Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
TITLE
2
Pathological T0 following cisplatin-based neo-adjuvant chemotherapy for muscle-invasive bladder
3
cancer: a network meta-analysis
4 5
Hyung Suk Kim, Chang Wook Jeong, Cheol Kwak, Hyeon Hoe Kim, Ja Hyeon Ku
6
Department of Urology, Seoul National University Hospital, Seoul, Korea
7 8
Running title: Neo-adjuvant chemotherapy for muscle-invasive bladder cancer
9 10
Correspondence
11
Ja Hyeon Ku, M.D. PhD.
12
Department of Urology, Seoul National University Hospital,
13
101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
14
Tel: 82-2-2072-0361, Fax: 82-2-742-4665, E-mail: [email protected]
15 16
Other authors
17
Hyung Suk Kim, M.D.
18
Department of Urology, Seoul National University Hospital
19
101 Daehak-ro, Jongno-gu, Seoul 110-744,Korea
20
Tel: 82-2-2072-1968, Fax: 82-2-742-4665, E-mail: [email protected]
21 22
Chang Wook Jeong, M.D.,-Ph.D.
23
Department of Urology, Seoul National University Hospital
24
101, Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea
25
Tel: 82-2-2072-3899, Fax: 82-2-762-2428, E-mail: [email protected]
26 27
Cheol Kwak, M.D., Ph.D.
28
Department of Urology, Seoul National University Hospital
29
101 Daehak-ro, Jongno-gu, Seoul 110-744,Korea 1
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
Tel: 82-2-2072-0817, Fax: 82-2-742-4665, E-mail: [email protected]
2 3
Hyeon Hoe Kim, M.D., PhD.
4
Department of Urology, Seoul National University Hospital,
5
101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
6
Tel: 82-2-2072-2425, Fax: 82-2-742-4665, E-mail: [email protected]
7 8
Financial Support: none
9
Disclosure of Potential Conflicts of Interest: The authors have declared that no competing interests
10
exist.
11 12
Word counts: Abstract (246), Text (3,033)
13
Total numbers of Figures and Tables: Four (4) figures and two (2) tables in the main text; three (3)
14
supplementary figures
15
2
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Statement of translational relevance
1 2 3
Although radical cystectomy with bilateral pelvic lymphadenectomy may be curable treatment option for
4
some patients with muscle invasive bladder cancer (MIBC), a substantial portion of patients experienced
5
disease recurrence after surgery. Therefore, the administration of neoadjuvant chemotherapy (NACH)
6
prior to surgery is currently recommended in almost all MIBC patients for the improvement of patient’s
7
survival.
8 9
Based on previously published articles, tumour down-staging to pathological complete response (pCR)
10
after NACH is considered to be a surrogate predictor of favourable outcomes after radical cystectomy for
11
MIBC. However, the optimal NACH regimen to achieve pCR has not yet been definitively established.
12 13
In this study, we analysed initial and updated publications along with subsequent meta-analyses with
14
respect to NACH for MIBC patients. Additionally, we sought to assess and compare the pCR rates of
15
various NACH regimens in patients with muscle-invasive urothelial carcinoma of the bladder on the basis
16
of the meta-analysis.
17
3
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract
1 2 3
Purpose: To systematically assess and compare the relationship between various NACH regimens and
4
pCR in MIBC patients.
5
Experimental design: We performed a literature search of PubMed, Embase, and the Cochrane Library
6
for all articles published prior to March 2015 and according to the Preferred Reporting Items for
7
Systematic Review and Meta-analysis (PRISMA) guidelines. There were 17 articles that met the study
8
eligibility criteria and were selected for the final analysis. A direct pair-wise meta-analysis was performed
9
for studies that compared the same regimen. Finally, a Bayesian network meta-analysis was used to
10
indirectly compare the regimens.
