Management
Principles
John
Horton, MB, ChB, FACP
Introduction
Breast
cancer is now diagnosed in 175,000 persons each year in the United
States, and almost 44,000 patients with the disease die annually.1
The vast majority of deaths are caused by the effects of metastasis,
ie, stage IV disease. In previous years, a significant proportion
of newly diagnosed patients presented with stage IV disease, but this
is no longer the case. Less than 10% of patients with newly diagnosed
cases (using conventional methods of staging) now present with distant
metastatic disease. The majority who have stage IV disease develop
metastasis after receiving prior local and systemic therapy for previously
apparently clinically localized stages (I, II, or III) of breast cancer.
Roles
for the Clinician
The
clinician who cares for patients with stage IV breast cancer has several
specific responsibilities. These include (1) estimating and communicating
prognosis, (2) evaluating and managing complications and recommending
prophylaxis against complications, (3) promoting physical and emotional
well-being as well as psychosocial adjustment and support, (4) predicting
response to antitumor treatments, (5) prescribing initial antitumor
treatments, (6) recommending when to stop or change antitumor treatments,
(7) prescribing salvage antitumor treatments, and (8) participating
in end-of-life decisions and care.
General
Approach to Stage IV Breast Cancer
It
is a good rule of thumb that, before deciding on treatment, clinicians
should accrue a sufficient database about each patient in order to estimate
prognosis, to determine if any significant complications are present,
and then to recommend initial management. All patients, of course, require
psychosocial and physical support, but these aspects of care are not
discussed here. Palliating symptoms and prolonging useful life are the
dominant goals of medical management of stage IV breast cancer.
Estimation
of Prognosis
Metastatic
breast cancer is best considered as a chronic and incurable disease.
The SEER database2 indicates a median observed survival of
18 months and a five-year survival of 13%. These figures, however, represent
data restricted to patients who presented with stage IV disease. The
CALGB experience3 of patients with previously untreated metastatic
disease (although they could have received adjuvant therapy) describes
a median survival of 1.6 years and a three-year survival rate of 26%.
Some patients survive apparently disease-free for many years, as shown
by the data of Greenberg et al4 in their large FAC-treated
cohort.
The global TNM term "M1" encompasses patients with a wide
spectrum of disease. Further examination of the CALGB data shows that
prior adjuvant therapy, presence of liver metastasis, and negative estrogen
receptor status all predicted a poorer survival. When patients were
grouped according to the presence or absence of these factors, outcomes
varied widely, ranging from a three-year median survival and a 50% three-year
survival for patients with none of these adverse risk factors to a six-month
median survival and 0% three-year survival when all factors pertained.
For most patients who present with stage IV disease, their survival
duration — prior to considering response to treatment — can
be predicted with reasonable accuracy based on these prognostic factors
plus consideration of performance status, comorbidity, and organ function.
It is conceivable that a strongly "positive" HER-2 tumor status
in metastatic disease may not now be as negative a predictive factor
as heretofore believed.
Diagnostic
Workup
Patients
with stage IV breast cancer have organ involvement assessed by symptoms
and physical examination. Knowledge of the tumor hormone receptor and
HER-2 status is needed, as well as radiographic assessment for bone,
liver, and intrathoracic metastasis and, in many cases, assessment of
cardiac function. I minimize the use of serum tumor markers such as
CA27-29 and/or CEA. Serial use of such markers not only engenders considerable
psychological stress in most patients, but also underestimates the risk
of prematurely stopping a treatment that might otherwise produce clinical
benefit. The ASCO guideline5 suggests that removing a patient
from effective therapy because of incorrect information from a tumor
marker test could occur in 34% of cases!
Complications
Several
complications are common in patients with stage IV breast cancer. These
include the effects of bone metastases, pleural and pericardial effusions,
brain and meningeal metastasis, and bone marrow failure. In addition
to recognizing and managing these complications, prophylaxis against
skeletal events can reduce their deleterious effects on quality of life.
Choice
of Initial Therapy
The
vast majority of patients who present with stage IV breast cancer are
candidates for systemic antitumor treatment. The initial choice is between
cytotoxic therapy (with or without biologic therapy) and hormone therapy
(Fig 1). When indicated, hormone therapy is preferred initially due
to both a lower toxicity profile and, often, a longer duration response
than from chemotherapy.
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Fig
1. — Initial systemic treatment approach for patients with
metastatic breast cancer.
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The
best candidates for hormone therapy are patients with limited metastasis
and positive hormone receptors. This group represents a minority of
patients with metastatic disease. Cytotoxic therapy with or without
biologic therapy is generally recommended first when hormone receptors
are negative or when extensive metastasis requires rapid tumor shrinkage.
