Sequential chemotherapy using gemcitabine + carboplatin followed by gemcitabine + carboplatin + docetaxel for advanced upper-tract urothelial cancer

Abstract

Retrospective evaluation of the effectiveness and adverse events (AEs) of a sequential chemotherapy regimen using gemcitabine + carboplatin (GCarbo) followed by GCarbo + docetaxel (GCarboD) for advanced upper-tract urothelial carcinoma (UTUC).
We treated 56 patients with advanced UTUC. Mean patient age was 68.9 years, creatinine clearance was 51.2 mL/min, and the observation period was 20 months. Patients received two courses of GCarbo comprising 800 mg/m(2) gemcitabine on days 1, 8, and 15, and carboplatin at an area under the curve of four on day 2. If this regimen was effective, we administered two more courses of GCarbo; if the regimen was ineffective, we switched to two courses of GCarboD (70 mg/m(2)).
Complete (n = 3) and partial response (PR; n = 25) were achieved after GCarbo. Mean response duration was 9.7 months. Two of 17 cases achieved PR after GCarboD treatment (mean duration, 31.5 months). Median survival was 14.0 months with the GCarbo/GCarboD regimen. Responders to GCarbo therapy survived significantly longer. AEs with the GCarbo regimen included 31 instances of G3/4 blood toxicity and 8 instances of G3/4 urticaria; however, there were only 6 instances of G3/4 gastrointestinal complications. AEs with the GCarboD regimen included 16 instances of blood toxicity and 8 instances of gastrointestinal complications. Neither regimen resulted in G3/4 renal toxicity.
GCarbo and GCarboD chemotherapy may be administered safely to patients with advanced UTUC, with or without renal dysfunction. Response to GCarbo was high (50.0 %) whereas GCarboD was of limited effectiveness for non-responders to GCarbo.

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Int J Clin Oncol (2015) 20:1179–1184
DOI 10.1007/s10147-015-0846-z
ORIGINAL ARTICLE
Sequential chemotherapy using gemcitabine + carboplatin
followed by gemcitabine + carboplatin + docetaxel for advanced
upper‑tract urothelial cancer
Takahiro Yoneyama1 · Atsushi Imai1 · Shingo Hatakeyama1 · Yasuhiro Hashimoto1 ·
Takuya Koie1 · Chikara Ohyama1
Received: 9 March 2015 / Accepted: 4 May 2015 / Published online: 26 May 2015
© Japan Society of Clinical Oncology 2015
Conclusions GCarbo and GCarboD chemotherapy may
be administered safely to patients with advanced UTUC,
with or without renal dysfunction. Response to GCarbo
was high (50.0 %) whereas GCarboD was of limited effec-
tiveness for non-responders to GCarbo.
Keywords Upper-urinary tract · Urothelial carcinoma ·
Carboplatin · Gemcitabine · Docetaxel
Introduction
Upper-tract urothelial carcinoma (UTUC) is a relatively
rare and aggressive disease accounting for 10 % of renal
malignancies and 5 % of urothelial carcinomas (UC) [1, 2].
Although radical nephroureterectomy (RNU) and bladder
cuff resection are the standard treatment for non-metastatic
UTUC, patients often develop local or metastatic recur-
rence, so the prognosis is very poor [3–7].
Despite recent developments in systematic chemother-
apy for advanced UC, successful outcomes after treatment
for metastasis or the local recurrence of UTUC remain elu-
sive [3–7]. Tanaka et al. [3] described the prognostic factors
and reported the oncological outcomes for 204 Japanese
UTUC patients who experienced disease recurrence after
RNU. Of these, 132 (64.7 %) underwent systemic chemo-
therapy, of whom 116 (87.9 %) underwent cisplatin-based
chemotherapy. However, 1 and 3-year overall and cancer-
specific survival were only 53.6 and 54.4 % and 12.9 and
13.3 %, respectively, with most patients succumbing to
UTUC within 3 years, even though systemic chemotherapy
was administered after relapse.