11
Results: In a pair-wise meta-analysis, the methotrexate/vinblastine/Adriamycin®/cisplatin (MVAC)
12
(odds ratio [OR] 4.36, 95% confidence interval [CI] 2.71–7.02) and gemcitabine/cisplatin (GC) regimens
13
(OR 4.92, 95% CI 2.93–8.24) were significantly associated with a better pCR than RC alone. In a
14
network meta-analysis, there was no significant difference in terms of pCR achievement between the GC
15
and MVAC regimens (OR 1.14, 95% CI 0.85–1.70). However, in a sub-group network meta-analysis that
16
only included prospective randomized trials, the MVAC regimen was significantly correlated with a
17
higher rate of pCR (OR 5.75, 95% CI 1.96–24.18).
18
Conclusions: The results of this meta-analysis suggest that a GC regimen was associated with a pCR rate
19
that was similar to that of a MVAC regimen based on retrospective data, but only the MVAC regimen
20
was proven to achieve pCR in prospective randomized trials. Additional prospective randomized trials
21
comparing both regimens will be necessary to establish the optimal NACH regimen.
22 23
KEYWORDS: Urinary bladder neoplasm, neo-adjuvant chemotherapy, cystectomy, risk assessment
4
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
Introduction
2 3
Radical cystectomy (RC) with bilateral pelvic lymphadenectomy is the recommended treatment for
4
patients with muscle-invasive bladder cancer (MIBC). This is a curative procedure for many patients;
5
however, some patients may experience disease recurrence (1-3). Bladder cancers usually recur distantly
6
rather than loco-regionally. In patients with pT2 and pT3/pT4 tumours, local recurrence has been
7
observed in 3–4% and 11–16% of patients, respectively, whereas distant failure has occurred in 10–27%
8
and 19–35% of patients, respectively (1, 4). The latter findings make a strong argument for the
9
administration of perioperative chemotherapy, since a failure to cure is usually due to the presence of
10
occult metastatic disease at sites that are beyond the margins of local therapy. In addition, these findings
11
indicate that radical surgery alone may be inadequate for the majority of patients with locally advanced
12
bladder cancer. Thus, some form of effective systemic treatment is required in order to improve patient
13
survival. A meta-analysis that included 11 randomised studies suggested that neo-adjuvant chemotherapy
14
(NACH) followed by RC was associated with a 5% improvement in overall survival and a 9%
15
improvement in disease-free survival (5). Therefore, NACH is recommended for nearly all MIBC patients.
16 17
Despite this recommendation, only 15–20% of MIBC patients have received NACH, though the
18
prevalence has increased over time (6). Importantly, the optimal regimen of NACH is controversial
19
because few studies have compared the efficacy of the different NACH regimens. The European Society
20
of Medical Oncology does not recommend one particular NACH regimen (7). The National
21
Comprehensive Cancer Network (NCCN) recommends the use of gemcitabine/cisplatin (GC) NACH
22
based
23
methotrexate/vinblastine/Adriamycin®/cisplatin (MVAC) regimen as the preferred neo-adjuvant
24
regimens (8). However, this trial was performed in patients with advanced and metastatic bladder cancer,
25
and therefore the results may not be applicable to patients in a neo-adjuvant setting.
on
the
data
from
several
comparative
trials,
as
well
as
the
26 27
Patients that do not respond to NACH may experience reduced quality of life and substantial delays in
28
definitive treatment. Tumour down-staging might be a valuable measurement for individualising MIBC
29
treatment until adequate molecular markers to detect chemo-sensitive tumours are identified. Previous 5
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
studies have demonstrated that NACH increased the rate of down-staging, leading to an improved
2
prognosis (9-11). In contrast, a lack of response to NACH was associated with a significantly higher rate
3
of local and distant recurrence, and with lower overall survival (12). Therefore, several investigators have
4
suggested that tumour down-staging might be used as a surrogate end-point for overall survival (13). In
5
particular, down-staging to pT0 (pathological complete response, pT0N0M0; pCR) is currently the best
6
predictor of favourable outcomes (14, 15). The results of the SWOG 8710 trial demonstrated that patients
7
who achieved pCR status after RC had an 80% probability of survival at five years (14). Patients with
8
pCR in the four main prospective NACH trials experienced similar survival times, which exceeded those
9
of the groups that did not achieve pCR (15). A recent meta-analysis also demonstrated that patients who
10
achieved pCR after NACH had better overall and recurrence-free survival times than those who did not
11
achieve pCR (16).
