Annals of Oncology 13: 243–250, 2002
DOI: 10.1093/annonc/mdf017
Original article
Weekly chemotherapy with docetaxel, gemcitabine and cisplatin
in advanced transitional cell urothelial cancer: a phase II trial
D. Pectasides*, J. Glotsos, N. Bountouroglou, A. Kouloubinis, N. Mitakidis, N. Karvounis,
N. Ziras & A. Athanassiou
First Department of Medical Oncology, Metaxa’s Memorial Cancer Hospital, Piraeus, Greece
Received 21 May 2001; revised 25 July 2001; accepted 17 August 2001
Purpose: To evaluate the efficacy and toxicity of a combination of weekly docetaxel, gemcitabine and
cisplatin in advanced transitional cell carcinoma (TCC) of the bladder.
Patients and methods: Thirty-five chemotherapy-naïve (adjuvant and neoadjuvant chemotherapy
was allowed) patients with advanced TCC received intravenous docetaxel 35 mg/m2, gemcitabine
800 mg/m2 and cisplatin 35 mg/m 2, on days 1 and 8 every 3 weeks. Prophylactic granulocyte-colony
stimulating factor was given from days 3 to 6 and days 10 to 15; anti-emetics were used routinely.
Results: Most (27) patients (77.1%) had a performance status of 0 to 1 and eight (22.9%) had received
prior adjuvant or neoadjuvant cisplatin-based chemotherapy. In the intention-to-treat analysis, the
objective response rate was 65.6% [23/35 patients, 95% confidence interval (CI) 47.8% to 80.9%]. Ten
patients (28.5%) achieved a complete response (95% CI 14.6% to 46.3%) and 13 (37.1%) a partial
response (95% CI 21.5% to 55.0%). Median survival time was 15.5 months, median duration of
response was 10.2 months and median time to progression was 8.9 months. Ten patients (28.5%) developed grade 3/4 neutropenia, including five (14.3%) who experienced febrile neutropenia, which was
successfully treated. Grade 3/4 anaemia and thrombocytopenia occurred in 20% and 25.7% of patients,
respectively; four patients required platelet transfusions. There were no treatment-related deaths.
Conclusions: Weekly docetaxel, gemcitabine plus cisplatin is a highly effective treatment for chemotherapy-naïve advanced TCC, and causes only moderate toxicity. This regimen should be considered as
a suitable option that deserves further prospective evaluation through randomised phase III trials.
Key words: cisplatin, docetaxel, gemcitabine, transitional cell carcinoma, urothelial cancer
Introduction
Carcinoma of the bladder is the fourth most common cancer in
men and the ninth in women [1]. Of patients with muscle invasive transitional cell carcinoma (TCC) of the bladder, ∼50%
develop pelvic recurrence or distant metastases [2].
Cisplatin is one of the most effective single-agent treatments for metastatic urothelial TCC, with response rates of
12–40% [3–6], and forms the cornerstone of combination
chemotherapy. Cisplatin-based combination chemotherapy
has become standard care for patients with advanced urothelial TCC [7]. Combinations of methotrexate (MTX)/vinblastine (VLB)/doxorubicin/cisplatin (M-VAC) and cisplatin/
MTX/VLB (CMV) are considered the most active regimens
for metastatic TCC, with reported response rates of 46–72%
[8–10]. One study recently reported a 5-year survival rate
of 40% with M-VAC [11]. M-VAC has been shown to be
*Correspondence to: 51 Botassi Street, 18537 Piraeus, Greece.
Tel: +30-1-6008610; Fax: +30-1-6008610; E-mail: [email protected]
© 2002 European Society for Medical Oncology
superior to single-agent cisplatin, in terms of response rate and
survival [3], and also to cisplatin, cyclophosphamide and
adriamycin (CISCA) in terms of response rate [12]. Cisplatinbased chemotherapy has also been shown to be superior to
carboplatin-based chemotherapy in advanced bladder carcinoma [13].
However, M-VAC is associated with significant toxicity,
including grade 3/4 myelosuppression, mucositis, nephrotoxicity, nausea and vomiting, as well as drug-related mortality
[3, 9]. Moreover, despite the use of haematopoietic growth
factors to reduce myelotoxicity and allow dose intensification
of M-VAC, response rates with this regimen have not
improved. Therapeutic approaches with new agents are therefore required to improve response rate and survival while
reducing toxicity [14].