According to the 2014 European Association of Urology
(EAU) guidelines [8], UTUCs are urothelial tumors; there-
fore, platinum-based chemotherapy is expected to lead to
Abstract
Background Retrospective evaluation of the effectiveness
and adverse events (AEs) of a sequential chemotherapy
regimen using gemcitabine + carboplatin (GCarbo) fol-
lowed by GCarbo + docetaxel (GCarboD) for advanced
upper-tract urothelial carcinoma (UTUC).
Methods We treated 56 patients with advanced UTUC.
Mean patient age was 68.9 years, creatinine clearance was
51.2 mL/min, and the observation period was 20 months.
Patients received two courses of GCarbo comprising
800 mg/m2 gemcitabine on days 1, 8, and 15, and carbo-
platin at an area under the curve of four on day 2. If this
regimen was effective, we administered two more courses
of GCarbo; if the regimen was ineffective, we switched to
two courses of GCarboD (70 mg/m2).
Results Complete (n = 3) and partial response (PR;
n = 25) were achieved after GCarbo. Mean response dura-
tion was 9.7 months. Two of 17 cases achieved PR after
GCarboD treatment (mean duration, 31.5 months). Median
survival was 14.0 months with the GCarbo/GCarboD
regimen. Responders to GCarbo therapy survived signifi-
cantly longer. AEs with the GCarbo regimen included 31
instances of G3/4 blood toxicity and 8 instances of G3/4
urticaria; however, there were only 6 instances of G3/4 gas-
trointestinal complications. AEs with the GCarboD regi-
men included 16 instances of blood toxicity and 8 instances
of gastrointestinal complications. Neither regimen resulted
in G3/4 renal toxicity.
* Yasuhiro Hashimoto
bikkuri@opal.plala.or.jp
1 Department of Urology, Hirosaki University Graduate School
of Medicine, 5 Zaifucho, Hirosaki, Aomori 036-8562, Japan

1180 Int J Clin Oncol (2015) 20:1179–1184
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similar results to those observed for bladder cancer. How-
ever, not all patients receive this treatment owing to the
risks of comorbidity and impaired renal function after radi-
cal surgery.
Kaag et al. [9] reported a decrease of 24 % in mean esti-
mated glomerular filtration rate (eGFR) for 388 patients
undergoing nephroureterectomy for UTUC with a cut-off
value of 60 mL/min/1.73 m2. Of these, 49 % were eligi-
ble for chemotherapy before surgery; however, only 19 %
remained eligible postoperatively.
Although cisplatin-based chemotherapy is effective, its
nephrotoxic properties render it unsuitable for patients with
renal dysfunction. Carboplatin is an alkylating anticancer
agent that is less nephrotoxic than cisplatin; therefore, car-
boplatin-containing chemotherapeutic agents are presumed
to be useful for treatment of patients with advanced UC and
renal impairment. The combination of gemcitabine and car-
boplatin (GCarbo) was developed for patients with meta-
static UC of the bladder who were unfit for the cisplatin-
based therapy and has subsequently been adopted by other
investigators for the treatment of such patients [10–17].
We have previously reported the feasibility and effec-
tiveness of carboplatin-based combination chemotherapy
for patients aged ≥70 years with advanced bladder cancers
[18]. However, there is currently no established chemo-
therapy regimen for advanced UTUC. Although gemcit-
abine + cisplatin or methotrexate, vinblastine, doxorubicin,
cisplatin (M-VAC) may be promising for advanced UTUC
and bladder cancer, renal dysfunction is common among
patients with advanced UTUC and cisplatin is often unsuit-
able for such patients. Here we retrospectively evaluated
the effectiveness and adverse events (AEs) of a sequen-
tial chemotherapy regimen using GCarbo followed by
GCarbo + docetaxel (GCarboD) for advanced UTUC.
