Download Adjuvant Therapy for All Patients With Breast Cancer?

EDITORIALS
Adjuvant Therapy for All Patients With Breast Cancer?
Marc E. Lippman, Daniel F. Hayes
In this issue of the Journal, Fisher et al. (1) from the National
Surgical Adjuvant Breast and Bowel Project (NSABP) provide a
retrospective analysis of the prognosis and treatment of patients
with tumors 1 cm or less and negative axillary lymph nodes.
They address a critical question about adjuvant therapy decision
making: whether or not these therapies should be applied to
patients with tumors smaller than 1 cm. They examine a series of
contributory randomized trials conducted by the NSABP over
the past quarter century and conclude, “chemotherapy and/or
tamoxifen should be considered for the treatment of women with
ER [estrogen receptor]-negative or ER-positive tumors of 1 cm
or less and negative axillary lymph nodes.” This finding is a
paradigm-shifting conclusion, especially in regard to chemotherapy, and we believe that this conclusion needs to be examined carefully.
The question is probably not whether chemotherapy works at
all in such patients. As far as can be determined, one should not
expect a qualitative difference in response to chemotherapy or
hormone therapy in patients with smaller tumors when compared with those with larger or lymph node-positive breast cancers. Results from the most recent Oxford Overview of Early
Breast Cancer Treatments (2) suggest that, overall, chemotherapy reduces annual odds of recurrence and death by 23% and
15%, respectively. Likewise, 5 years or more of tamoxifen produces a proportional reduction in annual odds of recurrence and
death in ER-rich patients by approximately 40% and 30%, respectively (3). The Oxford Overview data suggest that patients
with lymph node-negative tumors are no more or less likely to
benefit than those with lymph node-positive tumors. By extrapolation, therefore, one should not expect small tumors to be more
or less responsive to the beneficial effects than larger tumors.
Therefore, no matter what the prognosis, there is no patient
with invasive breast cancer who might not benefit from adjuvant
chemotherapy and/or hormone therapy, since no patient has a
zero chance of recurrence or death. Thus, other factors must also
be brought into the equation when considering whether to recommend adjuvant systemic therapy: the prognosis of the individual patient and the degree of benefit required to justify the
toxic effects of the treatment. We will consider the latter first. If
patients are willing to accept any toxicity for as small as a 1%
increase in odds of survival, then the investigators from the
NSABP make a salient point: All should consider treatment. In
fact, three studies (4–6) have investigated the willingness of
patients to accept small incremental odds of survival for either
chemotherapy. Surprisingly (or perhaps, not so surprisingly), as
many as 50% of patients state that they would accept the toxic
effects of chemotherapy for an incremental benefit of an extra
1% survival advantage after 5 years. Of course, the corollary is
that 50% would not. However, most if not all patients would
accept chemotherapy for an additional 10% chance of survival.
So, what “cutoff” of absolute benefit is sufficient to recommend
chemotherapy: 1%, 3%, 5%, or 10%? Arbitrarily, many physi80 EDITORIALS
cians consider a cutoff of an additional 3% or more added benefit sufficient to justify recommending treatment, at least for
chemotherapy.
Results from similar studies examining patient preferences
are unavailable regarding tamoxifen. Given the relatively favorable toxicity profile of tamoxifen, one might assume that more
patients would be willing to accept this therapy for less potential
added benefit. However, the prolonged period of treatment and
the frequent occurrence of highly annoying, but seldom lifethreatening, toxic effects are of concern to both patients and
caregivers.
The second important consideration is that of absolute prognosis. Obviously, the chance that a patient will benefit from
therapy increases as her absolute odds of recurrence increase.
One can assume that adjuvant chemotherapy will proportionally
reduce the annual odds of recurrence by no more than 25% after
15 years of follow-up (which is the figure suggested by the most
recent overview). In that case, a patient with a 95% chance of
disease-free survival after surgery alone will have her absolute
odds of survival increased by no more than 1% or 2% from
adjuvant chemotherapy. Is this worth the risk of nausea, hair
loss, infection, bleeding, and perhaps even lethal toxic effects?
Most guideline panels think not, but, of course, individual patients and caregivers may choose otherwise (7).
Finally, discussions of all of these considerations may be
confused by which end points are being considered. The most
reliably measured end point is death. However, death often lags
far behind other end points. Therefore, studies that rely on this
end point must be substantially larger or more mature, since
there are fewer events to provide statistical power. Furthermore,
death may be confounded by causes other than breast cancer.
Investigators and patients have often considered recurrence to be
a reasonable surrogate for morbidity and mortality. Arguments
have risen over whether one should include only distant recurrence or whether local regional disease should be counted as
well. The NSABP has included ipsilateral breast recurrence and
even new contralateral breast cancers as events. Since the prognosis after these events is much better than after distant recurrences, they are not reliable surrogates of morbidity and mortality.
Having reviewed these considerations, should the results
from the NSABP experience lead to more liberal recommendations for adjuvant systemic therapy, especially in regard to chemotherapy? Let us first consider chemotherapy in ER-negative
Affiliation of authors: Breast Cancer Program, Lombardi Cancer Center,
Georgetown University Medical Center, Washington, DC.
Correspondence to present address: Marc E. Lippman, M.D., Department of
Internal Medicine, University of Michigan Health System, 3101 Taubman
Health Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109–0368 (e-mail:
[email protected]).
© Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 2, January 17, 2001
patients. In this cohort of patients, the control group of patients
who received surgery alone consisted of 36 patients treated from
1982 through 1988 versus 60 patients treated with chemotherapy, of whom only 26 were randomly assigned to therapy.
No statistically significant advantage in relapse-free survival,
event-free survival, or overall survival for chemotherapy was
noted for the patients accumulated in the concurrent randomized
trial. We do not question the efficacy of chemotherapy in this
group. We do question whether the prognosis for untreated patients, which is relatively poor in NSABP studies, represents the
population as a whole. Even though the study is meant to describe patients with tumors of 1 cm or less, there are only 11
patients with T1a (艋5 mm) lesions in the ER-negative group
who received surgery alone and 25 patients with tumors of 5 mm
or less who received chemotherapy—a miniscule subset of their
patient population. Nearly 60% of the patients had exactly 1-cm
tumors, twice the size of the group of patients who had tumors
of 6–9 mm, suggesting some kind of “bundling” effect by the
pathologist. It is difficult to imagine that the majority of patients
had exactly 10-mm tumors. Whether or not this clustering represents contamination of patients whose tumors were larger or
not is probably impossible to ascertain at this time. In any event,
less than half of the patients reviewed had tumors less than 10
mm in size and only a handful less than 5 mm. In a separate
analysis provided by the authors for tumors that are 1 cm versus
those less than 1 cm, the risk ratios for recurrence are half for the
smaller tumors, independent of therapy. This comparison is
made up almost entirely of patients with 1-cm tumors versus
those with 6- to 9-mm tumors. Because of sample size, no conclusions concerning smaller tumors are possible; however, certainly, these patients have an even better natural history. Furthermore, these ground-breaking clinical trials were performed
at a time when any adjuvant systemic therapy for lymph nodenegative patients was truly avant-garde. Although it is difficult
to ascertain, subtle biases in these early treatment trials may
have led clinicians to encourage some patients who may have
appeared to have a worse prognosis (for whatever reasons) to
participate in these studies.
The data for ER-positive tumors are equally problematic. For
example, there are only 17 patients with T1a lesions among the
ER-positive control group and only 13 who received chemotherapy plus tamoxifen. Clearly, these nonconcurrently treated
patients (the tamoxifen plus chemotherapy group was treated
from 1988 through 1993; most of the surgery-only patients were
treated in the early 1980s) provide a dataset that is completely
under-powered for any conclusion concerning small tumors.
Once again, approximately 60% of the tumors were determined
to be exactly 10 mm and only one third were between 6 and 9
mm, suggesting some kind of potential artifact in staging. Furthermore, as the authors point out, in the earliest cohorts, 1 g of
tumor was required for ligand-binding hormone receptor studies,
but, for patients accrued later, smaller samples were adequate.
Moreover, in the most recent set of patients, immunohistochemical analyses were used. Thus, since less material was required
for receptor analyses, there could easily be a subtle drift in size
toward smaller tumors in later samples, which are predominantly
made up of the systemically treated patients. Clearly, increased
numbers of smaller tumors in cohorts treated with systemic
therapy will bias the data, given the critical impact of tumor size
in lymph node-negative patients.
Results from previously reported population-based studies
[reviewed in (8)] have suggested that patients with T1a tumors
have a substantially better prognosis than those with T1b tumors
(>5 mm but 艋10 mm in size). In fact, in small tumors, prognosis
changes millimeter by millimeter. Some data (9) show that patients with predominantly in situ cancer but with a millimeter or
less of invasion have a prognosis similar to that of patients with
noninvasive breast cancer. In the recent era, tumors of less than
1 cm are in the majority and tumors of less than 5 mm are
increasingly common. In these subsets, many of which have
event-free survival in excess of 95%, the small but real risks of
infection, hemorrhage, cardiomyopathy, deep-vein thrombosis,
pulmonary emboli, cardiomyopathy, uterine cancer, etc., may
approach, if not exceed, therapy gains. Given this substantially
improved prognosis and the lack of information in the current
study concerning tumors of 9 mm or less, it seems difficult to us
to share the conclusion of the authors that chemotherapy should
be considered for these patients in the absence of definitive
clinical trials or other prognostic information to the contrary.
While more tumors are being detected that are less than 1 cm,
some of these will be biologically aggressive and not be cured
by local therapy alone. We agree with Fisher et al. (1) in the
NSABP, who suggest in their discussion, “Use of the histopathologic and ER status of a tumor 1 cm or less in size or other
aspects of a patient’s clinical status is apt to be more helpful for
making a decision about systemic therapy than is use of precise
tumor size.” Unfortunately, neither of these classic factors is
sufficiently strong to be of much clinical use (8,10). For example, in NSABP studies, the risk of recurrence for ER-negative
patients treated with surgery only was only 5% worse than that
for ER-positive patients (81% versus 86%, respectively). Survival was actually superior for untreated ER-negative compared
with ER-positive patients (93% versus 90%, respectively). As
screening becomes more widespread and detection of cancers at
smaller sizes becomes the norm, we need substantially more
clinical and translational research to identify strong prognostic
factors. It is only through such research that clinicians will be
able to reliably distinguish those patients whose prognosis is
sufficiently good that they can forgo the risks of treatment from
those patients for whom the benefits far outweigh these risks,
thus permitting us to apply beneficial but risky adjuvant therapy
efficiently.
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Journal of the National Cancer Institute, Vol. 93, No. 2, January 17, 2001
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Journal of the National Cancer Institute, Vol. 93, No. 2, January 17, 2001