During the last decade, several new chemotherapeutic
agents have shown activity against advanced TCC, including
docetaxel [15, 16] and gemcitabine [17–20]. Docetaxel and
gemcitabine exert differing mechanisms of cytotoxic activity to
cisplatin. Docetaxel binds to the β-subunit of tubulin, inhibiting
244
the formation of stable microtubule bundles, which leads to
cell death [21]. It also acts through phosphorylation of Bcl-2,
which promotes apoptosis [22]. Gemcitabine is an antimetabolite that inhibits DNA synthesis and ribonucleotide
reductase [23].
Both agents have shown single-agent activity in advanced
or metastatic TCC. Single-agent docetaxel 100 mg/m2 has
achieved response rates ranging from 31–50% in patients with
chemotherapy-naïve metastatic TCC, and 13% in previously
treated patients [15, 16, 24, 25]. Single-agent gemcitabine, at
doses ranging from 875–1350 mg/m2, yielded response rates
of 23% and 28% in previously untreated patients [18, 19] and
27% and 23% in patients who had received prior chemotherapy with cisplatin [17, 20].
Combinations of these two agents with cisplatin have been
found to achieve higher response rates than either docetaxel or
gemcitabine alone. In three studies, cisplatin 75 mg/m2 plus
docetaxel 75 mg/m2 produced response rates of 57–62% in
chemotherapy-naïve patients with metastatic TCC [26–28].
Similarly, gemcitabine 1000 mg/m2 plus cisplatin 70–100
mg/m2 every 4 weeks achieved response rates ranging from
40–66% in untreated and previously treated patients with
advanced TCC [29–32].
In a study of gemcitabine 800 mg/m2 (given on days 1, 8 and
15) and docetaxel 80 mg/m2 (given on day 1) in TCC patients
who were either chemotherapy-naïve or had failed one prior
non-gemcitabine or non-taxane-containing regimen [33], the
overall response rate in the 14 evaluable patients was 43%.
Given these findings and the different mechanisms of action
of cisplatin, docetaxel and gemcitabine, we conducted a phase
II study to evaluate the efficacy and toxicity of a combination
of all three agents, administered on a weekly basis. The
weekly administration and sequence of agents was chosen on
the basis of previous experience with combination studies
[25–32, 34, 35]. It was also based on our unpublished data
from a dose-finding phase I trial of weekly administration of
these agents in advanced TCC and our experience using
weekly chemotherapy for non-small-cell lung cancer.
Patients and methods
Patients
This study enrolled patients with histologically proven, bidimensionally
measurable, advanced TCC of the bladder, renal pelvis or ureter, who had
received no prior chemotherapy for advanced disease. Eligible patients
were required to have an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 to 3, life expectancy of at least 12 weeks, adequate
haematological [white blood cell count (WBC) ≥4000 cells/µl, absolute
neutrophil count (ANC) ≥2000 cells/µl, platelet count ≥100 000/µl,
haemoglobin ≥10 g/dl], renal (serum creatinine <1.5 mg/dl, creatinine
clearance ≥60 ml/min) and liver functions [bilirubin <1.5-fold the upper
normal limit (UNL) and AST <2-fold the UNL, unless liver metastases
were present, in which case <5-fold the UNL was allowed]. Patients who
had previously received intravesical chemotherapy or immunotherapy
were not excluded, and prior adjuvant or neoadjuvant treatment was per-
mitted if it had been completed more than 6 months before study entry.
Patients who had previously been treated with radiotherapy were entered
into the study, provided that measurable disease existed outside the radiation field.
Exclusion criteria comprised patients who had only malignant effusion,
bone metastases or lesions assessable only by endoscopy; patients with
brain metastases, history of atrial or ventricular cardiac arrhythmias, congestive heart failure, documented myocardial infarction or pre-existing
motor or sensory neurotoxicity grade ≥1 according to the WHO scale.
Patients with active infection or other serious underlying medical conditions that would impair administration of the protocol treatment were
also ineligible.
The study protocol was approved by the local ethics committee, and
informed consent was obtained from all patients before enrolment.