Materials and methods
Study design and population
Fifty-six patients (37 men and 19 women; mean age
68.9 years; age range 43–89 years) with advanced UTUC
were enrolled in this study from September 2004 to Decem-
ber 2012. Eligible patients had been histologically proved
to have recurrent or metastatic UC. Twenty-three cases
after RNU and 33 inoperable cases were enrolled. Nine
patients of those enrolled had received chemotherapy with
M-VAC before enrolling in this study. The study protocol
was approved by the ethics committee of Hirosaki Uni-
versity (Hirosaki, Japan) and all patients provided written
informed consent before administration of chemotherapy.
Eligible patients had an Eastern Cooperative Oncology
Group (ECOG) performance status of 0–1, adequate bone
marrow function (absolute neutrophil count of ≥1,500/
mm3 and platelet count of ≥100,000/mm3), and adequate
hepatic function (total bilirubin level <1.5 mg/dL). eGFR
was calculated by use of the Cockcroft–Gault equation.
Patients were excluded from this study if they had central
nervous system metastasis, mental retardation, or a severe
bacterial infection. Patients were judged as unfit for cis-
platin-based chemotherapy if they met at least one of five
criteria:
1. ECOG performance status of 2;
2. creatinine clearance <60 mL/min;
3. grade 2 or higher hearing loss;
4. grade 2 or higher neuropathy; or
5. New York Heart Association class III heart failure [19].
Treatment schedule
The therapeutic regimen comprised two lines:
1. GCarbo therapy as first-line therapy, with two courses
as a set; and
2. GCarboD therapy as second-line therapy if the
response to the first-line therapy was insufficient.
GCarbo therapy comprised 800 mg/m2 gemcitabine
on days 1, 8, and 15 and carboplatin at an area under the
curve of 4 according to the Calvert formula [20] on day
2. If this regimen was effective, another two courses of
GCarbo therapy were administered. If this regimen did not
induce reduction in tumor size, however, the treatment was
switched to GCarboD therapy, which comprised 800 mg/
m2 gemcitabine on days 1 and 8, 70 mg/m2 docetaxel on
day 1, and carboplatin (area under the curve of 4) on day 2.
Patient evaluation
Baseline evaluations included complete history and physi-
cal examinations, assessment of ECOG performance sta-
tus, abdominal and pelvic computed tomography (CT) or
magnetic resonance imaging, and chest radiography or CT.
Tumor response was assessed by use of the Response Eval-
uation Criteria in Solid Tumors (RECIST) version 1.1. Tox-
icity was evaluated before each treatment cycle and graded
in accordance with the National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE) version
3.0.
End points and statistical analysis
The end points of this study were overall survival (OS)
and toxicity. OS was defined as the time from the start of
treatment to death from any cause. For surviving patients,

1181Int J Clin Oncol (2015) 20:1179–1184
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outcomes were determined on the last follow-up day. Data
were analyzed by use of SPSS statistical software (version
18.0; SPSS, Chicago, USA). Correlations between survival
and subgroup classification were identified by use of the
log-rank test. Statistical significance was set at p < 0.05.
Results
Patient characteristics
Demographic and baseline characteristics of the patients
are presented in Table 1. The median age was 68.9 years
(range 43–89 years). Average creatinine clearance was
51.2 mL/min (range 11.6–99.3 mL/min). ECOG perfor-
mance status was 0 for 41 of 56 patients (73.2 %) and 1 for
the other 15 (26.8 %). Nine (16.1 %) patients had previ-
ously received M-VAC chemotherapy. The mean observa-
tion period was 20.0 (range 3–62) months. There were 23
cases with recurrent disease after nephroureterectomy and
33 cases with unresectable tumors. Metastasis to at least
one region outside the urothelial tract was observed for
51 (91.1 %) patients. The most frequent sites of metasta-
sis were the lymph nodes (47 of 56 patients; 83.9 %); 38
(67.9 %) patients were deemed unfit for cisplatin-based
chemotherapy.
Treatment administered
All 56 patients received GCarbo chemotherapy, with
an average of 2.2 (range 1–4) treatment courses, and 17
patients received GCarboD chemotherapy with an average
of 2.1 (range 1–5) treatment courses.
