded lower values for sensitivity for the tumor markers cytology,
bladder tumor antigen and BTA stat. CONCLUSIONS: Cytology has the best
specificity and telomerase the best sensitivity. However, none of the markers
studied here is sensitive enough to be recommended for daily routine.
Publication Types:
Meta-Analysis
Review
Review, Academic
PMID: 12771702 [PubMed]
5: J Urol. 2003 Jan;169(1):90-5.
Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder
cancer: a formal meta-analysis of comparative studies on recurrence and
toxicity.
Bohle A, Jocham D, Bock PR.
Department of Urology, Medical University of Lubeck, Lubeck, Germany.
PURPOSE: We compare the therapeutic efficacy and toxicity of intravesical
bacillus Calmette-Guerin (BCG) with mitomycin C on recurrence of stages Ta and
T1 bladder carcinoma. MATERIALS AND METHODS: Combined published and unpublished
data from comparative studies on BCG versus mitomycin C for superficial bladder
carcinoma considering possible confounding factors were analyzed. Odds ratio
(OR) and its 95% CI were used as primary effect size estimate. Toxicity data
were evaluated descriptively. RESULTS: In 11 eligible clinical trials 1,421
patients were treated with BCG and 1,328 were treated with mitomycin C. Within
the overall median followup time of 26 months 38.6% of the patients in the BCG
group and 46.4% of those in the mitomycin C group had tumor recurrence. In 7 of
11 studies BCG was significantly superior to mitomycin C, in 3 studies no
significant difference was found, while in 1 study mitomycin C was significantly
superior to BCG. An overall statistically significant superiority of BCG versus
mitomycin C efficacy in reducing tumor recurrence was detected (OR 0.56, 95% CI
0.38 to 0.84, p = 0.005). In the subgroup treated with BCG maintenance all 6
individual studies showed a significant superiority of BCG over mitomycin C (OR
0.43, 95% CI 0.35 to 0.53, p <0.001). In 4 of the 5 studies with reported data
on toxicity BCG associated cystitis was significantly more frequent than in the
mitomycin C group (53.8% versus 39.2%). The combined cystitis OR was 1.81 (95%
CI 1.48 to 2.23, p <0.001). The OR for cystitis in the BCG maintenance group did
not significantly differ from that in the nonmaintenance therapy group.
CONCLUSIONS: The results suggest superiority of BCG over mitomycin C for
prevention of tumor recurrences in the combined data and particularly in the BCG
maintenance treatment subgroup, irrespective of the actual (intermediate or
high) tumor risk status. The toxicity with BCG is higher but does not differ
between BCG maintenance and nonmaintenance groups.
Publication Types:
Meta-Analysis
PMID: 12478111 [PubMed]
6: J Urol. 2002 Nov;168(5):1964-70.
Intravesical bacillus Calmette-Guerin reduces the risk of progression in
patients with superficial bladder cancer: a meta-analysis of the published
results of randomized clinical trials.
Sylvester RJ, van der MEIJDEN AP, Lamm DL.
European Organisation for Research and Treatment of Cancer Data Center,
Brussels, Belgium.
PURPOSE: We determine if intravesical bacillus Calmette-Guerin (BCG) reduces the
risk of progression after transurethral resection to stage T2 disease or higher
in patients with superficial (stage Ta, T1 or carcinoma in situ) bladder cancer.
MATERIALS AND METHODS: A meta-analysis was performed of the published results of
randomized clinical trials comparing transurethral resection plus intravesical
BCG to either resection alone or resection plus another treatment other than
BCG. RESULTS: We identified 24 trials with progression information on 4,863
patients. Based on a median followup of 2.5 years and a maximum of 15 years, 260
of 2,658 patients on BCG (9.8%) had progression compared to 304 of 2,205
patients in the control groups (13.8%), a reduction of 27% in the odds of
progression on BCG (OR 0.73, p = 0.001). The percent of patients with
progression was low (6.4% of 2,880 patients with papillary tumors and 13.9% of
403 patients with carcinoma in situ, reflecting the short followup and
relatively low risk patients entered in many of the trials. The size of the
treatment effect was similar in patients with papillary tumors and in those with
carcinoma in situ. However, only patients receiving maintenance BCG benefited.
There was no statistically significant difference in treatment effect for either
overall survival or death due to bladder cancer. CONCLUSIONS: Intravesical BCG
significantly reduces the risk of progression after transurethral resection in
patients with superficial bladder cancer who receive maintenance treatment.
Thus, it is the agent of choice for patients with intermediate and high risk
papillary tumors and those with carcinoma in situ.
Publication Types:
Meta-Analysis
PMID: 12394686 [PubMed]
7: Anticancer Res. 2001 Jan-Feb;21(1B):765-9.
Impact of intravesical chemotherapy on recurrence rate of recurrent superficial
transitional cell carcinoma of the bladder: results of a meta-analysis.
Huncharek M, McGarry R, Kupelnick B.
Division of Radiation Oncology, Department of Clinical Oncology, Marshfield
Clinic Cancer Center, Marshfield, WI, USA. metaresearch@hotmail.com
BACKGROUND: The impact of in tranvesical chemotherapy on preventing recurrence
of superficial transitional cell carcinoma of the bladder is controversial. The
objective of this report is to present a meta-analysis of the available clinical
trial data to quantify the effect of intravesical chemotherapy on tumor
recurrence following trans-urethral resection (TURB) in patients with recurrent
superficial bladder cancer. METHODS: A prospective study protocol outlining a
meta-analysis was developed followed by a thorough search of the existing
published literature using strict eligibility criteria. Eight randomized trials
were found which met protocol specifications. These studies contained data on
1,609 patients which were statistically combined using a fixed effects model
(Peto). The outcome of interest was the proportion of patients with tumor
recurrence at one, two and three years post-TURB. RESULTS: Combining all 8
studies using 1 year recurrence as the outcome measure yielded a Peto odds ratio
(ORp) of 0.62, demonstrating a 38% reduction in one year recurrence among
patients treated with intravesical chemotherapy versus TURB alone. Using 2 and 3
year recurrence as the outcome measure yielded ORp's of 0.46 and 0.35
respectively, favoring TURB + intravesical chemotherapy versus TURB alone. A
statistical test for heterogeneity (Q) showed the 2 and 3 year outcome data to
be heterogeneous (i.e. the studies are not measuring an effect of the same
magnitude). Sensitivity analyses showed that drug type appeared to account for
the observed heterogeneity with a stratified analysis demonstrating that
adriamycin is less effective in reducing subsequent tumor recurrences than all
other drugs studied. CONCLUSION: Intravesical chemotherapy appears to have a
major impact on decreasing the chance of recurrence of recurrent superficial
bladder cancer. Three year recurrence is decreased by as much as 70% when
compared with TURB alone. These data are in contrast to prior analyses
suggesting only modest efficacy of such treatment in this clinical setting.
Publication Types:
Meta-Analysis
PMID: 11299841 [PubMed]