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Update on the Management of Advanced Breast Cancer

Update on the Management of Advanced Breast Cancer

ABSTRACT: Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as “state-of-the art” treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLC D-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials. [ONCOLOGY 13(5):647-658:1999]

Introduction

Breast cancer is the most frequently diagnosed
cancer in American women, and the second most common cause of cancer
death.[1] Over the past several decades, there has been a fairly
steady increase in the incidence of the disease. Epidemiologic data
from the United States analyzed between 1988 and 1990 indicate that
the lifetime risk of developing breast cancer is 12.2%, or, stated in
another way, one in eight women will develop the disease at some
point during her life.[2]

Although approximately 80% of breast cancer patients present with
disease limited to the breast and/or axillary lymph nodes, almost
half of these patients later develop metastatic disease and
eventually succumb to it. Metastatic breast cancer represents a
historically incurable condition despite the judicious use of various
hormonal manipulations, as well as surgical and radiotherapeutic
interventions, and the application of active cytotoxic
chemotherapeutic agents for hormone-refractory disease. For most
patients with metastatic disease, treatment provides only temporary
control of cancer growth. Outside of experimental protocols, the
goals of management, therefore, are to palliate symptoms with as
little treatment-related toxicity as possible and to extend the
duration of high-quality life.

Metastatic breast cancer is moderately sensitive to chemotherapy,
with 25% to 40% of patients achieving a partial or, less commonly,
complete response to single-agent therapy; the duration of such
responses averages 6 months.[3] Historically, the most commonly used
cytotoxic agents in the management of metastatic breast cancer have
been cyclophosphamide (Cytoxan, Neosar), methotrexate, fluorouracil,
doxorubicin, and, more recently, the taxanes. When the disease
progresses further, vinorelbine (Navelbine) and other vinca
alkaloids, mitomycin (Mutamycin), mitoxantrone (Novantrone),
gemcitabine (Gemzar), etoposide, and cisplatin (Platinol) represent
some of the other frequently used cytotoxic drugs.

Combination vs Single-Agent Chemotherapy

Combinations of two, three, or more chemotherapeutic agents are
occasionally employed based on preclinical data suggesting improved
antitumor activity (ie, additive or synergistic effects); many of
these combinations are derived empirically, however. Although
combination regimens may sometimes yield higher response proportions
than single-agent therapy, this can occur at the cost of greater
toxicity, perhaps resulting in an overall lower therapeutic index.[4]
This issue was specifically addressed by two studies presented at the
34th annual meeting of the American Society of Clinical Oncology
(ASCO) in 1998.

The first study, conducted by the Finnish Breast Cancer Group,
randomized 303 breast cancer patients with distant metastases to one
of two regimens: (1) single-agent chemotherapy with epirubicin (20
mg/m² weekly until disease progression or a cumulative dose of
1,000 mg/m²), followed by mitomycin (8 mg/m² every 4 weeks)
as second-line therapy; or (2) the CEF polychemotherapy regimen,
consisting of cyclophosphamide (500 mg/m²), epirubicin (60
mg/m²), and fluorouracil (500 mg/m²) every 3 weeks,
followed by mitomycin (8 mg/m²) and vinblastine (6 mg/m²)
every 4 weeks. Although responses to CEF tended to last modestly
longer than responses to epirubicin alone (median duration, 12 vs
10.5 months; P = .07), no significant difference in time to
progression (P =.28) or overall survival (P = .65) was found between
the two arms.

Moreover, no difference in survival was seen when only the patients
who received both the first- and second-line treatments were compared
(P = .96), or when survival was calculated from the beginning of
second-line therapy (P = .56). Single-agent therapy was also
associated with less toxicity and better quality of life.[5]

The second report, presented by the International Taxotere 304 Study
Group, described the results of a phase III study comparing
single-agent docetaxel (Taxotere) therapy vs the combination of
mitomycin and vinblastine in patients with metastatic breast cancer
whose disease had progressed following an anthracycline-containing
regimen. In this experience, single-agent docetaxel therapy proved
more effective than mitomycin plus vinblastine, not only with respect
to response rate and time to treatment failure, but, most
gratifyingly, with regard to survival. Median survival duration was
11.4 months in the docetaxel group vs 8.7 months in the
mitomycin-vinblastine group (P = .0097).[6]

In this context, the experience of Sledge and colleagues, reported at
the 1997 ASCO meeting, should be considered.[7] In that study,
Eastern Cooperative Oncology Group Study (ECOG) 1193, single-agent
therapy with either doxorubicin or paclitaxel (Taxol) was compared
with the combination of doxorubicin and paclitaxel as first-line
therapy in 739 patients with metastatic breast cancer. Patients
receiving single-agent therapy were crossed over to the other agent
at the time of disease progression.

