Metastatic breast cancer is considered an
incurable disease, with a median overall survival of 18 to 24 months and a
5-year survival ranging from 3% to 12%. Even if chemotherapy can induce high
response rates, its main objective is symptom palliation. However, patients who
achieve a complete response to first-line chemotherapy can become long-term
survivors. Of the many cytotoxic drugs tested in metastatic breast cancer,
anthracyclines have shown superior activity. For this reason,
anthracycline-based regimens are considered the standard of care.
Both FAC (fluorouracil [5-FU]/doxorubicin
[Adriamycin]/cyclophosphamide [Cytoxan, Neosar]) and CEF
(cyclophosphamide/fluorouracil/epirubicin [Ellence]), the commonly used
anthracycline-based regimens, produce response rates of 50% to 60%. However,
only 10% to 20% of patients achieve a complete response. Interestingly, among
complete response patients, 18% remain disease-free for more than 5 years, and
10% are alive for more than 20 years.[2,3] Therefore, the availability of new
active agents and new combinations might improve the outcome of patients with
metastatic breast cancer.
The possible strategies to introduce a new agent are either the
development of new combination regimens or the sequential administration of
active agents at full doses. The latter approach is based on a theoretical model
predicting that tumor-cell killing is maximized with the sequential
administration of non-cross-resistant drugs. The feasibility of this method
has been proven in high-risk, early breast cancer; the concept of dose-dense
sequential treatment is being tested in metastatic breast cancer patients. An
ongoing study of our cooperative group, Gruppo Oncologico Nord Ovest (GONO),
compares eight courses of epirubicin given in combination with paclitaxel
(Taxol) with four doses of epirubicin followed by four doses of paclitaxel.
Clearly, if combination regimens can be administered with
individual drugs given at optimal dose, the complete response rate may increase,
and hopefully, more long-term survivors will be observed. Thus, based on high
activity and incomplete cross resistance, several trials have evaluated the
feasibility and toxicity of anthracyclines combined with taxanes. The results
from nonrandomized phase II trials have shown that this association is very
active; overall response rates range from 75% to 95%, with complete response
rates as high as 40%.[4-6]
In particular, the combination epirubicin and paclitaxel (Taxol)
(ET) can be administered at optimal doses with a response rate of 84%, which
includes a 19% complete response rate. We have also shown that
pharmacokinetic interactions between epirubicin and paclitaxel could account for
the activity and toxicity of this association.
Phase III Trials
These results have been partially confirmed by recently reported
phase III randomized studies. A large, randomized Eastern Cooperative Oncology
Group trial has shown that, in terms of activity and time to disease progression
without any survival advantage, the combination of doxorubicin (Adriamycin) plus
paclitaxel (Taxol) (AT) administered over 24 hours is significantly superior to
doxorubicin or paclitaxel given as single agents.
A French Canadian study (TAX 306) comparing AC (doxorubicin
[Adriamycin]/cyclophosphamide) vs AD (doxorubicin/docetaxel [Taxotere]) showed
a significant increase in overall response rate and progression-free survival
for the AD arm. These data have been recently confirmed by an Eastern
European trial where patients were randomized to receive either FAC or AT,
showing a significant increase in both overall and progression-free survival for
the AT arm.
Finally, a German trial of ET vs EC
(epirubicin/cyclophosphamide) reported a slight increase in time to progression
in favor of ET with no difference in overall response rates. A European
Organization for Research and Treatment of Cancer (EORTC) trial of AT vs AC
showed no difference in overall response rates and progression-free
Unfortunately, the complete response rates in all these trials
were lower than expected. There are some possible reasons why the
anthracycline/taxane combinations have shown only a slight superiority over the
anthracycline/alkylator combinations. First, it may be due to negative
pharmacokinetic interactions between doxorubicin and paclitaxel. A second
possibility is the administration of suboptimal doses (in particular in the
EORTC trial) with more dose reductions in the anthracycline/taxane arms. Or it
could be the use of taxanes as salvage treatment in control arms.
We can conclude from these trials that (1) the pharmacokinetic
interferences of epirubicin/paclitaxel combinations produce less pharmacodynamic
effect than doxorubicin/paclitaxel regimens, (2) paclitaxel is more easily
combined when infused over 3 hours, and (3) administration of optimal doses of
both agents is important.