Treatment plan
Chemotherapy was administered on an outpatient basis. Patients received
the following chemotherapy sequence on days 1 and 8 of a 21-day cycle:
docetaxel 35 mg/m2 in 250 ml 5% glucose as a 30 min intravenous (i.v)
infusion with oral steroid premedication (dexamethasone 8 mg orally
every 12 h for four doses); gemcitabine 800 mg/m2 in 500 ml normal
saline as a 30 min i.v infusion; and cisplatin 35 mg/m2 in 250 ml normal
saline as a 1 h i.v. infusion, with brief pre- [500 ml 5% glucose + 500 ml
normal saline + 2 Amp KCl (26.8 mEq KCl) as a 2 h i.v. infusion] and
post- [500 ml 5% glucose + 500 ml normal saline + 2 Amp KCl (26.8 mEq
KCl) + 8 ml MgSO4 (2 g MgSO4 or 16.32 mEq Mg2+) + 100 ml mannitol
20% as a 3 h i.v. infusion] hydration and mannitol (50 ml i.v. bolus before
the administration of cisplatin) diuresis. Anti-emetic prophylaxis (ondansetron) was given before the administration of each cycle. Prophylactic
recombinant human granulocyte-colony stimulating factor (G-CSF)
150 µg/m 2 was given subcutaneously from day 3 to day 6 and day 10 to
day 15.
Doses of chemotherapy agents were modified according to WBC and
platelet counts, as well as renal and hepatic function. Chemotherapy was
given as above on day 1 if the ANC was >2000 cells/ µl and the platelet
count was >100 000/µl on the day of treatment. However, if the ANC
nadir was <1000 cells/µl and/or platelet nadir was <75 000/µl, the doses
were reduced to docetaxel 30 mg/m2, gemcitabine 700 mg/m2 and cisplatin 30 mg/m2 (level 1) if the ANC was <500 cells/µl and/or platelet count
<50 000/µl the doses were further reduced to docetaxel 25 mg/m2, gemcitabine 600 mg/m2 and cisplatin 25 mg/m2 (level 2). Any patient who
required treatment delay on day 1 because of toxicity had the dose reduced
to level 1 for subsequent cycles.
On day 8, the full doses were given if the ANC was >1500 cells/µl,
platelet count was ≥100 000/µl and any non-haematological toxicity was
grade 2 or lower. However, if the ANC was 1000–1500 cells/µl or the
platelet count was 75 000–99 000/µl, the dosage was reduced to level 1,
and if the ANC was <1000 cells/µl or the platelet count was <50 000/µl
the treatment was withheld. Any patient who required treatment to be
withheld on day 8 because of toxicity had the dosage reduced to level 2 for
subsequent cycles.
The dose of cisplatin was also adjusted according to creatinine clearance. If creatinine clearance was <50 ml/min, treatment was delayed until
recovery (but for no longer than 10 days, otherwise the patient was
removed from the study). A dose reduction of 25% was made if the
creatinine clearance was between 50 and 59 ml/min. If patients experienced any grade 3 or 4 non-haematological toxicity, chemotherapy was
withheld until recovery to grade 1 or less.
245
Assessments
Before entering the study, all patients underwent a physical examination,
complete blood count (CBC), blood chemistry, chest X-ray, bone scan
and abdominal computed tomography (CT) scan. A thoracic CT scan and
other specific tests were performed when indicated. Cystoscopic evaluation was performed only when necessary for local recurrence.
Response was assessed every two cycles of treatment according to
WHO criteria [36]. Most of the imaging examinations were performed in
different private centres. All these tests were reviewed by two consultant
radiologists at our institution. Patients were treated with at least six cycles
of chemotherapy unless there was evidence of disease progression or
unacceptable toxicity occurred during treatment. After completing six
cycles of treatment, patients were followed up. Patients who were stable
for six cycles were considered to have completed protocol therapy and
went off treatment. Patients who achieved either a complete or partial
response after six cycles could continue treatment for a further two cycles
at the discretion of the investigator. Complete blood count and serum
creatinine levels were monitored weekly and toxicity was evaluated
weekly. The WHO scale was used to grade toxicity.
Complete response was defined as the complete disappearance of all
measurable disease for at least 4 weeks. Partial response was defined as a
more than 50% reduction in all measurable disease for at least 4 weeks.
Stable disease was defined as a 50% or less reduction of all measurable
lesions. Progressive disease was defined as an increase in any lesion or the
appearance of new lesions. All responses were confirmed 4 weeks later.