12 13
In this study, we analysed initial and updated publications along with subsequent meta-analyses with
14
respect to NACH for MIBC patients. Additionally, we sought to assess and compare the pCR rates of
15
various NACH regimens in patients with muscle-invasive urothelial carcinoma of the bladder on the basis
16
of the meta-analysis.
17
6
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Materials and Methods
1 2 3
The meta-analysis was performed in agreement with the recommendations of the preferred reporting
4
items for systematic reviews and meta-analyses (PRISMA) (17).
5 6
Search strategy
7
A comprehensive literature search was conducted of studies published before March 30, 2015, using
8
PubMed, Embase, and the Cochrane Library. The search was restricted to articles for which the full-text
9
publications were available in English. The following key words were used: (urothelial cancer OR
10
urinary bladder OR bladder cancer OR bladder carcinoma) AND (neo-adjuvant chemotherapy OR
11
induction chemotherapy OR pre-operative chemotherapy) AND (radical cystectomy). The reference lists
12
from eligible studies and meta-analyses were also reviewed. Two independent evaluators (H.S.K., C.W.J.)
13
selected the articles and any discrepancies were resolved.
14 15
Eligible criteria
16
We defined study eligibility according to predefined selection criteria (17).
17 18
Population: Patients with muscle-invasive urothelial carcinoma of the bladder.
19
Interventions: Cisplatin-based combination NACH followed by RC.
20
Comparators: RC only.
21
Outcome: pCR rate.
22
Study design: Retrospective or prospective .
23 24
Published studies were included if they (1) included patients with muscle-invasive urothelial carcinoma
25
of the bladder; (2) evaluated neo-adjuvant cisplatin-based combination chemotherapy; and (3) reported
26
pCR following RC. The exclusion criteria were the following: non-human studies, review articles, letters,
27
editorial comments, case reports, and articles that did not include raw data. Studies that included neo-
28
adjuvant radiotherapy, single agent cisplatin chemotherapy, carboplatin-based chemotherapy, or studies in
29
which chemotherapy was delivered non-intravenously were also excluded. If multiple publications from 7
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
the same study or institution were available, we included the publication with the largest number of cases
2
and the most applicable information.
3 4
Data extraction
5
Two authors (C.K. and H.H.K.) completed an independent review of 1,337 articles. A total of 1,238
6
articles were excluded on the basis of the titles and abstracts, and the full-text versions of 99 articles were
7
evaluated. In accordance with the inclusion criteria, a final selection of 17 articles was performed (14, 18-
8
33) and any discrepancies were resolved. A PRISMA flow chart depicting the process for the systematic
9
literature search and selection of the studies is shown in Figure 1.
10 11
The following information was recorded for each eligible trial: author name, year of publication,
12
geographic location, period of recruitment, study design, total number of patients, median age, percentage
13
of patients achieving pCR, and systemic NACH regimen administered.
14 15
Statistical analysis
16
If two or more studies compared the same regimen, a direct meta-analysis was conducted and the random
17
effects odds ratio (OR) was calculated, according to the methods described by DerSimonian and Laird.
18
The Chi2 and I2 tests were used to assess heterogeneity of the ORs between studies. Significant
19
differences were defined as 50% for the I2 test. Publication bias was
20
evaluated for the OR analysis using Egger’s linear regression, the Begg rank correlation, and funnel plots.