Adverse effects
The frequencies of grade 3 or higher AEs are shown in
Table 2. Grade 3 or higher AEs occurred among 36 (64.3 %)
patients who received GCarbo therapy. With regard to AEs
with the GCarbo regimen, there were 31 (55.4 %) instances
of G3/4 blood toxicity and 8 (14.3 %) instances of G3/4
urticaria; however, there were only 6 (10.7 %) instances of
G3/4 gastrointestinal AEs. For the GCarboD regimen, there
were 16 (94.1 %) instances of blood toxicity, 8 (47.1 %)
instances of gastrointestinal AEs, and 1 (5.9 %) instance of
urticaria. There was no occurrence of G3/4 renal toxicity
after either regimen.
Tumor response
The response of the 56 patients who received GCarbo
therapy was 50 %. Of these, 3 (5.4 %) achieved complete
response (CR) and 25 (44.6 %) achieved partial response
Table 1 Clinical characteristics of UTUC patients
Characteristic Number (%)
Gender
Male 37 (66.1 %)
Female 19 (33.9 %)
Age (years)
Median 68.9
Range 43−89
Radical surgery 23 (41.1 %)
pT2 2
pT3 19
pT4 2
Lymph node metastasis 20
Lung metastasis 4
Bone metastasis 1
Local recurrence 4
Non-operative cases 33 (58.9 %)
cT2 4
cT3 20
cT4 11
Lymph node metastasis 27
Lung metastasis 6
Bone metastasis 2
Liver metastasis 4
Prior chemotherapy
MVAC 9 (16.1 %)
None 47 (83.9 %)
ECOG-PS
0 41 (73.2 %)
1 15 (26.8 %)
2 0
eGFR (mL/min) 51.2
Range 11.6−99.3
<60 mL/min 38 (67.9 %)
≥60 mL/min 18 (32.1 %)
Table 2 Adverse events
GCarbo (n = 56) GCarboD (n = 17)
Incidence of grade 3 or higher
adverse events
36 (64.3 %) 16 (94.1 %)
Anemia 13 (23.2 %) 7 (41.2 %)
Leukopenia 19 (33.9 %) 14 (82.4 %)
Thrombocytopenia 9 (16.1 %) 12 (70.6 %)
Nausea 6 (10.7 %) 8 (47.1 %)
Urticaria 8 (14.3 %) 1 (5.9 %)
Discontinuation of this
therapy
8 (14.3 %) 6 (35.3 %)

1182 Int J Clin Oncol (2015) 20:1179–1184
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(PR). The average response duration was 9.7 months (range
2–53 months). Of the patients with M-VAC resistance,
three achieved PR. The response of the 17 patients who
received GCardoD therapy was only 11.8 %, with an aver-
age response duration of 31.5 months (Table 3).
Survival
The outcome of GCarbo and GCarboD chemotherapy with
regard to OS duration (time from the first treatment with the
study drugs to death from any cause) was determined for
the 56 enrolled patients. The median OS was 14.0 months,
and 1, 3, and 5-year OS were 52.7, 34.1, and 20.4 %,
respectively (Fig. 1a). Of these 56 patients, 28 (50.0 %)
were responsive to GCarbo therapy and 28 (50.0 %) were
non-responsive. OS for the GCarbo responders was signifi-
cantly longer than for non-responders (28.0 vs 9.0 months,
respectively; log-rank test, p = 0.0084; Fig. 1b). Median
OS for patients treated with GCarboD was 12.0 months
(Fig. 1c).
Discussion
According to the 2014 EAU guidelines, UTUCs are urothe-
lial tumors; results for platinum-based chemotherapy are
therefore expected to be similar to those for bladder can-
cer [8]. Cisplatin-based chemotherapy is, therefore, widely
used for management of metastatic or locally advanced
UTUC. However, the prognosis for patients with UTUC
remains very poor and there is currently no strong evi-
dence regarding the effectiveness of chemotherapy against
advanced UTUC [3–7].
