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Integrating Gemcitabine Into Breast Cancer Therapy

Integrating Gemcitabine Into Breast Cancer Therapy

ABSTRACT: Gemcitabine (Gemzar) possesses meaningful antitumor activity in the treatment of breast cancer, repeatedly demonstrating superior outcomes without the price of excessive toxicity in most patients. In combination with other agents, it has a potential for nonoverlapping toxicities, a novel mechanism of action, as well as a potential lack of complete cross-resistance. Randomized phase III trials with gemcitabine have yielded response rates that have translated into time to disease progression and survival benefits. Thus, enthusiasm continues for gemcitabine, especially in combination with other cytotoxic agents. The augmentation of efficacy (ie, response rates, time to disease progression, overall survival) by the addition of gemcitabine to paclitaxel has established this regimen as a first-line treatment option for patients who might benefit from combination therapy. Gemcitabine now remains under active investigation for the treatment of early-stage breast cancer, with ongoing trials characterizing its role in the neoadjuvant setting.

As the treatment for breast cancer
continues to evolve, a
striking decline in breast
cancer-related deaths has followed.
Although largely reflecting improvements
in effective screening techniques
and the subsequent inherent
early diagnosis of disease, improvements
in treatment outcomes also bear
some responsibilities for the evident
decline in breast cancer mortality.
However, for both early stage and
metastatic disease, the goals of treatment
largely remain the same and include
reduction of the tumor burden,
prolongation of survival, extension of
the time until disease progression, as
well as improvement in overall symptoms.
All efforts are underscored by
the desire to preserve and maintain as
excellent a quality of life as possible.
With the advent of newer and less
toxic therapeutic options, physicians
have a better chance to achieve these
goals.

Although systemic treatment continues
to be the mainstay for both
early as well as advanced stages of
breast cancer, the impact of existing
chemotherapy on overall survival in
patients with metastatic disease remains
negligible. In this population,
toxicities of the recommended treatment
and the quality of life remain
foremost in their minds. Whether these
patients may have superior clinical
outcomes with combination chemotherapy
regimens or sequential single
agents remains of great debate. Given
the heterogeneity of the disease and
the lack of evidence-based guidelines
in selecting patients appropriate for
either of these choices, each of these
treatment preferences remains a valid
option.

Background on Gemcitabine

Gemcitabine (Gemzar) is a novel
nucleoside analog that has a broad
spectrum of antitumor activity in both
preclinical and solid-tumor models.
The drug requires intracellular phosphorylation
that results in the accumulation
of difluoro-deoxycytidine
triphosphate (dFdCTP).[1] The
dFdCTP competes directly with deoxycytidine
triphosphate (dCTP) for incorporation
into DNA, acting as a
fraudulent base that halts DNA synthesis.[
2] In addition, gemcitabine reduces
intracellular deoxynucleotide
triphosphate pools, presumably by inhibiting
ribonucleotide reductase, the
enzyme essential for both the intracellular
synthesis of deoxynucleotide
triphosphates and normal DNA production.[
3] This unique mechanism
of action has resulted in its subsequent
exciting development as an effective
antitumor strategy for multiple
solid tumors, including breast cancer.

Since its inception, gemcitabine has
consistently demonstrated a commitment
to overall improvement in quality
of life. Evidence of improved
survival and clinical benefit in cancer
patients has followed. In fact, its initial
US Food and Drug Administration
(FDA) approval, stemming from
early studies of gemcitabine in patients
with pancreatic cancer, was
predicated on gemcitabine's demonstrable
improvement in disease-related
symptoms, which was measured
by a composite assessment of pain
including analgesic consumption, pain
intensity, performance status, and
weight.[4] Other measures of efficacy
accompanying these considerations
included response rate, time to disease
progression, and overall survival.

From this point forward, the magnitude
attributed to chemotherapyinduced
palliation of disease-related
symptoms in cancer patients has continued
to evolve and be recognized as
an equally important end point. An
increasing focus on the quality of life
and sustained enhancement of these
parameters now accompany the other
well-established primary efficacy end
points of ongoing trials. Because of
gemcitabine's established antitumor
efficacy, over and beyond its impact
on clinical benefit in cancer patients,
its utilization in breast cancer has precipitously
increased. Its novel mechanism
of action in addition to its
nonoverlapping toxicity facilitates its
ideal combination with other effective
agents for the treatment of advanced
breast cancer.