21
A p
1
TITLE
2
Pathological T0 following cisplatin-based neo-adjuvant chemotherapy for muscle-invasive bladder
3
cancer: a network meta-analysis
4 5
Hyung Suk Kim, Chang Wook Jeong, Cheol Kwak, Hyeon Hoe Kim, Ja Hyeon Ku
6
Department of Urology, Seoul National University Hospital, Seoul, Korea
7 8
Running title: Neo-adjuvant chemotherapy for muscle-invasive bladder cancer
9 10
Correspondence
11
Ja Hyeon Ku, M.D. PhD.
12
Department of Urology, Seoul National University Hospital,
13
101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
14
Tel: 82-2-2072-0361, Fax: 82-2-742-4665, E-mail: [email protected]
15 16
Other authors
17
Hyung Suk Kim, M.D.
18
Department of Urology, Seoul National University Hospital
19
101 Daehak-ro, Jongno-gu, Seoul 110-744,Korea
20
Tel: 82-2-2072-1968, Fax: 82-2-742-4665, E-mail: [email protected]
21 22
Chang Wook Jeong, M.D.,-Ph.D.
23
Department of Urology, Seoul National University Hospital
24
101, Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea
25
Tel: 82-2-2072-3899, Fax: 82-2-762-2428, E-mail: [email protected]
26 27
Cheol Kwak, M.D., Ph.D.
28
Department of Urology, Seoul National University Hospital
29
101 Daehak-ro, Jongno-gu, Seoul 110-744,Korea 1
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
Tel: 82-2-2072-0817, Fax: 82-2-742-4665, E-mail: [email protected]
2 3
Hyeon Hoe Kim, M.D., PhD.
4
Department of Urology, Seoul National University Hospital,
5
101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
6
Tel: 82-2-2072-2425, Fax: 82-2-742-4665, E-mail: [email protected]
7 8
Financial Support: none
9
Disclosure of Potential Conflicts of Interest: The authors have declared that no competing interests
10
exist.
11 12
Word counts: Abstract (246), Text (3,033)
13
Total numbers of Figures and Tables: Four (4) figures and two (2) tables in the main text; three (3)
14
supplementary figures
15
2
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Statement of translational relevance
1 2 3
Although radical cystectomy with bilateral pelvic lymphadenectomy may be curable treatment option for
4
some patients with muscle invasive bladder cancer (MIBC), a substantial portion of patients experienced
5
disease recurrence after surgery. Therefore, the administration of neoadjuvant chemotherapy (NACH)
6
prior to surgery is currently recommended in almost all MIBC patients for the improvement of patient’s
7
survival.
8 9
Based on previously published articles, tumour down-staging to pathological complete response (pCR)
10
after NACH is considered to be a surrogate predictor of favourable outcomes after radical cystectomy for
11
MIBC. However, the optimal NACH regimen to achieve pCR has not yet been definitively established.
12 13
In this study, we analysed initial and updated publications along with subsequent meta-analyses with
14
respect to NACH for MIBC patients. Additionally, we sought to assess and compare the pCR rates of
15
various NACH regimens in patients with muscle-invasive urothelial carcinoma of the bladder on the basis
16
of the meta-analysis.
17
3
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract
1 2 3
Purpose: To systematically assess and compare the relationship between various NACH regimens and
4
pCR in MIBC patients.
5
Experimental design: We performed a literature search of PubMed, Embase, and the Cochrane Library
6
for all articles published prior to March 2015 and according to the Preferred Reporting Items for
7
Systematic Review and Meta-analysis (PRISMA) guidelines. There were 17 articles that met the study
8
eligibility criteria and were selected for the final analysis. A direct pair-wise meta-analysis was performed
9
for studies that compared the same regimen. Finally, a Bayesian network meta-analysis was used to
10
indirectly compare the regimens.
