Annals of Oncology 10: 1461-1465. 1999.
© 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Original article
Weekly gemcitabine and cisplatin combination therapy in patients with
transitional cell carcinoma of the urothelium: A phase II clinical trial
H. von der Maase,1 L. Andersen,1 L. Crino,2 S. Weinknecht3 & L. Dogliotti4
Department of Oncology, Aarhus University Hospital, Norrebrogade, Aarlnis C, Denmark; 2Ospedale Pohclimco, Perugia, Italy;
Abteihmg filr Urologie, Berlin, Germany: * Medical Oncology. San Luigi University Hospital, Orbassano, Torino, Italy
3
gressive disease 7.2 months (95% CI: 4.0-9.1 months) and
median survival 12.5 months (95% CI: 8.1-18.7 months); onePurpose: To determine the efficacy of gemcitabine and cisplatin year survival was 52%. Laboratory toxicities included leucocombination therapy in patients with advanced and/or meta- penia (44% grade 3; 17% grade 4), neutropenia (25% grade 3;
33% grade 4) and thrombocytopenia (29% grade 3; 49% grade
static transitional cell urothelial carcinoma.
Patients and methods: Forty-two chemonai've patients with 4). Four patients had grade 4 symptomatic toxicity (three
Karnofsky performance status (KPS) ^ 70 were treated with nausea and vomiting, one diarrhoea). There were no grade 4
cisplatin 35 mg/m2 followed by gemcitabine 1000 mg/m2 (30 infections and no toxic deaths.
min l.v. infusion) on days 1, 8, and 15 every twenty-eight days.
Conclusions: The combination of gemcitabine and cisplatin
Results: Thirty-eight patients were evaluable for efficacy. is active in patients with locally advanced and/or metastatic
Half had visceral disease. There were seven complete (18%) urothelial carcinoma. The weekly schedule of cisplatin is conand nine partial responses (24%), for a response rate of 42% sidered inappropriate.
(95% confidence interval (95% CI): 26%-59%). Responses
were independently reviewed. Median response duration was Key words: bladder cancer, gemcitabine-cisplatin combination,
13.5 months (95% CI: 8.5-18.1 months), median time to pro- phase II study, transitional cell carcinoma
Summary
Introduction
There are 50,000 new cases of urothelial carcinoma
in the US every year and over 66,000 in the European
Union. Currently over 10,000 patients in the US and
30,000 in the European Union die annually from this
disease [1, 2]. Prior to the development of effective
chemotherapy, the median survival for patients with
advanced or metastatic disease rarely exceeded three to
six months. The combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) is considered
the standard in the treatment of advanced bladder
cancer, with response rates of 39%-72% and a median
survival of 12.5-13.3 months [3-6]. Most importantly,
MVAC is the only regimen where the potential survival
benefit has been confirmed in phase III studies, where
MVAC has been compared with cisplatin alone [5] or
with cisplatin in combination with cyclophosphamide
and doxorubicin [4]. Long-term survival was rare, however, with only 3.7% of patients surviving for more than
six years [6]. Furthermore, toxicity is considerable, with
significant myelosuppression and febrile neutropenia
in 25% of patients treated with MVAC. Other significant
toxicities include mucositis, sepsis, renal toxicity and
neurotoxicity, and approximately 3%-4% of patients
treated with MVAC die as a result of treatment.
The need for alternative strategies for the treatment
of this disease, giving rise to improved long-term survival,
has fuelled the search for new treatment regimens for
patients with urothelial carcinoma. The nucleoside
analogue gemcitabine (GEMZAR®, Eli Lilly and Company, Indianapolis, IN) has been shown to have singleagent activity against urothelial carcinoma. In a phase I
trial of gemcitabine in patients with urothelial carcinoma, responses were seen in patients who had previously received MVAC, which had been used to treat all
but one patient [7]. Three subsequent phase II studies
have investigated the single-agent activity of gemcitabine in patients with advanced or metastatic transitional
cell carcinoma (TCC) [8-10]. In the first of these, an
Italian study, four of 31 evaluable patients had a complete
response and three a partial response, for a response rate
of 23% [8]. All patients had received cisplatin-containing chemotherapy, in most cases MVAC. The second,
a US study, reported four complete and seven partial
responses in 39 chemonaive evaluable patients for an
overall response rate of 28% [9]. In the third, a Canadian study, there were three complete and six partial
responses in 37 evaluable chemonaive patients, for a
response rate of 24% [10]. In all studies, treatment
with gemcitabine was very well tolerated, with a low
incidence of haematological and non-haematological
toxicities.
