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Optimizing Adjuvant Chemotherapy in Early-Stage Breast Cancer

Optimizing Adjuvant Chemotherapy in Early-Stage Breast Cancer

ABSTRACT: Mortality in breast cancer has declined in the past decade, owing to advances in diagnosis, surgery, radiotherapy, and systemic treatments. Adjuvant chemotherapy has had a major effect on increasing survival in women with locoregional breast cancer. Like all treatments, adjuvant chemotherapy is a work in progress, and it has evolved from single oral agents to complex multidrug regimens. The choice of regimens is not without controversy, however, and several have been shown to be more effective than others, especially in patients who are at high risk for recurrence. The taxanes paclitaxel and docetaxel (Taxotere) have been shown to be effective in the adjuvant setting, and they have also been shown to improve the outcomes in node-positive disease. Both disease-free and overall survival are greater with doxorubicin, paclitaxel, and cyclophosphamide given in a dose-dense, every-2-week schedule with growth factor support than with the same agents given in an every-3-week schedule. Disease-free and overall survival in patients with node-positive disease are greater with docetaxel, doxorubicin (Adriamycin), and cyclophosphamide (TAC) than with fluorouracil, doxorubicin, and cyclophosphamide (FAC). Febrile neutropenia is common with the TAC regimen, but it can be minimized with growth factor support. Based on these findings, dose-dense therapy and TAC are the current adjuvant treatments of choice in patients with node-positive disease; other, less-intense regimens may be appropriate in patients with lower-risk disease. Ongoing trials are investigating the efficacy of commonly used regimens, new chemotherapeutic and biologic agents, and novel doses and schedules of currently available agents.

It has been estimated that close to
213,000 persons will be diagnosed
with breast cancer in the United
States in 2005.[1] Most of these patients
will present with locoregional
breast cancer, which relapses despite
appropriate initial treatment. Mortality
from breast cancer has decreased
substantially, especially in patients
with localized disease.[2] Both endocrine
therapy and chemotherapy have
led to substantial increases in survival
among women with early-stage breast
cancer.[3] Adjuvant endocrine therapy,
which remains an essential component
of treatment for patients with
hormone receptor-positive disease, is
not discussed in this article.[4,5]

Adjuvant chemotherapy is a work
in progress: It started as single-agent
treatment,[6] was followed in the 1970s
by combination chemotherapy with
CMF (cyclophosphamide, methotrexate,
and fluorouracil [5-FU]),[7] and
now entails the use of various effective
agents. Among the chemotherapy
agents that are associated with greater
survival are older drugs such as the
alkylating agents (mainly cyclophosphamide),
the antimetabolites (methotrexate
and 5-FU), the anthracyclines
(epirubicin [Ellence] and doxorubicin),
and more recently, the taxanes
(paclitaxel and docetaxel [Taxotere]).

The 15-year update of findings
from the Early Breast Cancer Trialists'
Collaborative Group meta-analysis
has shown that the risk of recurrence
is 23.5% lower and the risk of
mortality is 15.3% lower with several
months of adjuvant combination chemotherapy
than with no chemotherapy (both 2P < .001).[8] This article
discusses the adjuvant regimens that
are associated with the best outcomes,
the selection of regimens on the basis
of patient characteristics, and trials
that have been completed or are in
progress and are expected to substantially
increase our knowledge in the
next several years.

Strategies for the Use of
Combination Chemotherapy
Choice of Agents

  • Anthracycline and Nonanthracycline
    Regimens
    -The 2001 update
    of the Early Breast Cancer Trialists'
    Collaborative Group meta-analysis
    reported that mortality was lower with
    anthracycline-containing regimens
    than with nonanthracycline regimens-
    a further proportional reduction
    of 11% in the annual rate and an
    absolute reduction at 5 years of about
    3%.[8] These reductions were greater
    in younger women and were not affected
    by lymph node status. This
    meta-analysis includes data on anthracyclines
    from several large trials of
    epirubicin-containing regimens. Doxorubicin-
    and epirubicin-containing
    regimens appear similar in efficacy,
    but epirubicin-containing regimens
    may be less cardiotoxic.
  • The optimal duration of adjuvant
    therapy with anthracycline-containing
    regimens is still being investigated.
    The efficacy of 2 months (four cycles)
    of AC (doxorubicin [Adriamycin]
    and cyclophosphamide) and of
    6 months (six cycles) of classic CMF
    using oral cyclophosphamide are similar.[
    9] Six months (six cycles) of an
    anthracycline-containing regimen
    (CEF [cyclophosphamide, epirubicin,
    and 5-FU) does, however, appear to
    be superior to six cycles of CMF in
    terms of disease-free and overall survival.[
    10] Furthermore, preliminary
    results from the National Epirubicin
    Adjuvant Trial (NEAT), a phase III
    trial that compared six cycles of classic
    CMF with four cycles of epirubicin
    followed by four cycles of CMF
    in 2,021 patients, showed significantly
    greater rates of recurrence-free survival
    (P < .001) and overall survival
    (P < .001) in the epirubicin-containing
    arm.[11]