Table 1. Patient characteristics at baseline
Characteristic
No. of patients (n = 35)
Sex
Male
26
Female
9
Age (years)
Median
65
Range
42–74
ECOG performance status
0
7
1
20
2
6
3
2
Previous treatment
Intravesical immunochemotherapy
5
Radiotherapy
4
Adjuvant/neoadjuvant chemotherapy
8
Sites of disease
Lymph nodes
22
Lung
7
Liver
10
Statistics
Bones
10
The primary endpoints of this study were to evaluate the response and
toxicity. Sample size was based on overall response rate. According to
Simon’s two-stage minimax design, assuming that the expected overall
response rate would not be ≤50% or ≥70%, a sample size of 20 patients
would be required for the first step and 15 patients for the second step. If
≤11 or ≥16 responses were seen at step 1, then the study would be discontinued. If 12 to 15 responses were observed, then an additional 15 patients
would be required.
Bladder
12
Survival was calculated from the day of commencement of chemotherapy to the day of death using the Kaplan–Meier method [37]. Duration of
response was calculated from the first day response was noted until the
date of progression. Time to tumour progression was defined as the time
elapsed from the start of treatment to renewed disease progression.
Results
Patients
From October 1997 to June 1999, 35 eligible patients were
enrolled and treated. The analysis was performed in May
2000; all patients were assessable for toxicity and 32 for
response. One patient withdrew consent after the first treatment cycle because of severe asthenia and fatigue, one had a
stroke and one died soon after the first cycle because of rapid
deterioration of his disease (in the liver). Baseline patient
characteristics are shown in Table 1. Median age was 65 years,
and three-quarters of patients were male. More than half of the
patients had an Eastern Co-operative Oncology Group (ECOG)
performance status of 1. Eight patients had previously received
Pelvis
4
Pleural effusion
1
Subcutaneous nodules
1
No. of disease sites
1
5
2
20
≥3
10
ECOG, Eastern Cooperative Oncology Group.
either adjuvant or neoadjuvant chemotherapy. In none of the
patients was the bladder the sole site of disease; almost twothirds of the population had lymph-node metastases, and
almost one-third had either liver or bone involvement.
Response
In the intention-to-treat analysis, the objective response rate
was 65.6% [23/35 patients; 95% confidence interval (CI)
47.8% to 80.9%]. Complete response was achieved in 10
patients (28.5%, 95% CI 14.6% to 46.3%) and partial response
in 13 (37.1%, 95% CI 21.5% to 55.0%). An additional six
patients met the criteria for disease stabilisation, and three
patients had progressive disease. The three patients who were
not assessable for response were also classed as having
progressive disease (Table 2). Responses by disease site are
246
Table 2. Response rates (n = 35)
Table 3. Response by disease site
n
Patients (%)
CI
Complete response
10
28.5
14.6% to 46.3%
Partial response
13
37.1
21.5% to 55.0%
Lung
Objective response rate
23
65.6
47.8% to 80.9%
Stable disease
Progressive disease
6
a
6
a
Includes three patients not assessable for response.
CI, confidence interval.
shown in Table 3. Some complete responses were noted in
patients with metastases at all disease sites except for bone.
The patient with pleural effusion who achieved complete
remission also had lymph-node and lung metastases.
The median duration of response was 10.2 months (range
3.1 to 24.8 months), the median time to progression was 8.9
months (range 4.2 to 22.6 months) and the median survival
time was 15.5 months (range 1.8 to 24.8 months). At a median
follow-up of 12.9 months, 18 patients were still alive.
Treatment administration
The median number of cycles per patient was five (range 1–8).
The median relative dose intensities were 0.87 for docetaxel,
0.88 for gemcitabine and 0.89 for cisplatin. Despite the prophylactic use of haematopoietic growth factors, dose reduction was required in seven patients (20%), three of whom
required two reductions. Five patients required dose reductions of cisplatin because of renal toxicity, but no cisplatin
doses were omitted or delayed. All dose reductions were due
to neutropenia, thrombocytopenia or renal toxicity, with no
dose reduction or treatment delay for any other grade 3/4
toxicity.
Toxicity
The main toxicity was myelosuppression (Table 4). Grade 4
neutropenia occurred in four patients (11.4%) and grade 3
neutropenia in six (17.1%) patients. Five patients were hospitalised with febrile neutropenia, which was treated with broadspectrum antibiotics. Grade 3/4 thrombocytopenia occurred in
nine patients (25.7%). Nine patients required hospitalisation
(five because of febrile neutropenia and four for platelet
transfusions). None of the patients who underwent platelet
transfusions had evidence of bleeding.