Because cisplatin is closely associated with nephro-
toxicity, eligibility for cisplatin-based therapy is highly
dependent on kidney function. Kaag et al. [9] reported a
mean eGFR decrease of 24 % after nephroureterectomy for
UTUC. If cut-off value of 60 mL/min/1.73 m2 was used,
49 % of patients were eligible for cisplatin before surgery;
however, only 19 % remained eligible postoperatively.
The combination of gemcitabine and carboplatin
(GCarbo) was developed for patients with metastatic UC of
the bladder who were deemed unfit for cisplatin-based ther-
apy, and the treatment was subsequently adopted for treat-
ment of such patients [10–17]. Therefore, we inferred that
this evidence indicates that GCarbo can be used for treat-
ment of advanced UTUC.
Table 3 Response for GCarbo and GCarboD
GCarbo (n = 56) GCarboD (n = 17)
Average treatment course
(range)
2.2 (1–4) 2.1 (1–5)
Treatment Effect
CR 3 –
PR 25 2
NC 21 8
PD 9 7
Response (%) 50.0 11.8
Average response duration
(range)
9.7 months (2–53) 31.5 months (7–56)
n=56
survival rate (%)
Median survival 14.0 months
Follow up (months)
0 20 40 60 80
0
20
40
60
80
100
A
Log Rank
p=0.0084
Follow up (months)
responder (n=28)
non-responder (n=28)
0 20 40 60 80
0
20
40
60
80
100
B
N=17
Follow up (months)
survival rate (%)
0 20 40 60 80
0
20
40
60
80
100
Median survival 12.0 months
C
Fig. 1 a Overall survival for all patients with unresectable metastatic
or locally advanced UC (n = 56). b Overall survival for GCarbo
responders and non-responders. c Overall survival for GCarboD
patients (n = 17)

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Docetaxel is an active single agent for patients previ-
ously treated with UC. In a phase II study of docetaxel
therapy for patients with advanced or metastatic UC who
had relapsed or become refractory to no more than one pre-
vious cisplatin-containing treatment regimen, ORR was
13.3 % and median OS was 9 months [21]. Furthermore,
combination GCarboD therapy has also been reported
to be active and well tolerated by patients with advanced
urothelial carcinoma [15, 22]. Tsuruta et al. reported use of
GCarboD for advanced or metastatic UC patients who had
relapsed or were considered unsuitable for cisplatin. ORR
was 52.4 % and median OS was 13.1 months. [22] We
therefore concluded that GCarboD was more active than
docetaxel monotherapy.
Renal dysfunction is common among patients with
advanced UTUC; thus, cisplatin is often unsuitable. In this
study, we retrospectively evaluated the effectiveness and
instances of AEs for a sequential chemotherapy regimen of
GCarbo followed by GCarboD for advanced UTUC.
Several sequential types of chemotherapy for UTUC
have been reported. Galsky et al. reported that they con-
ducted a phase II trial of dose-dense doxorubicin plus
gemcitabine then paclitaxel plus carboplatin for 25 patients
with advanced urothelial carcinoma and impaired renal
function. In their study, there were five complete responses
and nine partial responses, so the overall response was
56 % and median survival was 15 months [23]. Bouko-
vinas et al. reported use of sequential gemcitabine and
cisplatin then docetaxel for treatment of 38 patients with
advanced urothelial carcinoma. In their study, 5 patients
had complete response (13.1 %) and 16 patients had
partial response (42.1 %). Median overall survival was
13 months [24]. Artz et al. reported sequential chemother-
apy with docetaxel and methotrexate then gemcitabine and
cisplatin for 13 patients with metastatic urothelial cancer.
In their study, overall response was 54 % and median OS
was 13.6 months [25].