    These two studies suggest that treat
    ment with more than four cycles of
    chemotherapy (particularly anthracycline-
    containing regimens) is associated
    with the best outcomes. The ongoing
    CALGB 40101 clinical trial, which is
    comparing four and six cycles of AC in
    women with node-negative breast cancer,
    should help establish the optimal
    duration of anthracycline-based adjuvant
    therapy (Table 1).

  • Taxanes-There remains substantial
    room for improvement, however,
    and treatments with nonoverlapping
    toxicity are needed. The taxanes paclitaxel
    and docetaxel have been shown to
    be effective in both the metastatic and
    adjuvant settings (Figure 1).[12-19]
    Tumor cells have little cross-resistance
    to taxanes and anthracyclines, and the
    taxanes can be used with almost all
    other drugs in a variety of combinations
    and schedules. Single-agent taxanes
    are effective in metastatic disease,
    and combinations of taxanes and other
    agents have produced higher response
    rates and longer times to
    progression than older combination
    regimens.[20-22]
  • Paclitaxel and docetaxel have similar
    antitumor activity, owing to their
    high-affinity binding to beta-tubulin
    and subsequent blocking of cell division.[
    23] Paclitaxel has pharmacokinetic
    interactions with anthracyclines,
    resulting in greater cardiotoxicity when
    it is used concurrently with doxorubicin
    (if the cumulative dose of doxorubicin
    exceeds 300 mg/m2)[24,25] and greater
    myelotoxicity when it is used concurrently
    with epirubicin.[26] To
    minimize toxicity, paclitaxel should be
    administered after the anthracyclines.
    Unlike paclitaxel, docetaxel has no clinically
    significant effects on the pharmacokinetics
    of anthracyclines.[23]
    Ongoing trials that are expected to help
    define the optimal use of these agents
    are summarized in Table 1.

  • Paclitaxel-Cancer and Leukemia
    Group B (CALGB) trial 9344, the first
    large randomized trial to evaluate
    paclitaxel in the adjuvant setting, randomized
    3,121 patients with nodepositive
    primary breast cancer to four
    cycles of AC, using three different
    doses of doxorubicin (60, 75, and
    90 mg/m2), followed by either four
    cycles of paclitaxel (175 mg/m2 every
    3 weeks) or no further treatment.[14]
    The risk of recurrence was 17% lower
    (P = .002) and risk of death was
    18% lower (P = .006) with the addition
    of paclitaxel, with a moderate
    increase in toxicity. The survival benefit
    with paclitaxel was similar to that
    with an anthracycline-containing regimen
    over CMF.[3] Higher doses of
    doxorubicin, however, provided no
    improvement.
  • National Surgical Adjuvant Breast
    and Bowel Project (NSABP) trial
    B-28 also compared adjuvant AC
    alone with AC followed by paclitaxel,
    in 3,060 patients with node-positive
    operable breast cancer, using a higher
    dose of paclitaxel than that in CALGB
    9344 (225 rather than 175 mg/m2). The
    addition of paclitaxel reduced the risk
    of recurrence by 17% (P = .008) but
    did not have an effect on overall survival
    (P = 0.48).[15] Further followup
    is needed. Factors that may have
    contributed to the lack of an overall
    survival benefit in NSABP B-28 are
    that the patients had a better prognosis
    than those in CALGB 9344 and
    that a high proportion (25%) of the
    patients in the paclitaxel arm could
    not be treated with all four cycles of
    paclitaxel because of toxicity.[15] The
    results of NSABP B-28 may have been
    influenced by the concurrent use of
    tamoxifen with the chemotherapy,
    which has been associated with lower
    survival than that with the use of
    tamoxifen after the chemotherapy.[27]
    It is also possible that the treatment
    effect that was seen in both trials may
    be due to the duration of treatment
    rather than to the addition of a sequential,
    non-cross-resistant agent.