Given that cisplatin is considered to be the most
1462
active agent in urothelial carcinoma, and that gemcitabine has clearly demonstrable single-agent activity in
patients with advanced urothelial carcinoma, it seemed
reasonable to investigate the use of these two agents in
combination. The combination of gemcitabine and cisplatin has already been shown to be more active than
single-agent gemcitabine in patients with non-small-cell
lung cancer (NSCLC) [11-14]. The present study was
initiated to investigate the activity and toxicity profile of
a combination of gemcitabine and cisplatin administered weekly for three weeks, followed by one week of
rest, to chemonaive patients with advanced or metastatic urothelial carcinoma.
Patients and methods
Patients
Patients were eligible for entry into the study if they met the following
inclusion criteria: histological diagnosis of advanced and/or metastatic transitional cell carcinoma of the urothehum (stage III and IV
not amenable to curative surgery or radiotherapy); no prior systemic
immunotherapy or chemotherapy; local intravesicular immunotherapy
or chemotherapy was allowed if received > 6 months prior to study,
radiation therapy was allowed if received > 3 weeks prior to study and
if the irradiated area was not the only source of measurable disease.
Other eligibility requirements included: clinically measurable disease;
a Karnofsky performance status of 70%-100%; adequate bone marrow reserves defined by a white blood cell (WBC) count 3=3 x 109/l,
platelets > 100 x 10 g/dl or >7.0 mmol/1; adequate renal function,
defined as normal to moderately decreased chromium-ethylenediaminetelra-acetic acid (Cr-EDTA) clearance or calculated creatinine
clearance >60 ml/min; a life expectancy of at least 12 weeks and
signed informed consent. Exclusion criteria included' inadequate liver
function, defined as bilirubin levels greater than 1.5 times normal,
prothrombin and partial thromboplastin time greater than 1.5 times
normal and transaminases greater than 3 times normal; abnormal
calcium levels; active infection; central nervous system (CNS) metastases or any second primary carcinoma. Measurable disease was
defined as lesions of at least 1 cm x I cm as determined by computerised tomography (CT) scan, magnetic resonance imaging (MRI).
X-ray or physical examination.
Table I. Baseline patient characteristics
Total number of patients
Qualified for efficacy
Sex
Male
Female
Age (in years)
Median
Range
Disease stage
III
IV
Karnofsky performance status
90-100
$80
Number of sites of metastatic disease
1
2
S=3
Sites of metastatic disease (patients)
Lymph nodes
Liver
Bone
Lung
Other
42
38
31
II
64
48-74
5
37
22
20
18
14
10
20
12
9
4
19
received four additional cycles. Patients with SD received a maximum
of six cycles. A physical examination was conducted before each treatment and the number of units required for transfusion was recorded at
every cycle. Further safety and toxicity evaluations were as follows,
haematology was performed weekly and blood chemistry and urinalysis
performed every two weeks, renal function was monitored every eighth
week. Toxicity was assessed using WHO scales.
Endpoints and statistics
The primary study endpoint was response rate. The study was conducted in a two-stage design. An initial 20 qualified patients were
entered into the first stage of the study with at least two responses
required to proceed to the next accrual target. The study was designed
to accrue up to 42 patients if the initial two responses were observed.
Time to progressive disease and duration of response were also studied
using Kaplan-Meier estimations. Survival curves were generated by
the Kaplan-Meier method.