In our study, 3 (5.4 %) patients achieved CR and 25
(44.6 %) achieved PR by use of the GCarbo regimen, and
the mean duration of the response was 9.7 months (range
2–53 months). PR was achieved for three (33.3 %) of nine
M-VAC-resistant cases. GCarboD treatment was adminis-
tered to 17 cases and yielded two (11.8 %) PRs; the mean
duration of response was 31.5 months. Median survival
was 14 months for GCarbo/GCarboD regimens, with 1,
3, and 5-year survival of 50.8, 34.1, and 20.4 %, respec-
tively. Compared with previous studies, we believe that
overall response and median survival in our study were
acceptable.
Our study had several limitations. First, the patient
cohort was relatively small. Second, the study was a retro-
spective, single-group study. Third, in this study there were
18 patients (32.1 %) deemed fit for cisplatin. It is believed
that carboplatin-based chemotherapy does not compare
with cisplatin-based chemotherapy with regard to survival
time [26]. We conducted carboplatin rather than cisplatin-
based chemotherapy because our patients were likely to be
elderly and more seriously ill, because of metastatic dis-
ease, and, compared with cisplatin, it was easier to adjust
the dose of carboplatin on the basis of renal function or
general condition.
Although the patient cohort was relatively small
and the study was preliminary, the results suggest that
GCarbo/GCarboD sequential chemotherapy may be
safe and effective for treatment of advanced UTUC.
An acceptable response (50.0 %) against advanced
UTUC was achieved by use of the GCarbo regimen,
even among M-VAC-resistant cases. The median OS
of 14 months may be acceptable compared with OS
survival outcomes in previous studies. However, the
effectiveness of GCarboD was limited for GCarbo
non-responders.
Conflict of interest The authors declare that they have no conflict
of interest.
References
1. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics. CA
Cancer J Clin 59:225–249
2. Kaag MG, O’Malley RL, O’Malley P et al (2010) Changes in
renal function following nephroureterectomy may affect the use
of perioperative chemotherapy. Eur Urol 58:581–587
3. Tanaka N, Kikuchi E, Kanao K et al (2013) Patient characteris-
tics and outcomes in metastatic upper tract urothelial carcinoma
after radical nephroureterectomy: the experience of Japanese
multi-institutions. BJU Int 112:E28–E34
4. Audenet F, Yates DR, Cussenot O et al (2013) The role of chem-
otherapy in the treatment of urothelial cell carcinoma of the
upper urinary tract (UUT-UCC). Urol Oncol 31:407–413
5. Hellenthal NJ, Shariat SF, Margulis V et al (2009) Adjuvant
chemotherapy for high risk upper tract urothelial carcinoma:
results from the upper tract urothelial carcinoma collaboration. J
Urol 182:900–906
6. Youssef RF, Lotan Y, Sagalowsky AI et al (2013) Radical neph-
roureterectomy for pathologic T4 upper tract urothelial cancer:
can oncologic outcomes be improved with multimodality ther-
apy? Int Braz J Urol 39:614–621
7. Alva AS, Matin SF, Lerner SP et al (2012) Perioperative
chemotherapy for upper tract urothelial cancer. Nat Rev Urol
9:266–273
8. Roupret M, Babjuk M, Comperat E et al (2013) European guide-
lines on upper tract urothelial carcinomas: 2013 update. Eur Urol
63:1059–1071
9. Kaag MG, O’Malley RL, O’Malley P et al (2010) Changes in
renal function following nephroureterectomy may affect the use
of perioperative chemotherapy. Eur Urol 58:581–587
10. Bellmunt J, Ribas A, Eres N et al (1997) Carboplatin-based ver-
sus cisplatin-based chemotherapy in the treatment of surgically
incurable advanced bladder carcinoma. Cancer 80:1966–1972
11. Bamias A, Moulopoulos LA, Koutras A et al (2006) The combi-