11
Results: In a pair-wise meta-analysis, the methotrexate/vinblastine/Adriamycin®/cisplatin (MVAC)
12
(odds ratio [OR] 4.36, 95% confidence interval [CI] 2.71–7.02) and gemcitabine/cisplatin (GC) regimens
13
(OR 4.92, 95% CI 2.93–8.24) were significantly associated with a better pCR than RC alone. In a
14
network meta-analysis, there was no significant difference in terms of pCR achievement between the GC
15
and MVAC regimens (OR 1.14, 95% CI 0.85–1.70). However, in a sub-group network meta-analysis that
16
only included prospective randomized trials, the MVAC regimen was significantly correlated with a
17
higher rate of pCR (OR 5.75, 95% CI 1.96–24.18).
18
Conclusions: The results of this meta-analysis suggest that a GC regimen was associated with a pCR rate
19
that was similar to that of a MVAC regimen based on retrospective data, but only the MVAC regimen
20
was proven to achieve pCR in prospective randomized trials. Additional prospective randomized trials
21
comparing both regimens will be necessary to establish the optimal NACH regimen.
22 23
KEYWORDS: Urinary bladder neoplasm, neo-adjuvant chemotherapy, cystectomy, risk assessment
4
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
Introduction
2 3
Radical cystectomy (RC) with bilateral pelvic lymphadenectomy is the recommended treatment for
4
patients with muscle-invasive bladder cancer (MIBC). This is a curative procedure for many patients;
5
however, some patients may experience disease recurrence (1-3). Bladder cancers usually recur distantly
6
rather than loco-regionally. In patients with pT2 and pT3/pT4 tumours, local recurrence has been
7
observed in 3–4% and 11–16% of patients, respectively, whereas distant failure has occurred in 10–27%
8
and 19–35% of patients, respectively (1, 4). The latter findings make a strong argument for the
9
administration of perioperative chemotherapy, since a failure to cure is usually due to the presence of
10
occult metastatic disease at sites that are beyond the margins of local therapy. In addition, these findings
11
indicate that radical surgery alone may be inadequate for the majority of patients with locally advanced
12
bladder cancer. Thus, some form of effective systemic treatment is required in order to improve patient
13
survival. A meta-analysis that included 11 randomised studies suggested that neo-adjuvant chemotherapy
14
(NACH) followed by RC was associated with a 5% improvement in overall survival and a 9%
15
improvement in disease-free survival (5). Therefore, NACH is recommended for nearly all MIBC patients.
16 17
Despite this recommendation, only 15–20% of MIBC patients have received NACH, though the
18
prevalence has increased over time (6). Importantly, the optimal regimen of NACH is controversial
19
because few studies have compared the efficacy of the different NACH regimens. The European Society
20
of Medical Oncology does not recommend one particular NACH regimen (7). The National
21
Comprehensive Cancer Network (NCCN) recommends the use of gemcitabine/cisplatin (GC) NACH
22
based
23
methotrexate/vinblastine/Adriamycin®/cisplatin (MVAC) regimen as the preferred neo-adjuvant
24
regimens (8). However, this trial was performed in patients with advanced and metastatic bladder cancer,
25
and therefore the results may not be applicable to patients in a neo-adjuvant setting.
on
the
data
from
several
comparative
trials,
as
well
as
the
26 27
Patients that do not respond to NACH may experience reduced quality of life and substantial delays in
28
definitive treatment. Tumour down-staging might be a valuable measurement for individualising MIBC
29
treatment until adequate molecular markers to detect chemo-sensitive tumours are identified. Previous 5
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
studies have demonstrated that NACH increased the rate of down-staging, leading to an improved
2
prognosis (9-11). In contrast, a lack of response to NACH was associated with a significantly higher rate
3
of local and distant recurrence, and with lower overall survival (12). Therefore, several investigators have
4
suggested that tumour down-staging might be used as a surrogate end-point for overall survival (13). In
5
particular, down-staging to pT0 (pathological complete response, pT0N0M0; pCR) is currently the best
6
predictor of favourable outcomes (14, 15). The results of the SWOG 8710 trial demonstrated that patients
7
who achieved pCR status after RC had an 80% probability of survival at five years (14). Patients with
8
pCR in the four main prospective NACH trials experienced similar survival times, which exceeded those
9
of the groups that did not achieve pCR (15). A recent meta-analysis also demonstrated that patients who
10
achieved pCR after NACH had better overall and recurrence-free survival times than those who did not
11
achieve pCR (16).