    A recent randomized trial compared
    two paclitaxel regimens in 1,830 patients
    with stage I, II, or III breast cancer:
    four cycles of AC (60/600 mg/m2)
    followed by paclitaxel (Taxol) at
    175 mg/m2 every 3 weeks (AC→T) and
    four cycles of doxorubicin and paclitaxel
    (50/200 mg/m2) followed by paclitaxel
    at 80 mg/m2/wk for 12 weeks
    (AT→T).[28] At 3 years, there were
    significant differences favoring AT→T
    in both disease-free survival (90% vs
    86%; P = .02) and overall survival (95%
    vs 92%; P = .02). The incidence of
    neuropathy was greater in the AT→T
    arm, but there was no difference in
    cardiotoxicity. The results of this trial
    suggest that substituting paclitaxel for
    cyclophosphamide in the AC regimen,
    using weekly paclitaxel, or both, further
    improves on the AC→T regimen
    that proved superior to AC alone in
    CALGB 9344. Additonal follow-up of
    this important trial is needed.

  • Docetaxel-The combination of
    docetaxel, doxorubicin, and cyclophosphamide
    (TAC) has produced significantly
    higher complete and partial
    response rates than the combination
    of 5-FU, doxorubicin, and cyclophosphamide
    (FAC) in patients with metastatic
    breast cancer.[29] This regimen
    was tested in the adjuvant setting in
    the Breast Cancer International Research
    Group (BCIRG) 001 trial,
    which randomized 1,491 patients with
    node-positive breast cancer to six
    cycles of TAC (75/50/500 mg/m2)
    or FAC (500/50/500 mg/m2) every
    3 weeks (Table 2).[16]
  • Interim analysis at a median follow-
    up of 55 months showed that
    5-year disease-free survival was 7 percentage
    points greater and 5-year overall
    survival was 6 percentage points
    greater with TAC. The benefits of
    TAC on disease-free survival were
    not affected by hormone receptor status
    or HER2 status. Febrile neutropenia
    occurred in 24% of patients treated
    with TAC and in 2% of those treated
    with FAC.[30] Granulocyte colonystimulating
    factor (G-CSF, Neupogen)
    was used in all cycles after an occurrence
    of febrile neutropenia (secondary
    prophylaxis). An ongoing trial of
    TAC vs FAC in patients with nodenegative
    disease has confirmed the
    benefits of initiating G-CSF in the
    first cycle for minimizing neutropenic
    complications in patients treated
    with TAC.[31]

    NSABP B-27, a randomized trial
    of neoadjuvant chemotherapy in 2,411
    women with operable breast cancer,
    compared three treatments: preoperative
    AC alone, preoperative AC followed
    by preoperative docetaxel, and
    preoperative AC followed by postoperative
    docetaxel.[12] The doses were
    the same in each arm-four cycles of
    AC (60/600 mg/m2) every 3 weeks and
    four cycles of docetaxel (100 mg/m2)
    every 3 weeks. The pathologic complete
    response rate with preoperative
    AC and docetaxel was twice that with
    preoperative AC alone (26.1% vs
    13.7%; P < .001), and relapse-free survival
    at 5 years was also significantly
    higher (74% vs 69%; P = .03). Overall
    survival at 5 years was the same in all
    three arms. The concurrent use of
    tamoxifen and chemotherapy may have
    affected the outcomes in this trial.

    The PACS 01 trial compared three
    cycles of FEC (5-FU, epirubicin, and
    cyclophosphamide at 500/100/500
    mg/m2) followed by three cycles of
    docetaxel (100 mg/m2) with six cycles
    of adjuvant FEC (500/100/500 mg/m2)
    in 1,999 patients with node-positive operable
    breast cancer. At 5 years, both
    disease-free survival (78.3% vs 73.2%;
    P = .04) and overall survival (90.7%
    vs 86.7%; P = .05) were significantly
    higher with FEC followed by docetaxel
    than with FEC alone.[13] Since
    both regimens were used with the
    same total number of cycles (avoiding
    a potentially confounding factor
    seen in the earlier randomized trials
    of paclitaxel, CALGB 9344, and
    NSABP B-28, in which paclitaxel recipients
    were given more cycles of
    chemotherapy), the results in this trial
    suggest that docetaxel plays a major
    role in improving treatment outcomes.
    Moreover, cardiotoxicity was lower
    in the FEC/docetaxel arm.

