Despite the application of polychemotherapy, the majority of patients
with node-positive early stage breast cancer ultimately experience relapse
and die from their disease. Two efforts that aim to increase the curative
effect of systemic chemotherapy include increased dose-intensity and inclusion
of non-cross- resistant drugs or regimens. Because of paclitaxel's (Taxol)
activity and clinical non-cross-resistance with doxorubicin (Adriamycin)
in the treatment of metastatic breast cancer, its use in the adjuvant setting
is an exciting possibility.[2-5] However, the optimal means of incorporating
this drug while maximizing the benefit of the other active agents remains
unclear. One approach to applying combination chemotherapy is to simply
coadminister two or more active drugs. When synergy occurs, this is a desirable
strategy. Unfortunately, concurrent administration is more likely to be
associated with increased toxicity than with synergy. Further, the usual
strategy for coping with overlapping toxicities is to reduce the dose of
the individual drugs. In the case of drugs with a steep dose-to-response
relationship, dose reductions are especially undesirable, as they may reduce
the effectiveness of the regimen.
To avoid the problem of dose-limiting overlapping toxicities of agents
given in combination, non-cross-resistant drugs can be given separately
rather than concurrently. In the absence of synergistic cell kill, this
is a reasonable approach. Various models have been used to plan the optimal
delivery of non-cross-resistant regimens; however, it is the clinical result
that should determine the best model for use in subsequent studies.[6-8]
An elegant trial from Milan is especially informative, because it compared
the use of an alternating regimen with sequential administration. This
seminal trial, now reported with a 10-year
follow-up, confirmed the prediction of superiority for sequential therapy.
In this study, women with metastatic breast cancer, including women with
four or more involved nodes, were
treated with doxorubicin and cyclophosphamide/ methotrexate/5-fluorouracil
(CMF) using one of two schedules: In the alternating-treatment arm, two
cycles of CMF were delivered for
every one of doxorubicin (symbolized as CCACCACCACCA). In the sequential-treatment
arm, all four doses of doxorubicin were given first, followed by all eight
doses of CMF (AAAACCCCCCCC). Although it has been speculated that the
early use of doxorubicin was responsible for the improved results seen
in the sequential-treatment arm, a simpler explanation is that the benefits
resulted from the greater dose intensity of doxorubicin achieved with the
sequential-delivery approach.[7,11-13] To build on the exciting implications
of this study, we performed a follow-up series of clinical trials (Table
Doxorubicin Followed by High-Dose Cyclophosphamide (A®C)
In an attempt to capitalize on the steep dose-to-response relationship
associated with alkylating agents while incorporating the demonstrated
benefits of sequential therapy, our group evaluated a regimen comprising
doxorubicin (Adriamycin) followed by high-dose cyclophosphamide (A®C).
In this trial, cyclophosphamide 3,000 mg/m² was given intravenously
for three cycles at 14-day intervals, replacing the 24-week regimen of
CMF given every 21 days that was used in the earlier Milan model.
An earlier pilot study conducted in patients with advanced disease
prompted use of this dose and schedule of cyclophosphamide, given with
G-CSF administered between cycles of cyclophosphamide to facilitate rapid
recovery of peripheral blood counts and rapid retreatment. Radiation therapy
and tamoxifen were given after chemotherapy in appropriate cases.
In 74 patients with breast cancer and a median of nine involved nodes
(range, four to 49), our pilot study demonstrated that such a regimen was
not only feasible but also had a promising effect on relapse-free survival.
A prospective randomized Intergroup trial led by the Southwest Oncology
Group is currently testing this treatment approach in patients with zero
to three involved lymph nodes.
Sequential Therapy With Doxorubicin/Paclitaxel/ Cyclophosphamide
To maximize the potential benefit of paclitaxel as adjuvant therapy,
we chose to incorporate the agent into our sequential dose-dense treatment
plan with doxorubicin and cyclophosphamide. Given that every model of chemotherapy
that assumes fractional cell kill predicts increased effectiveness with
more frequent delivery of chemotherapy, we wanted both to shorten the intertreatment
intervals between dosing of the three agents[17,18] and to exploit the
dose-response relationship demonstrated for doxorubicin. We therefore
designed a regimen consisting of doxorubicin (Adriamycin) 90 mg/m²,
given every 14 days for three cycles, followed first by paclitaxel (Taxol)
250 mg/m² over 24 hours every 14 days for three cycles and then by
cyclophosphamide 3,000 mg/m² every 14 days for three cycles (A®T®C). All nine cycles of chemotherapy were supported by G-CSF, with
radiation therapy and tamoxifen as appropriate.