Based on these premises, we were interested in verifying whether
it was possible to increase the activity of the ET combination by adding a third
active drug. Gemcitabine (Gemzar) seemed to be the ideal candidate because of
its low myelotoxicity, tolerability profile, new mechanism of action, and
interesting single-agent activity.
Data from phase II studies have shown that single-agent
gemcitabine produces an objective response rate of up to 25% to 46% in
metastatic breast cancer patients.[15,16] Moreover, gemcitabine has a mild
toxicity profile with a low incidence of myelotoxicity and nonhematologic
toxicity. When administered in association with taxanes in pretreated metastatic
breast cancer patients, gemcitabine has shown an overall response rate ranging
from 41% to 51%.[17,18]
Study Design and Dosing
We, therefore, performed a phase II study with the combination
of gemcitabine, epirubicin, and paclitaxel (Taxol) (GET) as first-line
chemotherapy in advanced breast cancer. The study was designed to evaluate the
feasibility and activity of this regimen and to study the pharmacokinetic
interactions of these three drugs.
Metastatic breast cancer patients with bidimensionally
measurable disease were eligible to receive gemcitabine at 1,000 mg/m2
on days 1 and 4, plus epirubicin at 90 mg/m2 on
day 1, plus paclitaxel at 175 mg/m2/d every 21
days. After six courses of GET, patients less than 60 years old and in complete
or partial remission were treated with high-dose chemotherapy as consolidation
The study enrolled 36 patients. Grade 4 neutropenia was observed
in 64% of patients, with four episodes of febrile neutropenia. Other hematologic
toxicities were mild; grade 3/4 anemia and thrombocytopenia occurred in 10% of
the courses. Mild to moderate peripheral neuropathy was experienced by 36% of
patients; grade 2 or 3 mucositis occurred in 25% and 17%, respectively.
After six courses of GET, the overall response rate was 92% (95%
confidence interval: 77.53% to 98.25%), with a 31% complete response rate. Of
the 36 patients, 25 received high-dose chemotherapy, achieving a final overall
response rate of 97%, with a 47% complete response rate. At a median follow-up
of 25 months (range: 8 to 39 months), median progression-free survival is 21
months, while median overall survival has not yet been reached.
The pharmacokinetic data show that gemcitabine does not
influence the interactions between epirubicin and paclitaxel, while gemcitabine
kinetics remain unchanged. Moreover, the GET regimen can efficiently mobilize
the peripheral blood progenitor cells and might be considered as an induction
treatment before high-dose chemotherapy.
Multicenter GET Trial
On the basis of these results and to confirm the feasibility of
the GET regimen, a multicenter trial has been started in seven Italian centers.
The study has completed the planned accrual of 47 patients; preliminary results
are available for 36 patients. A total of 69% of patients had previously
received adjuvant chemotherapy; 17% had received chemotherapy with
Predominant metastatic sites were viscera (86%) and soft tissue
(14%); 21% of patients had one metastatic site, 52% two metastatic sites, and
27% three or more metastatic sites. Grade 3/4 neutropenia occurred in 59% of
cycles with four episodes of febrile neutropenia, while grade 3/4 anemia and
thrombocytopenia were mild (2% and 7% of cycles, respectively). Grade 3/4
mucositis occurred in 8% of cycles, while a grade 2 cutaneous toxicity was
observed in 20% of cycles. The toxicities observed in the multicenter study are
similar to those reported in our institution. Final data on response rates will
be available soon.
Based on the results of these phase II studies, an international
trial will compare GET with ET in patients with metastatic breast cancer. More
than 600 patients will be randomized, and the primary focus of the study will be
survival. This large trial will clarify if the combined administration of the
most active agents up front can improve the outcome of advanced breast cancer.
It is, however, clear that the GET regimen might produce the
best results in potentially curable patients. A prospective, randomized trial
will include more than 1,000 high-risk, early breast cancer patients to be
randomized to GET or to anthracycline/cyclophosphamide and paclitaxel.
Finally, to better define the activity and biologic effects of
this combination, we have started a phase II study with primary chemotherapy in
operable breast cancer. Patients with large primary tumors (> 3 cm) will be
surgically biopsied, treated with four courses of GET, and then submitted to
definitive surgery. The biologic profile of the tumor will be assessed before
and after chemotherapy by evaluating parameters of proliferation (MIB 1, S
phase, cyclines A and D1), apoptosis (bcl2, P53, and apoptotic index),
neoangiogenesis (VEGF receptor, vessel count), and c-erb B2 as a
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