Grade 3/4 nephrotoxicity occurred in five patients (14.3%)
and resulted in dose reduction in all five. Fluid retention grade
≥2 occurred in six patients (17.2%) but was easily managed
with oral diuretics. No patient had general skin changes, but
erythema, rash, pruritus, desquamation and nail changes were
observed in more than one-third of patients. Peripheral neuropathy was experienced by four patients (11.4%), usually after
two or three treatment cycles. Infusion-related allergic
Disease site
Complete response
Partial response
No.
%
No.
%
2
28.5
3
42.8
Liver
2
20
3
30
Bones
–
–
4
40
Lymph nodes
5
22.7
8
36.3
Subcutaneous nodules
1
100
–
–
Pleural effusion
1
100
–
–
Bladder plus pelvis
2
16.5
5
31.2
reactions occurred in five patients (14.3%), but all resolved
within 5–10 min. Two of these patients showed evidence of
hypersensitivity reaction (chest tightness, dyspnoea, cough
and flushing) that required treatment with adrenaline, antihistamines and corticosteroids; these events did not recur after
the patients were treated with a 2 h infusion of docetaxel and
gemcitabine.
Nausea and vomiting grade ≥2 occurred in 22 patients
(62.8%), grade 2/3 diarrhoea in seven patients (20%) and
mucositis grade ≥2 in 12 patients (34.3%). Ten patients
(28.6%) developed grade 2/3 fatigue that did not require dose
modification, but one patient who experienced grade 3 fatigue
withdrew from treatment after the first cycle. Alopecia was
universal but reversible. Constipation was not a problem.
There were no instances of cardiac toxicity and no treatmentrelated deaths during the study or follow-up.
Discussion
This phase II study of a combination of docetaxel, gemcitabine and cisplatin (the first reported for this drug combination)
given weekly was well tolerated and highly effective as a firstline treatment for metastatic TCC, as demonstrated by the
response rate, median time to progression and median survival. The overall response rate of 65.6% is one of the highest
reported to date; it is superior to response rates with the three
agents alone [3–6, 15–20] and matches or exceeds response
rates achieved with combinations of cisplatin/gemcitabine
[29–32] or cisplatin/docetaxel [26–28].
Methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC)
remains the standard treatment for many patients with
advanced TCC (10). Recently, M-VAC regimen was compared in a randomised, multinational, multicentre phase III
study with gemcitabine 1000 mg/m2 given on days 1, 8 and 15
and cisplatin 70 mg/m2 day 2 [38]. The response rate (46%
versus 49%), median time to progression (7.4 months for both
arms) and median survival (14.8 versus 13.8 months) were
similar in both arms. More gemcitabine plus cisplatin than
M-VAC patients had grade 3/4 anaemia and thrombocytopenia, while more M-VAC than gemcitabine plus cisplatin
247
patients had grade 3/4 neutropenia, neutropenic fever, neutropenic sepsis and toxic death. More patients on gemcitabine
plus cisplatin faired better regarding weight, performance
status and fatigue. The need exists, therefore, to develop new
combinations for the treatment of patients with metastatic TCC
in order to find more effective and less toxic combinations.
During the last few years a number of new chemotherapeutic
agents have been shown to be active against advanced TCC,
including paclitaxel [39–41], docetaxel [15, 16, 25], gemcitabine [18, 19], vinorelbine [42–44], liposomal doxorubicin
[45] and gallium nitrate [46–48].
This triple combination was also well tolerated, showing
only moderate toxicity—28.5% of patients developed grade
3/4 neutropenia and 25.7% thrombocytopenia; only nine
patients required hospitalisation. These figures compare well
with the findings of dual combinations of cisplatin/gemcitabine or cisplatin/docetaxel. In a phase II study of cisplatin/
gemcitabine, 55% of patients experienced grade ≥3 thrombocytopenia [32]. In recent phase I/II studies, the incidence of
neutropenia was 56% in patients receiving docetaxel/cisplatin
[27] and as high as 71% in those receiving cisplatin/gemcitabine [38]. No major infections occurred in this study, compared with an incidence of febrile neutropenia of 41%
reported in one study using M-VAC [3] and 38% grade 3/4
neutropenia reported in a study using paclitaxel, gemcitabine
and cisplatin every 3 weeks [34]. Nausea and vomiting grade
≥3 occurred in approximately one-quarter of our patients,
despite the use of ondansetron premedication, a finding that
compares well with incidences seen in studies of gemcitabine/
cisplatin [38] or docetaxel/cisplatin [27] in combination.