Therapy and patient monitoring
Patients were treated with cisplatin 35 mg/m 2 followed by gemcitabine
1000 mg/m 2 . on days 1. 8 and 15 of each 28-day cycle. Cisplatin was
administered after prehydration with 1000 ml saline and 20 meq
potassium chloride over 60 min. A further 1000 ml of normal saline or
glucose was given over the two-hour following cisplatin administration
and before gemcitabine. Cycles were repeated every 28 days, as
long as platelet counts were > 50 x 109/l, white blood cell counts were
> 1 x 109/l and creatinine clearance was >40 ml/min. Prophylactic
therapy for nausea and vomiting was recommended. Colony stimulating factors were not used.
Disease evaluation was performed every two cycles using chest
X-ray and the pretreatment method in evaluable tumour sites, while
radiological imaging studies demonstrated sites of disease other than
those chosen for evaluability.
Standard WHO criteria for response were used [15]. All responses
were reconfirmed after a minimal interval of four weeks. All responses
were reviewed by an independent radiologist.
Treatment was discontinued in patients with PD or in cases of
unacceptable toxicity. at the imestigators' discretion. Patients with a
CR received up to four additional cvcles. while patients with a PR
Results
Patients
Between March 1995 and July 1996, 42 patients were
entered into this multicentre study: 2 from 1 center in
Belgium; 6 in 2 centres in Germany; 16 from 5 centers in
Italy and 18 from 1 center in Denmark. All patients were
included in safety analyses. Their demographics are
shown in Table 1. The median age of patients at entry
was 64 years (range 48-74). Twenty patients had lymph
node involvement, 12 had liver metastases, 9 had bone
and 4 had lung metastases. Nine patients had lymph
node metastases only and two had advanced bladder
tumours (T4b) only. All 42 patients had undergone prior
surgery (mainly biopsies), three had received radiotherapy and one had prior intravesical chemotherapy
1463
Table 2. Response to treatment with gemcitabine and cisplatin.
Number of patients (%)
Evaluable patients
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable at follow-up
Follow-up measurements not performed
Overall response rate (95% Cl)
38 (100)
7(18)
9 (24)
10(26)
8 (21)
2 (5)
2 (5)
16 (42) (26-59)
Table 3. Maximum laboratory toxicities (WHO grade 3 and 4).
Toxicity
Leucopenia
Neutropenia
Thrombocytopenia
Anaemia
Total number
of patients
41
36
41
41
WHO grade 3.
n (%)
18(44)
9(25)
12(29)
12(29)
WHO grade 4.
n (%)
7(17)
12(33)
20 (49)
0(0)
(mitomycin) before entry into the trial. A further four
patients had intravesical bacillus Calmette-Guerin
(BCG) immunotherapy prior to study entry. In total, 38
patients qualified for efficacy analysis. Two patients did
not receive at least one cycle of treatment: one had a
performance status of 40 due to severe bone pain resulting from osseous metastases, the other had a creatinine
clearance of 57 ml/min which was lower than the
protocol-defined minimum of 60 ml/min. A further two
patients did not have bidimensionally measurable lesions
and could not be included in efficacy analysis.
Response
All responses were confirmed at four weeks and independently reviewed. There were seven CRs (18%) and
nine PRs (24%), for an overall response rate of 42%
(Table 2). A further 10 patients had SD and 8 patients
had PD. One patient with a CR had one residual lymph
node at the end of treatment. This lesion was surgically
removed and shown to be benign. One PR patient was
rendered disease free by surgical resection of a single
residual lymph node metastasis. Two patients were not
evaluable at follow-up and follow-up measurements
were not done for two others. Responses were seen in
lesions in the liver, lung, bone and penis, as well as
lymph nodes. Seven out of nine patients with disease
confined to the lymph nodes responded to treatment. All
seven complete responses were seen in patients with
stage IV disease.
The median duration of response for all responding
patients was 13.5 months (95% CI: 8.5-18.1 months) and
the median time to progressive disease was 7.2 months
(95% CI: 4.0-9.1 months). The median survival for
all patients was 12.5 months (95% CI: 8.1-18.7 months)
and the one-year survival rate was 52% (Figure 1). At the
time of analysis, four responses were ongoing (32+
Survival Time
Figure 1. Overall survival curve for all patients (« = 42) with advanced
urothelial carcinoma who received gemcitabine and cisplatin
months to 48+ months). One of these patients had bone
metastases as well as lymph node and bladder involvement. One patient had bladder and lymph node involvement and the two remaining patients had lymph node
disease only. The two patients with bladder involvement
had no further treatment following chemotherapy.