Single-Agent Studies
of Gemcitabine

To develop further effective systemic
therapies for patients with breast
cancer, gemcitabine has undergone
extensive evaluation, initially in the
metastatic setting, with single-agent
studies reporting a response rate of
15% to 42%.[5-16] Closer examination
of these trials revealed that the
highest response rates occurred in
minimally pretreated patients, with
overall regression of bidimensional
tumor measurements determining objective
responses. Survival for these
breast cancer patients receiving gemcitabine
monotherapy ranged from 3.5
to 18 months. In addition, significant
activity was evident for single-agent
gemcitabine following pretreatment
with both anthracyclines and the taxanes,
generating subsequent enthusiasm
to evaluate gemcitabine in
combination with these (and other)
agents. The findings of these trials are
of paramount importance, as there remains
considerable debate as to
whether the often lesser toxicity associated
with single-agent chemotherapy
might outweigh the benefits of
combination chemotherapy. This has
perhaps been most clearly delineated
with the evolution of the taxanes in
metastatic breast cancer and their subsequent
extended exploration in combination
with the anthracyclines, at
the time considered the single most
effective first-line agent for metastatic
breast cancer.

Eastern Cooperative Oncology
Group (ECOG) 1193, a trial assessing
the role of combination and single-
agent chemotherapy in metastatic
breast cancer, has raised the question
of the long-term benefits of combination
therapy [17]. In this prospective,
randomized phase III trial, investigators
compared single-agent doxorubicin
vs single-agent paclitaxel vs their
combination. As expected, the combination
arm demonstrated a statistically
superior response rate, albeit at
the price of increased hematologic toxicity;
disappointingly, neither overall
survival nor quality of life varied
among the three arms. However, time
to disease progression, a parameter
that truly reflects the administered
therapy and is not influenced by subsequent
posttherapy treatments, was
significantly in favor of the combination
arm statistically, despite a mandated,
built-in single-agent sequential
crossover for the respective single
agents. Consequently, given the enthusiasm
imparted by the addition of
the taxanes docetaxel and paclitaxel
to the treatment of metastatic breast
cancer, further exploration of these
compounds, as either single agents or
in combination with other agents, in
the metastatic, adjuvant, and neoadjuvant
settings has eagerly followed.

Rationale for Combining
Gemcitabine and the Taxanes

The rationale for combining gemcitabine
with the taxanes paclitaxel
and docetaxel (Taxotere) is based on
the fact that the spindle toxins were
two of the most active agents in the
treatment of breast cancer. In addition,
the taxanes remain active in anthracycline
failures, including both
anthracycline-resistant and -refractory
disease, and increasingly have become
utilized in early-stage disease.
Gemcitabine, which is effective following
pretreatment with both anthracyclines
and taxanes, has been
evaluated with both taxanes in a variety
of phase II metastatic breast cancer
trials. Since both of these
beta-tubulin-binding drugs have demonstrated
single-agent activity in metastatic
breast cancer, their union with
gemcitabine was inherent, supported
by their differing cellular mechanisms
of action and their largely nonoverlapping
toxicity. Although empiricism often
invokes the design of combination
regimens in the absence of provocative
in vivo preclinical data, a suggestion of
clinical synergism between these agents
prompted the further evaluation of this
doublet as an ideal and promising treatment
strategy.[18,19]

One of the first phase II trials evaluating
gemcitabine and the taxanes
was that of Murad et al who evaluated
29 patients treated with gemcitabine
and paclitaxel as second- or third-line
therapy in metastatic breast cancer.[
20] Visceral involvement was
evident in the majority of patients,
with all patients having received prior
chemotherapy for metastatic disease.
A remarkable 55% overall response
rate was noted with nearly 20% of the
patients achieving a complete remission.
Although the initial schedule administered
gemcitabine at 1,000
mg/m2 on days 1, 8, and 15, the day-
15 dose was subsequently deleted due
to hematologic toxicity in these heavily
pretreated patients.

Utilizing docetaxel, Fountzilas et
al evaluated the identical gemcitabine
dose and day 1 and 8 schedule reported
by Murad and colleagues in 40
anthracycline-resistant metastatic
breast cancer patients.[21] The study
population consisted of a more elderly
(median age, 60) and poorer prognosis
patient population, with 75% of
the patients exhibiting visceral metastases,
and yielded a 36% overall
response rate with three patients exhibiting
complete remission. Median
survival was consistent with that reported
by Murad et al, at approximately
12 months, with a median
duration of response at 10.3 months.
More hematologic toxicity was noted
for the docetaxel/gemcitabine doublet,
reflecting docetaxel's schedule-dependent
noncumulative myelosuppression,
with 49% of the patients
demonstrating grade 3/4 neutropenia.
The remarkable activity of the gemcitabine/
taxane doublet in pretreated
breast cancer patients with easily
demonstratable, consistent efficacy parameters,
in addition to manageable toxicity,
resulted in the further evaluation
of this combination as first-line treatment
in metastatic breast cancer.