12 13
In this study, we analysed initial and updated publications along with subsequent meta-analyses with
14
respect to NACH for MIBC patients. Additionally, we sought to assess and compare the pCR rates of
15
various NACH regimens in patients with muscle-invasive urothelial carcinoma of the bladder on the basis
16
of the meta-analysis.
17
6
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Materials and Methods
1 2 3
The meta-analysis was performed in agreement with the recommendations of the preferred reporting
4
items for systematic reviews and meta-analyses (PRISMA) (17).
5 6
Search strategy
7
A comprehensive literature search was conducted of studies published before March 30, 2015, using
8
PubMed, Embase, and the Cochrane Library. The search was restricted to articles for which the full-text
9
publications were available in English. The following key words were used: (urothelial cancer OR
10
urinary bladder OR bladder cancer OR bladder carcinoma) AND (neo-adjuvant chemotherapy OR
11
induction chemotherapy OR pre-operative chemotherapy) AND (radical cystectomy). The reference lists
12
from eligible studies and meta-analyses were also reviewed. Two independent evaluators (H.S.K., C.W.J.)
13
selected the articles and any discrepancies were resolved.
14 15
Eligible criteria
16
We defined study eligibility according to predefined selection criteria (17).
17 18
Population: Patients with muscle-invasive urothelial carcinoma of the bladder.
19
Interventions: Cisplatin-based combination NACH followed by RC.
20
Comparators: RC only.
21
Outcome: pCR rate.
22
Study design: Retrospective or prospective .
23 24
Published studies were included if they (1) included patients with muscle-invasive urothelial carcinoma
25
of the bladder; (2) evaluated neo-adjuvant cisplatin-based combination chemotherapy; and (3) reported
26
pCR following RC. The exclusion criteria were the following: non-human studies, review articles, letters,
27
editorial comments, case reports, and articles that did not include raw data. Studies that included neo-
28
adjuvant radiotherapy, single agent cisplatin chemotherapy, carboplatin-based chemotherapy, or studies in
29
which chemotherapy was delivered non-intravenously were also excluded. If multiple publications from 7
Downloaded from clincancerres.aacrjournals.org on October 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 26, 2015; DOI: 10.1158/1078-0432.CCR-15-1208 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1
the same study or institution were available, we included the publication with the largest number of cases
2
and the most applicable information.
3 4
Data extraction
5
Two authors (C.K. and H.H.K.) completed an independent review of 1,337 articles. A total of 1,238
6
articles were excluded on the basis of the titles and abstracts, and the full-text versions of 99 articles were
7
evaluated. In accordance with the inclusion criteria, a final selection of 17 articles was performed (14, 18-
8
33) and any discrepancies were resolved. A PRISMA flow chart depicting the process for the systematic
9
literature search and selection of the studies is shown in Figure 1.
10 11
The following information was recorded for each eligible trial: author name, year of publication,
12
geographic location, period of recruitment, study design, total number of patients, median age, percentage
13
of patients achieving pCR, and systemic NACH regimen administered.
14 15
Statistical analysis
16
If two or more studies compared the same regimen, a direct meta-analysis was conducted and the random
17
effects odds ratio (OR) was calculated, according to the methods described by DerSimonian and Laird.
18
The Chi2 and I2 tests were used to assess heterogeneity of the ORs between studies. Significant
19
differences were defined as 50% for the I2 test. Publication bias was
20
evaluated for the OR analysis using Egger’s linear regression, the Begg rank correlation, and funnel plots.
21
A p