Mucositis grade 3/4 occurred in 11.4% of patients, which is
comparable with incidences reported with M-VAC [3] and a
combination of gemcitabine/cisplatin [32]. Fatigue grade ≥3
also occurred in 11.4% of patients, comparing well with
reports for M-VAC [3] and a combination of gemcitabine/
cisplatin [32]. Neurotoxicity grade ≥2 was observed in 11.4%
of patients, but was reversible during the follow-up period.
Grade 2/3 cutaneous toxicity and fluid retention were limited
by the use of premedication and a low dose of docetaxel.
Hypersensitivity reactions were generally mild to moderate
and resolved within 5–10 min. Premedication was given to
reduce the risk of allergic reactions. Prophylactic haematopoietic growth factor was used to maintain the dose and weekly
administration, although 20% of patients required a dose
reduction and 8.6% required two reductions.
Our study was designed on the basis that paired combinations of docetaxel, gemcitabine and cisplatin, which represent
three of the most active single agents in advanced TCC, have
been shown to achieve higher response rates than any of the
three agents alone. Combination chemotherapy offers the
potential to optimise response rates and survival by using
agents with complementary mechanisms of action. In vivo and
Table 4. Incidence of toxicity
Incidence of toxicity (grade)a
0
1
2
3
4
Haematological
Neutropenia
2 (5.7)
7 (20)
16 (45.7)
6 (17.1)
4 (11.4)
Thrombocytopenia
4 (11.4)
8 (22.9)
14 (40)
4 (11.4)
5 (14.3)
Anaemia
5 (14.3)
9 (25.7)
14 (40)
5 (14.3)
2 (5.7)
24 (68.6)
6 (17.2)
3 (8.6)
2 (5.7)
0
11 (31.4)
Non-haematological
Allergy
Alopecia
1 (2.8)
6 (17.1)
7 (20)
Constipation
21 (60)
9 (25.7)
5 (14.3)
0
0
Diarrhoea
25 (71.4)
3 (8.6)
5 (14.3)
2 (5.7)
0
Fatigue
11 (31.4)
14 (40)
6 (17.2)
4 (11.4)
0
Fever
26 (74.3)
3 (8.6)
4 (11.4)
2 (5.7)
0
Fluid retention
14 (40)
15 (42.8)
3 (8.6)
3 (8.6)
0
Mucositis
16 (45.7)
8 (22.9)
3 (8.6)
1 (2.8)
5 (14.3)
8 (22.9)
13 (37.1)
7 (20)
2 (5.7)
Nephrotoxicity
18 (51.4)
9 (25.7)
3 (8.6)
4 (11.4)
1 (2.8)
Ototoxicity
26 (74.3)
6 (17.1)
2 (5.7)
1 (2.8)
0
Peripheral neuropathy
27 (77.1)
4 (11.4)
2 (5.7)
2 (5.7)
0
Skin changes
16 (45.7)
5 (14.3)
0
0
Nausea/vomiting
a
Graded according to WHO criteria.
7 (20)
10 (28.6)
14 (40)
248
in vitro studies of cisplatin plus gemcitabine have shown both
synergistic and additive effects [49]. Cisplatin and docetaxel
are not synergistic in vivo, but seem to be non-cross-resistant
clinically and have a predominantly non-overlapping toxicity
profile, and this combination may have at least an additive
effect clinically [50]. Gemcitabine and docetaxel have different cellular targets (DNA synthesis and microtubules, respectively) and act at different phases of the cell cycle (S phase and
mitosis, respectively). The interaction between gemcitabine
and paclitaxel has also been studied in cell-line models (A
549, lung; MCF 7, breast; and P-SW pancreas) [51]. Antagonism was noted for all three cell lines when gemcitabine and
paclitaxel were administered concurrently, while additive
effects were seen when gemcitabine preceded or followed
paclitaxel [51]. However, simultaneous and sequential combination schedules of gemcitabine and paclitaxel in human
bladder cancer cell lines showed additive cytotoxic properties
[52]. In addition, it seems that a schedule of weekly administration of these agents is probably better tolerated than schedules in which these agents are given every 3–4 weeks [53].