The principle of clinical synergism,
nicely highlighted by two trials, has
heralded the further investigation and
evaluation of this couplet in metastatic
as well as early-stage breast cancer.
In the first of these two trials, Mavroudis
et al reported the results of gemcitabine
and docetaxel in 52
anthracycline-resistant patients, half
of which had received treatment with
a prior taxane.[18] Visceral disease
was present in 75% of the patients,
with 50% of the patients receiving
this combination as third-line therapy
or greater. The overall response rate
was 54%, with approximately 15% of
the patients achieving complete responses.
Surprisingly, in the 25 patients
who were both anthracycline resistant
and who had received prior taxane therapy,
an overall admirable response rate
of 44% was noted, clearly higher than
expected in such a heavily taxane-pretreated
patient population.

In a second trial, Alexopoulos et al
evaluated 36 metastatic breast cancer
patients, all of whom had received a
prior anthracycline and taxane.[19]
Following four to six cycles of single-
agent docetaxel at a dose of 100
mg/m2 at 3-week intervals, the 22 patients
with stable disease and 14 patients
with progressive disease
continued receiving docetaxel, to
which gemcitabine (900 mg/m2 on
days 1 and 8) was added. An astonishing
response rate of 72% (with
complete remissions in 12% of patients)
was reported. Although previous
studies [22] reported a 25%
response rate for docetaxel administered
in paclitaxel-resistant advanced
breast cancer, the observation that the
docetaxel/gemcitabine combination
induces significant responses in patients
who progress while receiving
docetaxel-based front-line chemotherapy,
supports the consideration of an
in vivo synergistic effect between
these two agents. Certainly provocative,
the Hellenic Cooperative Group
for Breast Cancer's trial further defined
the activity of gemcitabine/
docetaxel.

This encouraging activity in heavily
pretreated patients fostered the evaluation
of the gemcitabine/taxane
doublet as first-line chemotherapy in
metastatic breast cancer. Delfino et al
presented data in the first-line treatment
setting employing gemcitabine
at a dose of 1,200 mg/m2 on days 1
and 8 with paclitaxel at 175 mg/m2 on
day 1.[23] An overall response rate of
55% (with 14% complete remissions),
and an estimated 1-year survival rate
of 65% were reported. Hematologic
toxicity was minimal, with only a 14%
incidence of grade 3/4 neutropenia.

However, the highest response for
a gemcitabine/taxane doublet was noted
by Laufman et al, who reported a
notable intent-to-treat response rate
of 79% accompanied by a median survival
of just over 2 years.[24] Neutropenia
was universal with this days 1,
8, and 15 gemcitabine schedule; however,
only six patients developed febrile
neutropenia. Prophylactic growth
factor use was prohibited. To capitalize
on the significant activity noted
for this schedule, Palmeri et al evaluated
a weekly docetaxel regimen in
lieu of the every 21-day standard docetaxel
schedule.[25] Preliminary
phase II results demonstrated preserved
efficacy, with response rates
of 75%; however, preliminary toxicities
have not yet been reported.
Whether hematologic toxicity was
minimized by incorporation of a
weekly docetaxel schedule is not yet
evident.

Differing gemcitabine infusion durations
have also been evaluated. Given
that the phosphorylation of
gemcitabine to the monophosphate by
deoxycytidine kinase is the rate-limiting
step in the subsequent accumulation
of the diphosphate and
triphosphate metabolites, the ability
of mononuclear cells to accumulate
triphosphate gemcitabine was optimized
using dosing rates of 10
mg/m2/min.[26,27] A comparison between
a gemcitabine fixed infusion
rate of 10 mg/m2/min vs a 30-minute
bolus infusion following a docetaxel
1-hour infusion in metastatic breast
cancer patients demonstrated that the
30-minute infusion schedule allowed
for higher doses of each drug to be
administered with less observed toxicity.[
28] In a recently reported randomized
phase II trial comparing a
30-minute infusion vs a fixed-dose
rate infusion in patients with pancreatic
cancer, Tempero et al reported a
statistically superior overall median
survival at 8 months vs 5 months in
favor of the fixed-rate infusion schedule,
albeit with consistently more hematologic
toxicity.[29] Future trials
will address whether increases in efficacy
are observed with this schedule
in breast cancer. In either regard, a
Financial Disclosure: Dr. Yardley has received
research support from Lilly, Pfizer,
Aventis, and Genentech. She has acted as a
consultant for Lilly and Aventis. She has served
on the speakers' bureaus for Lilly, Aventis,
Genentech, and Bristol-Myers Squibb.
high response rate and markedly prolonged
survival characterize this doublet
balanced with easily manageable
toxicity, either in the first-line setting
or as salvage therapy.

