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Gemcitabine Combination Chemotherapy in Metastatic Breast Cancer: Phase II Experience

Gemcitabine Combination Chemotherapy in Metastatic Breast Cancer: Phase II Experience

ABSTRACT: Gemcitabine has been evaluated in combination with paclitaxel, docetaxel, anthracyclines, vinorelbine, and cisplatin as first-line treatment and after prior chemotherapy in patients with metastatic breast cancer. Results with gemcitabine/taxane combinations have been especially encouraging, with these combinations providing promising outcomes with regard both to tumor response and tolerability. The combination of gemcitabine and paclitaxel has garnered particular interest for further phase III evaluation on the basis of high response rates and durable responses in both treatment-naive and treatment-experienced patients, including anthracycline-pretreated patients.

Gemcitabine (Gemzar) is a
nucleoside antimetabolite that
undergoes intracellular phosphorylation
to its activated diphosphate
and triphosphate forms. The
triphosphate form, which is competitive
with deoxycytidine-triphosphate,
is incorporated into DNA, resulting in
masked DNA chain termination; the
diphosphate form reduces deoxycytidine
triphosphate levels, resulting in
increased incorporation of gemcitabine
triphosphate. Gemcitabine exhibits
single-agent activity in metastatic
breast cancer, including in heavily pretreated
patients.[1,2] The agent has
been evaluated in patients with advanced
breast cancer in a variety of
two-drug chemotherapy combinations.[
2] Among these, the combination
of gemcitabine and paclitaxel or
docetaxel (Taxotere) has generated
considerable interest for evaluation in
phase III trials.

Gemcitabine/Paclitaxel

Five phase II trials have examined
the gemcitabine/paclitaxel combination
in advanced breast cancer (Table
1).[2-8] Among trials evaluating the
combination as first-line treatment, Colomer and colleagues reported use
of gemcitabine at 2,500 mg/m2 on day
1 and paclitaxel at 150 mg/m2 on day
1 every 14 days in 42 patients, of
whom 72% had received adjuvant
therapy.[3] Complete response was
observed in 10 patients (24%) and
partial response was observed in 19
(45%). Median response duration was
9 months. Grade 4 neutropenia occurred
in 17% of patients and grade 4
leukopenia occurred in 8%. One patient
developed neutropenic fever.
Grade 3 thrombocytopenia, nausea/
vomiting, neurosensory toxicity, and
constipation were each observed in
4% of patients. Grade 3 elevation of
aspartate aminotransferase level was
observed in 8% of patients.

Genot et al assessed gemcitabine
at 1,200 mg/m2 on days 1 and 8 and
paclitaxel at 175 mg/m2 on day 1 every
21 days in patients who had received
no previous chemotherapy for
metastatic disease.[4] Among 36 evaluable
patients, two (6%) had a complete
response and 13 (36%) had a
partial response; seven (19%) had stable
disease. At the time of reporting,
the median follow up was 175 days.
Median response duration was 11.5
months and median time to disease
progression was 7.5 months. The most
frequent grade 3 hematologic toxicities
were leukopenia (41 episodes) and
granulocytopenia (52 episodes); 24
episodes of grade 4 granulocytopenia
were observed.

Delfino et al assessed gemcitabine
at 1,200 mg/m2 on days 1 and 8 and

paclitaxel at 175 mg/m2 on day 1 every
21 days in 42 evaluable patients,
of whom 27 (64%) had received previous
adjuvant therapy. Complete response
was observed in 14% of
patients and partial response in 41%;
26% of patients had stable disease.
The median response duration was 19
months, median time to progressive
disease was 9 months, and median
time to treatment failure was 9 months.
At 1 year, 65% of patients remained
alive. Grade 3 or 4 toxicities consisted
of leukopenia in six patients, thrombocytopenia
in six patients, and
mucositis in seven patients.

In metastatic breast cancer patients
pretreated with chemotherapy, Sanchez-Rovira et al reported findings
in 44 heavily pretreated patients,
of whom nearly all had previously
received anthracyclines and 20% had
received paclitaxel.[6] Patients received
gemcitabine at 2,500 mg/m2
on days 1 and 15 and paclitaxel at 135
mg/m2 on days 1 and 15 every 28
days. Seven patients (16%) had a complete
response and 13 (30%) had a
partial response. The median response
duration was 8 months (range: 4 to 26
months) and median survival was 12
months (range: 4 to 28 months). Grade
3 or 4 hematologic toxicity occurred
in 15% of patients; 34% of patients
required granulocyte colony-stimulating
factor (G-CSF) support.