Responses
to Treatment
The
categories of response to antitumor treatment that include complete
and partial regressions are well known and accepted.6 Patients
usually feel better and live longer if they respond in these ways. It
is now clear that patients with advanced breast cancer who achieve stability
of their disease as a result of hormonal treatment also derive benefit,
and the survival of patients with disease stability is similar to those
who have enjoyed a partial response.7 Fig 2 illustrates several
possible outcomes that can occur in a patient with a tumor that is increasing
in size before treatment is begun.
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Fig
2. — Potential outcomes from treatment of a progressing tumor.
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease.
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The
preferred treatment outcome is a complete or partial response or stabilization
of disease. However, albeit a less desirable outcome, slowing of the
previous rate of progression (shown as PD[b]) may sometimes be regarded
by both patients and their clinicians as evidence of some clinical benefit
accruing from the intervention, especially when treatment is given in
the salvage setting.
When
to Stop Treatment
The
decision to stop a specific antitumor treatment in a patient with metastatic
breast cancer requires application of the art as well as the science
of medicine. It is useful to remember that stage IV disease is chronic
and incurable and that only a finite number of treatment options are
available for any individual patient. Also, some drugs, especially hormones,
may require several months to elapse before benefit is clinically apparent.
Care must be given to recognize the true meaning of the “worsening”
bone scan that in fact may reflect healing of bone metastasis if the
patient’s pain has been reduced by treatment.
The
Role of Salvage Therapy
In
many oncologic diseases, it is uncommon for systemic antitumor treatments
to induce meaningful remissions after the initial treatment has failed.
This is clearly not the case for metastatic breast cancer. Salvage chemotherapy
regularly provides significant benefits, and objective response rates
(partial plus complete) often exceed 20% even for third-line chemotherapy
programs. Adding responses in the “stable disease” category results
in an even greater incidence of responses. The decision on whether to
prescribe any salvage chemotherapy regimen is based on the patient’s
performance status, organ function, prior treatments, the wish of the
patient to try another program, and the likelihood that the salvage
treatment will work. In breast cancer, both second- and third-line interventions
are usually worthwhile, and surprisingly good responses occasionally
ensue from fourth- or even fifth-line treatments. Recent advances in
developing interventions that produce little hematologic toxicity have
extended the possibilities for benefit from cytotoxic chemotherapy even
in patients with poor bone marrow reserve. This is particularly pertinent
to patients who have recurred or progressed following high-dose chemotherapy
and autologous stem cell therapy, to patients who are frail, and to
those who are elderly.
Aims
of the Roundtable
This
roundtable discussion brings together a group of internationally recognized
experts in breast cancer management. In the often confusing and complicated
arena of treating metastatic breast cancer, the collective wisdom of
these experts can assist practicing oncologists in recommending the
most appropriate treatment approaches for their patients.
References
1.
Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1999. CA
Cancer J Clin. 1999;49:8-31.
2. AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven;
1998:164-165.
3. Mick R, Begg CB, Antman KH, et al. Diverse prognosis in metastatic
breast cancer: who should be offered alternative therapies? Breast
Cancer Res Treat. 1989;13:33-38.
4. Greenberg PA, Hortobagyi GN, Smith TL, et al. Long-term follow-up
of patients with complete remissions following combination chemotherapy
for metastatic breast cancer. J Clin Oncol. 1996;14:2197-2205.
5. 1977 update on recommendations for the use of tumor markers in breast
and colorectal cancer. Adopted on November 7, 1997, by the American
Society of Clinical Oncology. J Clin Oncol. 1998;16:793-795.
6. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria
of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
7. Buzdar A, Jonat W, Howell A, et al. Anastrozole versus megestrol
acetate in the treatment of postmenopausal women with advanced breast
carcinoma: results of a survival update based on a combined analysis
of data from two mature phase III trials. Arimidex Study Group. Cancer.
1998;83:1142-1152.
Discussion
Dr Horton: Does
anyone have a different opinion from mine on using tumor markers to
monitor systemic treatments in advanced breast cancer?
Dr
Muss: Tumor
markers are helpful in a small percentage of patients — for example,
for long-term follow-up of patients with slowly progressive bone metastases
— but in general I agree with your approach.
Early on, there may be flares in bone scans, in all the tumor markers,
and in standard tests such as alkaline phosphatase. Tumor flares can
occur not only with endocrine therapy, but also with chemotherapy.
Dr
Horton: Dennis,
are there data with trastuzumab and tumor flares?
Dr
Slamon: To
my knowledge, there is no evidence of tumor flares with trastuzumab.
The antibody doesn't behave the same way as tamoxifen in the sense that
there doesn't appear to be a biologically partial agonistic effect.
There are antibodies in the family that were initially developed that
can produce some agonistic effects, so while it is not impossible that
an antibody could give a flare, it doesn’t appear to be the case with
trastuzumab.
Dr
Perez: The
issue of tumor markers makes day-to-day patient care rather difficult.
There is no correct answer as to how to manage the patient, although
I generally base treatment decisions on clinical symptoms instead of
a serum marker.
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