Also, considerable experience has been accumulated with
weekly or rapidly repeated regimens. Results clearly indicate
that this strategy is feasible in many oncological settings, with
manageable toxicity and a limited number of toxicity-related
deaths when therapy is adequately monitored by well trained
oncologists. Response rates are impressive and a benefit in
disease-free survival or overall survival has been reported in a
number of malignances [54]. We therefore administered the
triple combination of docetaxel, gemcitabine and cisplatin to
investigate whether incorporating a third agent would prove
superior in terms of response rate, median survival and/or
toxicity. The sequence of agents was chosen on the basis of
previous experience with combination studies [26–32, 35, 38].
We administered the three agents on a weekly basis in the
following sequence: docetaxel, gemcitabine and cisplatin.
Recent studies have also evaluated the efficacy of other
triple combination regimens in advanced TCC. Again, overall
response rates and median survival were similar to those
reported with our triple regimen, but these regimens appeared
to give rise to higher levels of toxicity. In a previous phase II
study we investigated a combination of epirubicin (40 mg/m2)
i.v. push, docetaxel (75 mg/m2) in a 1-h infusion and cisplatin
(75 mg/m2), every 3 weeks in patients with advanced TCC
[55]. Overall response rate was 67% and median survival was
14.5 months. However, 53% of patients experienced grade ≥3
neutropenia and, despite the use of haematopoietic growth
factors, 53.3% of patients required dose reduction due to
myelosuppression (16.7% required two reductions). In another
phase II study evaluating cisplatin 70 mg/m2 on day 1, and
paclitaxel 80 mg/m 2 and gemcitabine 1000 mg/m2 on days 1
and 8, every 3 weeks in patients with previously untreated
locally unresectable or metastatic TCC, Bellmunt et al. [34]
reported an overall response rate of 77.6% (27.6% complete
response) and median survival of 24 months. Again, however,
toxicity was higher [main toxicity grade ≥3 neutropenia and
thrombocytopenia (55% and 22%, respectively)] than that
seen with the triple regimen described in the present study.
Frassoldati et al. [35] evaluated the combination of cisplatin
70 mg/m2, gemcitabine 800 mg/m2 plus paclitaxel 175 mg/m2
on day 1 every 3 weeks in chemotherapy-naïve patients with
metastatic or unresectable locally advanced TCC. Although
overall response rate was somewhat lower than that reported
with our triple regimen (33%; intention-to-treat response rate
26.6%; median time to progression of 4 months), grade ≥3
neutropenia and thrombocytopenia occurred in only 14% and
8% of patients, respectively. The authors consider that pharmacokinetic interaction due to the sequence of the drugs could
be responsible for this low response rate.
A recent triple regimen study, based on carboplatin rather
than cisplatin, has shown similar findings. A combination of
paclitaxel (200 mg/m2), carboplatin (target AUC of 5) on day
1, and gemcitabine (800 mg/m2 on days 1 and 8), every 3
weeks, gave a response rate of 68% (95% CI 56.26 to 82.86;
32% complete response) and a median survival of 14.7 months
(1-year survival 59%) [56]. However, neutropenia and
thrombocytopenia grade ≥3 occurred in 73% and 43% of
patients, respectively.
The response rate achieved with our triple regimen, administered weekly, was therefore similar to those reported with
other triple combination regimens administered every 3 weeks
[34, 35, 55]. In addition, our findings compare favourably with
those seen with M-VAC, also administered every 3 weeks [3],
and a combination of cisplatin/gemcitabine when both agents
were given weekly (65.6% in our study versus 40%) [29] or
3-weekly (65.6% in our study versus 49.4%) [38].
In conclusion, the weekly triple combination of docetaxel,
gemcitabine plus cisplatin investigated in this study is a highly
active regimen in patients with previously untreated advanced
TCC, and gives rise to moderate toxicity. Despite the need for
co-administration of G-CSF, its weekly regimen is attractive
because of its outpatient administration, high response rate
and median survival duration. Before a definite conclusion
can be made, prospective randomised studies are needed to
compare this triple regimen with the standard M-VAC regimen or other combinations using novel agents.
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