The 42 patients treated had resectable breast cancer with a median of
eight involved lymph nodes (range, four to 25). One patient developed disease
progression while receiving doxorubicin and was taken off study before
receiving paclitaxel and cyclophosphamide. Overall, 69% of the patients
required hospitalization (usually for neutropenic fever), and 67% required
transfusion of packed red blood cells. Platelet transfusion was required
in 10%. Dose reductions of doxorubicin and paclitaxel were required in
10% and 20% of patients, respectively. Despite the extent of toxicity,
relapse-free survival was impressive, with only three patients relapsing
after just over 1 year of follow-up. We concluded that this regimen was
feasible and worth further study, particularly in light of very promising
relapse-free survival in patients who had undergone definitive local control
Previous successful delivery of two cycles of cyclophosphamide 3,000
mg/m² combined with paclitaxel 250 to 300 mg/m², given over 24
hours, suggested that combination of these drugs might be just as feasible
as giving them purely by sequential administration.[20,21] Reasoning that
we might then be able to treat patients in the adjuvant setting with all
three agents over a shorter time period, while maintaining the dose-intensity
of the sequential plan, we conducted a randomized phase II trial to prospectively
compare the toxicity of this shorter regimen with sequential A®T®C. As before, treatment began with doxorubicin given every 14 days for
three cycles, with G-CSF support. However, because the earlier trial required
dose reductions of both doxorubicin and paclitaxel, we started with a lower
doxorubicin dose of 80 mg/m². Then, by random assignment, patients
were assigned to one of two treatment groups:
- Group A received paclitaxel 200 mg/m² over 24 hours for three
cycles, followed by cyclophosphamide 3,000 mg/m² every 14 days for
three cycles, again supported by G-CSF.
- Group B received three courses of combination treatment with both agents
at the same dose levels.
Thus, half of the patients had nine cycles of chemotherapy (doxorubicin
followed by paclitaxel followed by cyclophosphamide), and half had only
six (doxorubicin followed by combination paclitaxel/cyclophosphamide),
but all received the same total dose of the three study agents. Although
follow-up time is insufficient for comparison with previous studies, results
of this study showed that the feasibility of the shorter six-cycle regimen
was reduced in comparison to the longer, sequential-therapy regimen. Patients
had significantly more dose delays, dose reductions, blood transfusions,
and hospitalizations. Based on results of this trial, we concluded
that the nine-cycle, sequential regimen was preferable for further study.
Paclitaxel Plus Doxorubicin
Two European phase II trials[23,24] suggested that paclitaxel plus doxorubicin
might provide additive, if not synergistic, activity. A prospective randomized
trial comparing the combination versus either drug alone has been completed
but not yet published and promises to clarify the relative advantages and
toxicities of the combination versus single-agent therapy with either drug.
To assess the value of this doxorubicin/paclitaxel couplet, and based
on the exciting results of their phase II study, the group from Milan has
begun a randomized trial to evaluate this combination as adjuvant or neoadjuvant
therapy. Patients are randomly assigned to receive high-dose doxorubicin
followed sequentially by CMF, similar to the regimen used in the earlier
trial from Milan, or to receive lower-dose doxorubicin coupled with
a 3-hour infusion of paclitaxel, a regimen that
appears to be superior in phase II studies of patients with advanced disease.
In this trial, patients also have been randomized for the timing of surgery
Doxorubicin/Cyclophosphamide With or Without Paclitaxel
An alternative means of adding paclitaxel that may avoid the potential
for increased toxicity seen in some studies of concurrent dosing is delivery
of paclitaxel following administration of the other agents. Two multicenter
trials currently under way in the United States take this approach: The
first study, led by the Cancer and Leukemia Group B but available through
the Intergroup, randomizes patients to receive four courses of A®C using
standard, moderately increased, or markedly increased doses of doxorubicin.
Subsequently, half of the patients receive paclitaxel and half do not.
A second trial of similar design is being performed by the National Surgical
Adjuvant Breast and Bowel Project. In this trial, four courses of standard
A®C are followed by four courses of paclitaxel, compared with four courses
of standard A®C without paclitaxel in
women with resected node-positive breast cancer. Taken together, these
two trials can be expected to determine the value of adding paclitaxel
to A®C as adjuvant chemotherapy for node-positive breast cancer.
Currently, two prospective randomized trials are under way to test the
benefits of high-dose autologous stem-cell_supported chemotherapy for patients
with breast cancer involving 10 or more axillary lymph nodes. To compare
the efficacy and toxicity of sequential dose-dense therapy with A®T®C versus the more conventional dose-escalated approach, the Intergroup
has begun a trial led by the Southwest Oncology Group (SWOG) in women with
breast cancer and four to nine involved nodes. Eligible postoperative patients
are randomized to treatment with sequential A®T®C as described above
or to four cycles of A®C followed by high-dose, autologous stem-cell-supported
chemotherapy. Follow-up tamoxifen and radiotherapy are given as appropriate
on both arms. Together with the two trials evaluating the simple addition
of paclitaxel and the two trials evaluating high-dose chemotherapy, this
study should help to further define the role of single-agent paclitaxel
in the adjuvant setting and to clarify the relative benefits and toxicities
of the dose-dense approach.
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