Toxicity
WHO laboratory toxicities are summarised in Table 3.
Grade 3 and 4 leucopenia was reported in 44% and 17%
of patients, respectively. Grade 3 and 4 neutropenia was
seen in 25% and 33% of patients, respectively. One
patient with grade 4 neutropenia also had grade 3
infection, while three patients with grade 3 or 4 neutropenia had grade 2 infection. No grade 4 infections were
seen. Eight patients were hospitalised for fever; two
exhibited grade 3 or 4 neutropenia. Grade 3 and 4
thrombocytopenia was reported in 29% and 49% of
patients, respectively, resulting in grade 3 haemorrhage
in one patient. This patient had vaginal bleeding, and on
physical examination a large, bleeding, necrotic mass
was observed. Of the 20 patients with grade 4 thrombocytopenia, 9 received platelet transfusions. Six patients
had grade 3 haematuria, all of whom had grade 2-4
thrombocytopenia. Grade 3 anaemia was seen in 29% of
patients. In total, 30 patients had transfusions during the
study, 14 had platelet transfusions and 28 received red
blood cells.
Other laboratory toxicities included one patient with
grade 4 alkaline phosphatase, who also had liver metastases. No grade 3 or 4 liver toxicities were reported. It is
notable that no grade 3 or 4 renal toxicity was reported.
Only five patients had grade 1 blood urea nitrogen, with
no creatinine toxicity. Three patients were discontinued
as a result of decreasing renal function, one had decreasing creatinine clearance after five cycles, one had
baseline creatinine clearance below the required level
and was discontinued after the first injection, and one
had abnormal kidney function and reduced Cr-EDTA
1464
clearance (from 65.1 ml/min at baseline to 26.5 ml/min
after four cycles). This patient also had grade 1 creatinine toxicity.
Non-laboratory toxicities included grade 4 diarrhoea
in one patient who was removed from the study after one
cycle for progressive disease and grade 3 diarrhoea in
one other patient. Grade 3 and 4 nausea and vomiting
occurred in 29% of patients. Grade 3 pulmonary toxicity
was observed in three patients (7%), one of whom had
a previous history of severe obstructive pulmonary
disease. This patient was withdrawn from the study as
the symptoms worsened during treatment and the patient had not responded to therapy. Ten patients (24%)
had grade 2 and one patient had grade 3 alopecia.
Nine patients discontinued treatment during the study.
Reasons for discontinuation were (one patient each)
anaphylactic reaction to cisplatin, asthenia, increased
creatinine, pre-existing hydronephrosis, abnormal kidney
function, leucopenia, thrombocytopenia, pain, and pneumonia. There were no toxic deaths.
The median number of cycles received was four (range
0-8). The median gemcitabine dose administered was
768 mg/m2 per week (range 250-1002 mg/m2) and the
median cisplatin dose was 28 mg/m2 per week (range
9-37). Patients received, on average, 80% of the planned
cisplatin dose and 74% of the planned gemcitabine dose.
Of the total number of gemcitabine doses planned, 34%
were reduced and 20% omitted, while 21% of cisplatin
doses were reduced and 16% omitted. Haematological
toxicity accounted for the majority of these alterations.
Leucopenia was responsible for 14% and 27% of cisplatin and gemcitabine reductions, respectively, while
thrombocytopenia was responsible for 36% and 41% of
cisplatin and gemcitabine reductions, respectively. Abnormal renal function, as assessed by measured creatinine clearance and Cr-EDTA, led to reductions in 30%
and 17% of cisplatin and gemcitabine doses, respectively.
These were not generally associated with increased
creatinine levels.
