Introduction

In this era of cost containment, the benefits of all therapies
are under intense scrutiny. In breast cancer management, the definitions
of refractory advanced breast cancer and of its management are
controversial. For the purpose of this article, refractory advanced
breast cancer is partially and arbitrarily defined as primary
or acquired resistance to hormonal therapies, anthracycline resistance,
and failure of some otherwise undefined number of prior cytotoxic
chemotherapeutic regimens. Attempting to determine the number
of prior chemotherapeutic regimens that help to define refractory
advanced breast cancer is both an interesting and often frustrating
exercise in literature review.

To establish a frame of reference, what is known about the median
survival from first relapse (MSFR) of patients with breast cancer
must be explored. In a recent review of this topic in the context
of presenting statistics from the University of Miami [1] (in
which the overall MSFR of 26 months was similar to that in most
reports in the literature), the most striking finding was the
variability in MSFR, which depended on patient characteristics
(Table 1). By combining these characteristics into prognostic
categories, patient subgroups with a MSFR ranging from 15 to more
than 90 months were defined (Table 2). Thus, when reviewing the
literature on survival after any therapeutic intervention, it
must be considered that such survival statistics are dependent
on the heterogeneity of the population in question.

Difficulties With Response Rates

Other problems inherent in this literature review stemmed from
an overreliance on response rates, which may be a relatively poor
surrogate for clinical benefit. A significant percentage of women
with metastatic breast cancer do not have bidimensionally measurable
disease, and a large number of women have bony metastases that
are difficult to evaluate. This frequently leads to defining "response"
in populations of patients with lung, soft-tissue, and liver metastases,
with the overall conclusion being that bony metastases "respond"
poorly to treatment. Many medical oncologists believe that time
from initiation of treatment to time of clear-cut tumor progression,
or the "time to treatment failure" from any cause, might
be a better end point than response rate. Howell et al [2] and
Robertson et a l[3] have suggested that disease stability lasting
longer than 5 or 6 months should be considered similar to an objective
response.

Different definitions of response have been applied to different
clinical trials, with resultant discordant "response rates"
for similar regimens in similar clinical circumstances. A recent
phase II trial of medroxyprogesterone for metastatic breast cancer
reported an objective response rate of 38.6% [4]. In contrast,
two major, randomized, phase III trials of megestrol acetate vs
the new aromatase inhibitor, anastrozole (Arimidex), yielded response
rates of approximately 10% for both agents [5]. In the latter
trials, the stringent International Union Against Cancer (UICC)
response criteria were used. In these trials, adding patients
with stable disease for longer than 24 weeks to the "responders"
probably provided a more realistic assessment of clinical benefit,
approximating the 30% rate expected from second-line hormonal
treatment. As the definition of antitumor response becomes more
stringent for quantitative purposes, it is important not to lose
sight of the major goals of treatment: palliation, clinical benefit,
and survival.

Similar problems exist with other tumor types. In lung cancer,
the Eastern Cooperative Oncology Group conducted a study demonstrating
that carboplatin (Paraplatin) resulted in the lowest response
rate and the longest median survival among several different regimens
tested [6] In pancreatic cancer, a new term, "clinical benefit
response"[7] ,as well as an analysis according to that definition,
has gained Food and Drug Administration (FDA) approval for gemcitabine
(Gemzar), even in the face of low objective response rates. Perhaps,
this encouraging precedent will lead to acceptance of alternative
end points that more realistically reflect clinical benefit.

Other problems in this literature review stemmed from the different
definitions of "heavily pretreated" used in various
series. It was frequently impossible to determine individual response
rates for second-, third-, or fourth-line therapies. In addition,
information on anthracycline resistance was either impossible
to discern or was complicated by different definitions. Finally,
in terms of survival durations, many articles cited medians, whereas
others cited survival rates for responders and nonresponders;
in some series, "stable" patients were combined with
responders, and in others, they were grouped with nonresponders.

With these inherent problems in mind, this article will now endeavor
to make some sense of the confusing literature on "salvage
chemotherapy" for refractory advanced breast cancer.