    Two other large randomized trials
    are further evaluating the dose and
    sequence of anthracycline-docetaxel
    combinations (see Table 1). In NSABP
    B-30, patients with node-positive disease
    have been randomized to four
    cycles of concurrent doxorubicin and
    docetaxel (50/75 mg/m2), four cycles
    of TAC (75/50/500 mg/m2), or four
    cycles of AC (60/600 mg/m2) followed
    by four cycles of docetaxel
    (100 mg/m2). All cycles are repeated
    at 3-week intervals. In BCIRG 005,
    patients are randomized to six cycles of
    TAC (75/50/500 mg/m2) or four cycles
    of AC (60/600 mg/m2) followed by
    four cycles of docetaxel (100 mg/m2).
    The results of these trials should shed
    light on the optimal dosing and scheduling
    of anthracycline-docetaxel combinations
    in patients with early-stage
    breast cancer.

Increasing Dose Intensity
Strong evidence supports the concept
that the dose intensity of the chemotherapy,
or the amount of drug
delivered per unit of time, correlates
with outcomes in the adjuvant setting.[
32-34] A 30-year follow-up of
patients in an early trial of adjuvant
CMF shows that the survival advantage
was greatest in those who were
treated with more than 85% of the
planned dose intensity (overall survival
= 40% vs 21%).[35]

At least three randomized trials
have investigated the relationship between
dose intensity and outcomes
with anthracycline-based regimens.
CALGB 8541 compared three regimens
of adjuvant CAF (cyclophosphamide,
doxorubicin, and 5-FU) in 1,550
patients with node-positive breast cancer:
four cycles of 600/60/600 mg/m2
every 4 weeks (high dose intensity),
six cycles of 400/40/400 mg/m2 every
4 weeks (moderate dose intensity),
and four cycles of 300/30/300 mg/m2
every 4 weeks (low dose intensity).[
33] The rates of both disease-free
survival (P < .001) and overall survival
(P = .004) were greater with the
high- and moderate-dose-intensity
regimens than with the low-doseintensity
regimen.

In a later trial in patients with nodepositive
disease (CALGB 9344), the
outcomes with the dose of doxorubicin
increased to 75 or 90 mg/m2
were no better than those with the
60-mg/m2 dose.[14] Bonneterre and
colleagues showed that an FEC regimen
with epirubicin, 100 mg/m2, was
superior to FEC with epirubicin,
50 mg/m2.[34] The results of these
trials suggest that the effect of doxorubicin
is maximal at a dose of about
50 to 60 mg/m2 and that the effect of
epirubicin is maximal at a dose of
about 100 mg/m2.

More-intensive schedules of AC,
tested in several large NSABP randomized
trials, have proved to be no
more efficacious as a standard schedule
but much more toxic.[36,37] Extremely
high doses of chemotherapy
with stem cell rescue have not been
found to be superior to standard regimens
in randomized trials.

Increasing Dose Density
Dose intensification can be achieved
not only by increasing the dose intensity
(increasing the dose of the
drug per cycle) but also by increasing the dose density (decreasing the
interval between the cycles while
keeping the dose of the drug the
same).[38] Mathematic models of tumor
growth predict that shortening
the interval between chemotherapy
treatments would minimize tumor regrowth
between cycles[39] and also
lessen the emergence of drug-resistant
mutations.[38,40]

Bonadonna and colleagues were
among the first to test dose-dense adjuvant
therapy. In a study in women
with early-stage breast cancer involving
four or more lymph nodes, they
compared 4 cycles of doxorubicin followed
by 8 cycles of CMF (sequential
regimen) and 2 cycles of CMF
alternated with 1 cycle of doxorubicin
for a total of 12 cycles (alternating
regimen).[41] Overall survival at 10
years was 58% in the sequential arm
and 44% in the alternating arm
(P = .002). Thus, a clear survival advantage
was shown for the sequential
arm, which used the same total doses,
but each agent was given at a higher
dose density than in the alternating arm.