Nevertheless, findings from several
recent phase I studies identifying
the biweekly schedule as perhaps one
of the most advantageous gemcitabine-
administration schedules have
challenged this schedule as the besttolerated
one. Demonstrating a favorable
toxicity profile in the setting of
significant activity in previously treated
patients with advanced breast cancer,
the fortnightly schedule permits
easily achieved dose intensification
for both agents. Enhanced activity
(with surprisingly less hematologic
toxicity) characterizes this every-2-
week schedule.

Accumulated data generated from
several phase I trials led to[28,30,31]
Colomer et al's evaluation of gemcitabine
at 2,500 mg/m2 with paclitaxel
at 150 mg/m2 administered every 14
days.[32] They reported a 69% response
rate, with one-quarter of the
patients demonstrating complete responses.
Grade 3/4 neutropenia was
minimal, at 17%, with febrile neutropenia
evident in only one patient; nonhematologic
toxicity was insignificant.
The median duration of response was
11 months; mature survival data have
not yet been reported. Pelegr and coworkers
evaluated the taxane docetaxel
at 65 mg/m2 with Colomer et
al's gemcitabine regimen,[33] again
noting significant activity evident with
a 66% response rate and 13% CRs
with the biweekly schedule. With docetaxel,
the grade 3/4 neutropenia was
higher at 46%, with only two cases of
febrile neutropenia; additional efficacy
parameters were not available at
the time of their report.

Whether dose intensification of
these combinations results either in
enhanced progression-free or overall
survival cannot be discerned at this
time. Nonetheless, it is evident that
the biweekly schedule, with the accompanying
two- to threefold increase
in delivered dose of gemcitabine, produces
response rates that are significantly
higher without incurring
additional toxicity. Perhaps most astounding
is that this accelerated or socalled
dose-intense program was delivered
without the need for growth
factor support. This attractive approach
offers an active and appealing
schedule with significant future development
potential.

Phase III Data With
Gemcitabine in Breast Cancer

Based on the significant activity
demonstrated for the gemcitabine/taxane
doublet, Albain et al subsequently
conducted a randomized,
prospective phase III trial (JHQG) at
98 centers in 19 countries to characterize
specifically and identify the potential
benefit of adding gemcitabine
to standard-dose paclitaxel compared
with standard-dose paclitaxel monotherapy
(n = 529 evaluable).[34] Anthracycline-
pretreated, locally
advanced and metastatic breast cancer
patients having received no prior
chemotherapy for metastatic breast
cancer were enrolled and randomized
to receive gemcitabine at 1,250
mg/m2 on days 1 and 8 plus paclitaxel
at 175 mg/m2 on day 1 vs paclitaxel
alone every 21 days until disease progression.
With a median age of 53,
patient characteristics and demographics
were balanced in both treatment
arms. Visceral metastases were noted
in 70%, with two or more sites of
metastatic disease present in 76%.
Unlike most other combinations, including
the combination arm of ECOG
1193, full doses of both gemcitabine
and paclitaxel were administered in
the combination arm, with P P P = .018),
with median overall survival also increased
in those receiving the couplet
(18.5 vs 15.8 months). One-year survival
was significantly increased for
the gemcitabine plus paclitaxel arm
(70.7% vs 60.9%; P = .019). Definitive,
protocol-specified overall survival
analysis will take place in 2005.

Perhaps even more impressive is
that this benefit did not come at the
cost of excessive toxicity or impaired
quality of life, as is often the case
when combining two or more antineoplastic
agents. In addition, three parameters
assessing pain relief (with
the Brief Pain Inventory [BPI]), overall
patient functioning, and quality of
life while receiving the gemcitabine/
paclitaxel combination were also measured
in a subset of patients. With
regard to pain relief (291 patients completed
the BPI questionnaire), patients
receiving single-agent paclitaxel manifested
unchanged pain scores
throughout their treatment, whereas
patients receiving the combination
couplet demonstrated a trend toward
improvement. This result also translated
into a 25% decrease in usage
(investigator rated) of analgesic medications
for those patients treated with
the combination (vs 14% for patients
receiving paclitaxel alone), based on
patients requiring analgesics at baseline.[
35]

Investigators used the Rotterdam
System Checklist for overall qualityof-
life assessment (370 patients completed
the questionnaire), and no
significant differences were evident
between the single-agent and combination
gemcitabine/paclitaxel arm.
However, for those patients receiving
gemcitabine and paclitaxel, the main
quality-of-life scores were significantly
improved over baseline scores statistically,
notably at cycles 5 and 6
(P = .005 and .0036, respectively) but
not for those treated with single-agent
paclitaxel. The incidence of grade 3/4
febrile neutropenia (5% vs 2% of patients),
anemia (7% vs

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