nation of gemcitabine and carboplatin as first-line treatment in

1184 Int J Clin Oncol (2015) 20:1179–1184
1 3
patients with advanced urothelial carcinoma. A Phase II study of
the Hellenic Cooperative Oncology Group. Cancer 106:297–303
12. De Santis M, Bellmunt J, Mead G et al (2012) Randomized
phase II/III trial assessing gemcitabine/carboplatin and metho-
trexate/carboplatin/vinblastine in patients with advanced urothe-
lial cancer who are unfit for cisplatin-based chemotherapy:
eORTC study 30986. J Clin Oncol 30:191–199
13. Park JH, Lee SW, Kim HS et al (2013) Combination of gemcit-
abine and carboplatin as first line treatment in elderly patients or
those unfit for cisplatin-based chemotherapy with advanced tran-
sitional cell carcinoma of the urinary tract. Cancer Chemother
Pharmacol 71:1033–1039
14. Koie T, Ohyama C, Hashimoto Y et al (2013) Efficacies and
safety of neoadjuvant gemcitabine plus carboplatin followed by
immediate cystectomy in patients with muscle-invasive bladder
cancer, including those unfit for cisplatin: a prospective single-
arm study. Int J Clin Oncol 18:724–730
15. Hoshi S, Ohyama C, Ono K et al (2004) Gemcitabine plus car-
boplatin; and gemcitabine, docetaxel, and carboplatin combined
chemotherapy regimens in patients with metastatic urothelial
carcinoma previously treated with a platinum-based regimen:
preliminary report. Int J Clin Oncol 9:125–129
16. Xu N, Zhang XC, Xiong JP et al (2007) A phase II trial of gem-
citabine plus carboplatin in advanced transitional cell carcinoma
of the urothelium. BMC Cancer 7:98
17. Hoschke B, May M, Seehafer M et al (2004) Our experience
with 23 consecutive patients on gemcitabine/carboplatin chemo-
therapy for treatment of metastasized transitional cell carcinoma
of the urothelium. Int J Urol 11:461–466
18. Yoneyama T, Tobisawa Y, Yoneyama T et al (2014) Carbopl-
atin-based combination chemotherapy for elderly patients with
advanced bladder cancer. Int J Clin Oncol (in press)
19. Galsky MD, Hahn NM, Rosenberg J et al (2011) Treatment of
patients with metastatic urothelial cancer “unfit” for cisplatin-
based chemotherapy. J Clin Oncol 29:2432–2438
20. Calvert AH, Newell DR, Gumbrell LA et al (1989) Carboplatin
dosage: prospective evaluation of a simple formula based on
renal function. J Clin Oncol 7:1748–1756
21. McCaffrey JA, Hilton S, Mazumdar M et al (1997) Phase II trial
of docetaxel in patients with advanced or metastatic transitional-
cell carcinoma. J Clin Oncol 15:1853–1857
22. Tsuruta H, Inoue T, Narita S et al (2011) Combination therapy
consisting of gemcitabine, carboplatin, and docetaxel as an
active treatment for advanced urothelial carcinoma. Int J Clin
Oncol 16:533–538
23. Galsky MD, Iasonos A, Mironov S et al (2007) Phase II trial of
dose-dense doxorubicin plus gemcitabine followed by paclitaxel
plus carboplatin in patients with advanced urothelial carcinoma
and impaired renal function. Cancer 109:549–555
24. Boukovinas I, Androulakis N, Vamvakas L et al (2006) Sequen-
tial gemcitabine and cisplatin followed by docetaxel as first-line
treatment of advanced urothelial carcinoma: a multicenter phase
II study of the Hellenic Oncology Research Group. Ann Oncol
17:1687–1692
25. Artz A, Stadler WM, Vogelzang NJ et al (2005) A phase II trial
of sequential chemotherapy with docetaxel and methotrexate fol-
lowed by gemcitabine and cisplatin for metastatic urothelial can-
cer. Am J Clin Oncol 28:109–113
26. Dogliotti L, Carteni G, Siena S et al (2007) Gemcitabine plus
cisplatin versus gemcitabine plus carboplatin as first-line chem-
otherapy in advanced transitional cell carcinoma of the urothe-
lium: results of a randomized phase 2 trial. Eur Urol 52:134–141