In a trial reported by Murad et al,
patients previously treated with an
anthracycline-containing regimen
were treated initially with gemcitabine
at 1,000 mg/m2 on days 1, 8, and
15 and paclitaxel at 175 mg/m2 on
day 1 every 28 days.[7] After unacceptable
thrombocytopenia occurred
in the first five patients treated, dosing
was changed to a 21-day schedule
with gemcitabine given on days 1
and 8 and paclitaxel on day 1. Five of
29 (17%) evaluable patients had a
complete response and 11 (38%) had
a partial response; six patients (21%)
had stable disease. Median response
duration was 8 months (range: 4 to
26 months) and median survival was
12 months (range: 4 to 28+ months),
with 1- and 2-year survival rates of
45% and 30%, respectively. Grade 3
or 4 thrombocytopenia was observed
in five (19%) of 27 cycles using the
28-day schedule compared with six
(5%) of 110 cycles using the 21-day
schedule (P = 0.04). Eight patients
had grade 3 neutropenia; two had
grade 4 neutropenia associated with
fever, both during the 28-day treatment
cycle. Two patients had grade 3
neuropathy.

These findings suggest that gemcitabine/
paclitaxel is effective as firstline
treatment and in pretreated
patients, with high responses rates and
durable responses being observed. It
is particularly encouraging that a high
response rate was observed in anthracycline-
pretreated patients, since
low response rates have been reported
with paclitaxel alone after anthracycline
anthracycline
failure. The gemcitabine/paclitaxel
combination currently is being
investigated as first-line therapy
in metastatic breast cancer patients
who have received prior anthracycline-
based adjuvant therapy in a large
phase III study.[8]

Gemcitabine/Docetaxel

Laufman and colleagues evaluated
gemcitabine at 800 mg/m2 on days
1, 8, and 15 plus docetaxel at 100
mg/m2 on day 1 every 4 weeks as
first-line treatment in 39 evaluable
metastatic breast cancer patients, of
whom the majority had received adjuvant
anthracycline treatment (Table
1).[2,9] Objective responses were
observed in 79% of patients. Granulocyte
colony-stimulating factor was
not used prophylactically, and grade
3 or 4 neutropenia occurred in all
patients.

In a study by Kornek et al, 52 patients
(43 chemotherapy-naive) received
gemcitabine at 1,500 mg/m2
plus docetaxel at 50 mg/m2 on days 1
and 15 every 4 weeks with G-CSF
support.[10] Among 34 evaluable patients,
the objective response rate was
59% (64% in patients receiving firstline
treatment) and median time to
progression was 7 months. Grade 3 or
4 neutropenia occurred in 10 patients.

Pelegri et al evaluated gemcitabine
2,500 mg/m2 on day 1 plus docetaxel
65 mg/m2 on day 1 every 2 weeks in
36 patients, of whom less than half
had received adjuvant therapy.[11]
Objective responses were observed in
72% of 25 evaluable patients. Grade
3 or 4 neutropenia occurred in 13 of
29 patients evaluable for toxicity.

Mavroudis et al assessed gemcitabine
at 900 mg/m2 on days 1 and 8
plus docetaxel at 100 mg/m2 on day 8
every 3 weeks with G-CSF support in
52 patients who had relapsed following
anthracycline-based chemotherapy,
of whom approximately half had
received prior taxane treatment.[12]

The objective response rate was 54%
(including 44% in patients with prior
taxane treatment), and the median time
to progression was 8 months. Grade 3
or 4 neutropenia was observed in 15
patients.

Alexopoulos and colleagues assessed
gemcitabine at 900 mg/m2
on day 1 and 8 and docetaxel at
100 mg/m2 every 3 weeks in 36 patients,
of whom half had received prior
anthracyclines or taxanes.[13]
Objective responses were observed in
72% of patients and the median response
duration was 3.2 months.

Brandi et al assessed gemcitabine
at 1,000 mg/m2 on day 1 and 8 plus
docetaxel at 80 mg/m2 on day 8 every
3 weeks in 37 patients whose disease
had progressed after first-line anthracycline
treatment.[14] The objective
response rate was 60%, and median
time to progression was 6 months.
Grade 3/4 neutropenia occurred in
33% of patients.

In a study in 40 patients with anthracycline-
resistant disease, Fountzilas
et al examined a regimen of
gemcitabine at 1,000 mg/m2 on days
1 and 8 plus docetaxel 75 mg/m2 on
day 1 every 3 weeks with G-CSF support.[15] The objective response rate
was 36% and the median time to progression
was 7 months. Grade 3 or 4
neutropenia occurred in 19 patients.