Discussion
The combination of gemcitabine and cisplatin, administered on days 1, 8 and 15 of a 28-day cycle, has been
shown to be active in patients with advanced urothelial
carcinoma. In this study, 42% of qualified patients had
an objective response to treatment and 18% had a complete response. Responses, which were independently
reviewed, were seen in a variety of metastatic sites,
including liver, lung, and bones. The median response
duration of 13.5 months and the median survival of
12.5 months for all patients, including five long-lasting
responses, was encouraging, given the fact that the
majority of patients had stage IV disease (88%), 50%
had visceral disease and almost half (47%) had a KPS of
80 or less.
Many of the conventional treatments for advanced
urothelial carcinoma, including the MVAC regimen,
have been associated with considerable toxicities. Gemcitabine, on the other hand, is generally well tolerated as
a single agent and the combination of gemcitabine and
cisplatin is already known to be well tolerated in patients
with NSCLC [11-14]. In the present study, myelosuppression was the most frequently reported side effect.
Grade 4 neutropenia and thrombocytopenia were seen
in 33% and 49% of patients, respectively, but there was
only one case each of grade 3 infection and haemorrhage and there were no toxic deaths. Thus haematological toxicity was mainly a laboratory concern, which did
not result in major clinical problems. Renal toxicity, a
potential complication arising from cisplatin therapy,
was not common with this combination, although three
patients were withdrawn from the study as a result of
decreased renal function. There were no reports of grade
3 or 4 renal toxicity (creatinine clearance or blood urea
nitrogen). Indeed, one patient had creatinine clearance
levels that did not meet the entry criteria. The main nonlaboratory toxicity was nausea and vomiting: 12 patients
(29%) had grade 3 and 4 nausea and vomiting. The high
incidence of this toxicity and the frequency of dose
reductions and omissions was considered to be at least
partly due to the weekly administration of cisplatin,
which is felt to be inappropriate in this patient group.
There was only one other incidence of grade 4 nonlaboratory toxicity, and only occasional reports of grade
3 non-laboratory toxicities.
As an alternative to the dosing schedule used in this
study, Stadler et al. [16] have used gemcitabine (1000
mg/m2) on days 1, 8 and 15, and cisplatin (75 mg/m2) on
day 1 of a 28-day cycle in patients with metastatic
urothelial cancer. This combination appears to be well
tolerated and highly active, with a response rate of 66%
(95% CI: 51%-79%). Day 2 administration of cisplatin
is also under investigation and preliminary results
suggest good activity, with four complete responses and
eight partial responses in 17 evaluable patients, for a
response rate of 71%, and reasonable toxicity [17].
Grade 3 and 4 neutropenia and thrombocytopenia were
less frequent in the two studies using a single dose of
cisplatin once every 28 days than in the present study.
Consequently, a phase III trial, comparing the combination of day 2 cisplatin (70 mg/m2) and days 1, 8 and 15
gemcitabine (1000 mg/m2) with MVAC, has been initiated.
We conclude that the combination of gemcitabine
and cisplatin is active in patients with transitional cell
carcinoma of the urothelium. We consider the weekly
schedule of cisplatin administration to be inappropriate
and the schedule has been optimised by use of monthly
cisplatin. A direct comparison with MVAC is underway.
Acknowledgements
The authors would like to thank Eli Lilly and Company
for supporting this study and to acknowledge the contribution of the following clinicians who entered patients
1465
into this study: Dr P. F. Conte, Ospedale Santa Chiara,
Pisa, Italy; Prof. Y. Humblet, UCL St. Luc, Brussels,
Belgium; Prof. G. Jakse, Urologische Klinik der RWTH,
Aachen, Germany; Prof. L. Weissbach, Urban Hospital,
Berlin, Germany; Dr D. Perroni, Ospidale Santa Croce,
Cuneo, Italy; Dr G. F. Porcile, Ospidale San Lazzaro,
Alba, Italy; Prof. M. Tonato, Policlinico Monteluce,
Perugia, Italy.
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Received 28 July 1999; accepted 25 October 1999.
Correspondence to.
Prof. H. von der Maase, MD
Department of Oncology
Aarhus University Hospital
Norrebrogade
DK-8000 Aarhus C
Denmark