Monotherapy with either doxorubicin or paclitaxel had equivalent
therapeutic activity; the combination of the two drugs resulted in
superior overall response rate and time to treatment failure. Despite
this, combination therapy was not superior to sequential single-agent
therapy with regard to overall survival and quality of life.

Taken together, these trials should prompt a reconsideration of the
conventional wisdom that combination chemotherapy is the “gold
standard” for the treatment of metastatic breast cancer.

Is More Better?

Ultimately, the treatment of stage IV breast cancer often represents
an attempt to reach an equilibrium between the palliation conferred
by response to therapy, on the one hand, and treatment-related
toxicity, on the other.
Thus, the issue of the value of dose intensification is of utmost
importance, since increased doses are commonly associated with
greater toxicity.

Dose-Intensified Regimens

A trial of the Italian group Gruppo Oncologico Nord-Ouest (GONO),
reported at ASCO 1998 by Lionetto et al, is instructive in this
regard. This trial randomized patients to receive either standard
doses of CEF or the same regimen in an intensified manner with growth
factor support; patients in the “intensified CEF” arm
actually received an 80% increase in dose intensity compared to those
in the standard CEF arm.[8] Quality of life was also assessed.

In the 151 randomized patients, no differences between the two arms
were observed with respect to response rates or progression-free
survival. However, the intensified regimen was associated with more
toxicity. Grade 3 and 4 events were more frequent with intensified
CEF than with the standard regimen (anemia, 18% vs 3%; leukopenia,
26% vs 6%; thrombocytopenia, 8% vs 2%; and mucositis, 13% vs 3%).

High-Dose Chemotherapy With Stem-Cell Support

Regarding dose escalation, the potential role of high-dose
chemotherapy with stem-cell rescue still awaits definition. Although
some authors have reported 5-year disease-free survival proportions
of approximately 20% in selected patients treated with such
regimens,[9,10] to date there has been no demonstration of clear
superiority of high-dose consolidation over other strategies in the
management of stage IV breast cancer.

Most studies of high-dose chemotherapy have been uncontrolled phase I
and II trials, often accompanied by the irresistible, but problematic
and unfortunate, comparisons with historical controls. Moreover, the
inherent bias of patient selection for these trials has also been an
issue. The first reported randomized trial of standard chemotherapy
vs high-dose chemotherapy with either autologous bone marrow or
peripheral blood stem-cell support, conducted by Bezwoda et al,
showed that high-dose therapy significantly extended the durations of
response and survival.[11] However, the median follow-up was only 72
weeks, the study was small, and the standard-dose chemotherapy arm
has been criticized for being suboptimal.

At the 1998 ASCO meeting, several presentations evaluated different
transplant modalities, ie, single vs tandem high-dose chemotherapy,
tandem vs triple high-dose chemotherapy, and purging of tumor cells
from peripheral blood stem cells.[12,13] The exploratory nature of
these trials and preliminary results underscore the need for large,
prospective clinical trials to address these questions.

On the basis of the limited data available to date from randomized,
prospective trials, high-dose chemotherapy cannot yet be considered
“state-of-the-art” treatment for advanced breast cancer and
should be offered only to patients in the setting of clinical trials.
The final results of such large prospective trials are eagerly
awaited (Table 1).

If multiagent chemotherapy and dose escalation prove to be suboptimal
in conferring a consistent survival advantage in metastatic breast
cancer, other strategies must be pursued. These include the
development of newer active drugs, or the exploration of different
alternatives, for example, biological therapies.

Taxanes and Beyond

The taxanes, ie, paclitaxel and docetaxel, are a relatively new
addition to the chemotherapeutic arsenal against breast cancer. Their
mechanism of action involves the formation of polymerized
microtubules and their stabilization against the forces that lead to
depolymerization. Proapoptotic effects, as well as antiangiogenic
actions, may also be clinically relevant.[14,15]

The determination of optimal dosing and scheduling of taxanes has
been an important objective during their development. While the
clinical development of docetaxel has largely involved a single
administration schedule (1-hour infusion) and a narrow dose range (60
to 100 mg/m²), the range of paclitaxel doses and schedules has
been broader (varying from 80 to 250 mg/m² infused over 1 hour
weekly to 3-, 24-, or even 96-hour infusions every 3 weeks).

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