First- and Second-line Chemotherapeutic
Regimens

In the United States, many first- and second-line chemotherapeutic
regimens include combinations, such as cyclophosphamide, methotrexate,
fluorouracil (CMF) or cyclophosphamide + doxorubicin (Adriamycin)
± fluorouracil (CA ± F)[8,9], with paclitaxel (Taxol)
used mostly as second-line (or third-line) treatment. In Europe
and Canada, other commonly used first-line regimens substitute
epirubicin for doxorubicin; in addition, the mitomycin, methotrexate,
mitoxantrone (MMM) combination is widely used as an alternative
first-line regimen.

Commonly accepted "response rates" are in the 50% to
60% range for first-line therapy, with low complete response rates
approximating 10% and response durations (depending on their definitions)
approximating 8 months. Standard second-line chemotherapeutic
regimens produce reasonably consistent response rates, which vary
from 35% to 45% for patients in whom first-line, nonanthracycline-containing
regimens failed (Table 3) [9-13] to 20% to 27% for patients in
whom an anthracycline-containing regimen (Table 4) failed [14-16].

Among the newer agents, vinorelbine (Navelbine), at 30 mg/m²/wk,
has produced an objective response rate of 32% as second-line
therapy in patients in whom nonanthracycline regimens failed in
an American trial [13], with higher response rates reported from
Europe. Response rates with paclitaxel have been highly variable
(32% to 62%), depending on the dose and schedule employed, even
when it was used as first-line treatment of metastatic breast
cancer (Table 5) [13,17-22]. In a single pure second-line trial
by Seidman et al [23] using 250 mg/m² of paclitaxel given
as 24-hour infusions with granulocyte colony-stimulating factor
(G-CSF, filgrastim [Neupogen]) support, the response rate was
44%, with little difference between anthracycline- and nonanthracycline-resistant
patients. Lower doses and shorter durations of paclitaxel therapy
appear to yield response rates similar to those of vinorelbine
therapy in previously treated patients [20,24,25].

Results for the taxanes (Table 6) [26,27] and vinorelbine (Table
7) [28-31] as second-line therapy for patients in whom anthracycline
treatment has failed currently seem to favor the taxanes, but
controlled, randomized trials in this subset of patients are needed
to clarify this issue definitively. To date, the best results
seen for the taxanes in anthracycline-resistant patients are with
96-hour paclitaxel infusions [26] or 1-hour docetaxel (Taxotere)
infusions [27].

The Controversy Surrounding Salvage Chemotherapy

It seems that most clinicians would accept that first-line chemotherapy
with response rates of 50% to 60% and survival longer than 1.5
years is generally worthwhile for patients with metastatic breast
cancer. In addition, the population of patients with response
rates of 35% to 45% for second-line therapy in whom nonanthracycline-containing
first-line regimens failed should also be considered for treatment.

The use of second-line therapy for patients in whom first-line,
anthracycline-containing regimens failed is controversial. Perhaps,
it was this group that led to pessimism on the part of oncologists
in Maryland; during a survey, these oncologists indicated that
although they used second-line chemotherapy 74% of the time, they
did so without much enthusiasm. In their commentary on these results,
Benner et al [32] suggested that "standard chemotherapy be
stopped after breast cancer fails to stabilize or respond on a
standard regimen." They stated that "the frequent utilization
of second-line regimens probably reflects an effort to offer marginal
regimens to patients who want them." This conclusion appears
to be supported by Porkka et al [14] in a wellwritten article
from Finland. Although 24% of their patients responded to second-line
treatment after first-line anthracycline failure, only 10% of
these patients had a time to treatment failure of longer than
6 months. In addition, they found that no patient treated with
a third salvage chemotherapeutic regimen responded. They concluded
that "the value of offering more than two salvage chemotherapy
programs to an unselected group of patients is questionable."

Undoubtedly, the findings of Benner's [32] and Porkka's [14] groups
will be widely cited by managers of health maintenance organizations,
as guidelines are written for the purpose of cost containment.
In contrast, this degree of therapeutic nihilism comes at a time
when a wide variety of potential salvage regimens are available
(Table 8) and an unprecedented number of new investigational drugs
with proven effectiveness for metastatic breast cancer are under
development (Table 9).

The problem is compounded by the general unavailability of stringently
controlled trials to define the value of third-line and fourth-line
(or higher level) therapies in patients with metastatic breast
cancer. Clinicians are faced with a large number of small, uncontrolled
trials often citing results at variance with the existing bias
that third-line (or higher level) chemotherapy is generally ineffective.