Based on these promising phase II
studies, a randomized phase III study
comparing docetaxel/gemcitabine to
docetaxel/capecitabine is currently
under way.

Gemcitabine/Anthracyclines

Perez-Manga et al evaluated firstline
gemcitabine at 800 mg/m2 plus
doxorubicin at 25 mg/m2 on days 1, 8,
and 15 every 4 weeks in 42 patients,
of whom 29 had received adjuvant
therapy (Table 2).[2,16] The objective
response rate was 55% and the
median response duration was 12
months. There was significant hematologic
toxicity, but no grade 3 or 4
cardiotoxicity.

Rivera et al treated 49 patients, of
whom 27 had received adjuvant therapy,
with gemcitabine at 800 mg/m2
on days 1 and 8 plus pegylated liposomal
doxorubicin at 24 mg/m2 on
day 1 every 3 weeks. Objective responses
were observed in 52% of 46
evaluable patients; the median response
duration was 5.6 months and
the median time to progression was
4.5 months. Hematologic toxicities
were the most common grade 3 or 4
toxicities; one patient previously treated
with an anthracycline developed a
transient decrease in left ventricular
ejection fraction.[17]

Campone et al assessed a regimen
of gemcitabine at 1,500 mg/m2 on days
1 and 8 plus epirubicin at 75 mg/m2
on day 1 every 3 weeks.[2, 18] In the
first 20 patients, of whom approximately
half received the regimen as
first-line treatment, significant doselimiting
toxicities were observed and
the response rate was 33%; altering
the regimen to gemcitabine at 1,250
mg/m2
on days 1 and 4 and epirubicin
on day 1 every 3 weeks resulted in an
objective response rate of 67% in 15
subsequently enrolled patients.

Gemcitabine/Vinorelbine

Haider et al evaluated gemcitabine
at 1,000 mg/m2 on days 1, 15, and
21 plus vinorelbine (Navelbine) at 40 mg/m2 on days 1 and 21 every 4
weeks with G-CSF support in 45 patients
as first-line therapy and in 15
patients as second-line therapy (prior
anthracyclines in two-thirds) (Table
3).[2,19] Objective response rates
were 56% in patients receiving firstline
treatment and 40% in those receiving
second-line treatment (52%
overall) and median times to progression
were 9.5 and 7 months, respectively
(8.5 months overall). Grade 3
or 4 neutropenia occurred in 11 patients.

Moser et al assessed gemcitabine
at 1,200 mg/m2 on days 1 and 8 plus
vinorelbine at 25 mg/m2 on days 1
and 8 every 21 days as first- or second-
line treatment in 30 evaluable
patients (38 evaluable for toxicity).[
20] The objective response rate
was 30%. Grade 3 or 4 neutropenia
occurred in seven patients.

Valenza et al reported a 48% response
rate in 29 patients (prior anthracycline/
taxane adjuvant therapy in
25) receiving gemcitabine at 1,000
mg/m2 on days 1, 8, and 15 plus vinorelbine
at 25 mg/m2 on days 1 and
8 every 4 weeks.[21] The objective
response rate was 48% and the mean
time to progression was 6.8+ months.

Nicolaides et al evaluated gemcitabine
at 1,000 mg/m2 plus vinorelbine
at 30 mg/m2 on days 1 and 8
every 3 weeks in 31 patients who had
received prior taxanes.[22]. Responses
were observed in 22% of patients
and the median time to progression
was 3.5 months. Grade 3 or 4 neutropenia
occurred in 15 patients.

Donadio et al reported an objective
response rate of 39% among 26
patients receiving gemcitabine at
1,000 mg/m2 plus vinorelbine at 25
mg/m2 on days 1 and 8 every 3
weeks.[23] Gokmen et al assessed
gemcitabine at 1,200 mg/m2 plus vinorelbine
at 30 mg/m2 on days 1 and 8
every 3 weeks in 26 patients as first-,
second-, or third-line treatment.[24] The
objective response rate was 45% in 22
evaluable patient and the median time
to progression was 5.5 months.

Mariani et al assessed the same
regimen in 31 patients, of whom most
had received anthracycline or taxane
treatment.[25] The objective response
rate was 22% in 27 evaluable patients.
Grade 3 or 4 neutropenia occurred
in 15 patients. Stathopoulos
and colleagues evaluated gemcitabine
at 1,000 mg/m2 plus vinorelbine at
25 mg/m2 on days 1 and 15 every
4 weeks in 51 patients, of whom all
had received anthracyclines and half
had received taxanes.[26] The objective
response rate was 54% in 50
evaluable patients and the median
time to progression was 6 months.
Grade 3 or 4 neutropenia occurred in
4 patients.

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