More recently, Hudis and colleagues
showed the feasibility of sequential
doxorubicin, paclitaxel, and
cyclophosphamide (A→T→C) given
every 2 weeks (dose-dense regimen)
with G-CSF support in 42 women with
node-positive breast cancer.[42] The
majority of patients (69%) developed
febrile neutropenia, and red blood cell
transfusions were required in 67%,
but a 78% disease-free survival at 48
months was promising.

Designed to further explore dosedense
regimens, CALGB 9741 was a
2 * 2 trial that compared concurrent
AC followed by paclitaxel and sequential
A→T→C, both given either
every 2 weeks (dose dense) or every
3 weeks, in 2,005 women with nodepositive
breast cancer (Table 3).[43]
The doxorubicin, cyclophosphamide,
and paclitaxel were given at the
same doses (60/600/175 mg/m2) in
both arms. Patients in the dose-dense
arms were given G-CSF to allow neutrophil
recovery before the next cycle.
Sequence had no effect on
survival, but rates of both diseasefree
survival (P = .01) and overall
survival (P = .01) were significantly
higher at a median follow-up of
36 months in the dose-dense arms.

Furthermore, dose-dense therapy
was not associated with greater toxicity,
and the incidence of grade 4
neutropenia was greater in the every-
3-week sequential arm than in the two
dose-dense arms (24%-43% for the
every-3-week regimen vs 3%-9% for
dose-dense therapy).[43] Platelet
transfusions were not required in any
patients, but red blood cell transfusions
were required in 13% of patients
in the concurrent dose-dense arm and
in 3% of those in the every-3-week
arm. An interim analysis of 89 patients
(135 enrolled) treated with dose-dense
therapy found that darbepoetin alfa
(Aranesp), given at 200 ?g when the
hemoglobin level dropped to less than
12 g/dL and administered thereafter according
to a preplanned algorithm, eliminated
the need for red blood cell
transfusions.[44]

The results of two European trials
of dose-dense epirubicin-based regimens
have been disappointing. Venturini
and colleagues conducted a
phase III trial in 1,214 patients with
node-positive or high-risk node-negative
operable breast cancer who were
randomized to six cycles of FEC
(600/60/600 mg/m2) at either 2- or
3-week intervals with G-CSF.[45]
There were no significant differences
in survival. In the neoadjuvant setting
in patients with locally advanced
breast cancer, survival with doseintense
EC (120/830 mg/m2) given
with G-CSF every 2 weeks for six
cycles was no greater than that with
FEC (500/60/75 mg/m2) given every
4 weeks for six cycles.[46] These data
suggest that dose density may be more
important with the taxanes than with
other drugs. The benefits seen with
dose density should not be extrapolated
to untested regimens.

Another strategy used with the taxanes
is weekly regimens. A regimen
of weekly paclitaxel was found to have
greater efficacy than an every-3-week
regimen, especially in metastatic disease.[
47,48] The benefits of weekly
paclitaxel in the neoadjuvant setting
have also been shown: In a study in
258 patients with operable breast cancer,
the response rate with preoperative
weekly paclitaxel followed by
FAC was double that with standard
paclitaxel followed by FAC (29% vs
14%; P < .01).[47] The value of weekly
paclitaxel as adjuvant therapy continues
to be investigated and should
be determined in ongoing trials.
ECOG 1199, a randomized four-arm
trial is comparing paclitaxel and docetaxel
given either weekly or every
3 weeks after four cycles of AC. In
another 2 * 2 trial design, SWOG S0221
will evaluate AC (weekly or every
2 weeks) followed by paclitaxel (weekly
or every 2 weeks). The ongoing Intergroup
S0221 trial is the only trial
that is comparing weekly and every-2-
week paclitaxel in the adjuvant setting.

These data support the importance
of delivering full chemotherapy doses
on schedule. Dose reductions and
delays, however, are common in clinical
practice,[49,33,34] and when
substantial, may affect outcomes. Clinicians
should therefore avoid dose
reductions whenever possible and
should attempt to maintain the dose
and schedule of the regimens that have
been established in clinical trials.

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