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Educational Supplement: Appendix
Preoperative
Chemotherapy: NSABP Protocols B-18 and B-27
Norman
Wolmark, M.D.
If the sole
purpose of this review were to determine whether preoperative chemotherapy
should be used as part of the standard armamentarium in the treatment
of breast cancer, the answer would be straightforward if not banal.
Since the data have clearly demonstrated that there is no disadvantage
to the use of preoperative chemotherapy with respect to disease-free
survival and survival, its use as an intervention to downstage tumors,
making them amenable to breast-preserving procedures, is not likely
to generate intense controversy. To view preoperative chemotherapy
in this narrow context, however, belies its compelling biologic
significance.
The emergence
of preoperative adjuvant therapy as an intervention in primary operable
Stage I and II breast cancer is a direct consequence of data generated
from a series of randomized prospective clinical trials. The rationale
and justification for this intervention evolved on the heels of
the retreat from radical mastectomy. Only with the acceptance of
breast-preserving operations and the abandonment of en bloc resection
could the primacy of the operation be challenged. The tentative
and seemingly heretical question could finally be addressed: Should
the operation now be regarded as adjuvant treatment? In order for
this hypothesis to reach the point where it could be tested in randomized
prospective clinical trials, it first had to be demonstrated that
adjuvant therapy when used in the traditional postoperative setting
could prolong disease-free survival and survival in both stage I
and II carcinoma of the breast.
NSABP B-18 was
conceptually provocative in that preoperative chemotherapy was given
to women with tumors that were readily amenable to treatment by
more traditional means. These were not women with locally advanced
breast cancer whose tumor had reached the point where it was no
longer curable with operative intervention and in whom
chemotherapy was used as salvage treatment. But perhaps
the greatest potential of preoperative adjuvant therapy is yet to
be realized. This is a unique settingthe tumor is readily
accessible to surgery while the patient is undergoing other treatment.
A potentially powerful tool may become available whereby molecularly
characterized tumor discriminants can be correlated with the efficacy
of preoperative adjuvant treatment and, more importantly, with subsequent
survival. Although it is premature to suggest that objective tumor
regression during the course of adjuvant therapy is a definitive
bioassay that presages efficacy, the data for NSABP B-18 suggest
that this is a possibility.
NSABP Protocol
B-18
Between October
1988 and April 1993, 1,495 eligible patients were randomized to
receive either four cycles of Adriamycin (A) and cyclophosphamide
(C) preoperatively followed by surgery, or to the same chemotherapeutic
regimen administered in the traditional postoperative setting. Eligibility
was restricted to women with clinical Stage I and II breast cancers
whose tumors were palpable. Because minimal perturbation of the
tumor in the preoperative setting was thought to be essential, open
biopsy was not permitted; the diagnosis was established by either
fine needle aspiration or core needle biopsy. In those women undergoing
breast-preserving procedures, radiotherapy was administered within
4 weeks of the operation in the preoperative arm and within 4 weeks
of the completion of chemotherapy in the postoperative arm. Over
a quarter of the women in this trial had tumors whose diameter was
>=2 cm in diameter.
The data at
six-year followup demonstrate definitively that the four cycles
of preoperative chemotherapy used in this trial were effective in
downstaging the size of the primary tumor and of involved regional
nodes. Of the 685 women undergoing preoperative chemotherapy, 36
percent demonstrated a complete clinical response with no evidence
of palpable residual tumor at the completion of chemotherapy. An
additional 43 percent demonstrated a partial response to treatment,
providing an overall objective response of 79 percent. Of the 36
percent of women demonstrating a complete clinical response, approximately
one-third had no evidence of invasive cancer by histologic exam
of the operative specimen. There also was evidence of nodal downstaging
attributable to preoperative chemotherapy; 58 percent of women randomized
to traditional postoperative chemotherapy had histologically positive
nodes, compared with 40 percent of those patients who received preoperative
chemotherapy.
The overall
rate of ipsilateral breast tumor recurrence (IBTR) in those women
undergoing breast-preserving operations was 7.9 percent for those
who received preoperative chemotherapy, compared to 5.8 percent
in those who were treated with postoperative therapy. Since there
were only 66 ipsilateral breast tumor recurrences in the 954 eligible
patients with breast-preserving procedures, further subset analysis
of IBTR relative to patient age, tumor size, and initial response
to therapy is of questionable merit.
The data are
equally noteworthy for what was not demonstrated. There was no advantage
for preoperative chemotherapy relative to disease-free survival
and overall survival. The life table curves for the two treatments
were virtually superimposable. These findings are significant when
related to the specific aims of the trial. Prior to the initiation
of NSABP B-18, it was postulatedon the basis of a number of
kinetic modelsthat preoperative chemotherapy would be superior
to chemotherapy given in the postoperative setting. One popular
kinetic model suggested that as a result of spontaneous mutations
a progressively increasing subset of drug-resistant cells developed
with time, thus favoring the preoperative setting. The results of
NSABP B-18 are not supportive of this hypothesis.
Perhaps the
most interesting finding of NSABP B-18 is the correlation between
local tumor response and subsequent outcome. Women who demonstrated
a complete clinical tumor response had a better outcome than those
who did not. Moreover, the most favorable outcome occurred in women
who had no evidence of residual histologic invasive cancer. In a
multivariate analysis in which other baseline prognostic variables
were included, breast tumor response to preoperative chemotherapy
continued to be a significant independent predictor of patient outcome
(Fisher, Brown, Mamounas, et al., 1997; Fisher, Bryant, Wolmark,
et al., 1998).
NSABP Protocol
B-27
This later study
was a natural extension of B-18. Patients with similar characteristics
to those in B-18 are randomized to one of three treatment options,
all utilizing preoperative chemotherapy. The control arm consists
of the same regimen that was used in the preoperative setting of
B-18, namely, four cycles of AC. Arm 2 will determine whether adding
four additional preoperative cycles of sequential Taxotere following
AC will result in a higher proportion of women with clinical and
pathologic tumor response. Patients randomized to the third arm
receive the same preoperative four cycles of AC, with the four cycles
of Taxotere delayed until after the operation has been completed.
The trial was initiated in December of 1995, and the required sample
size of 2,400 patients is expected to be achieved by the end of
this year.
B-27 will assess
whether the addition of the taxane regimen will prolong disease-free
survival and survival, and whether these endpoints can be correlated
with the response of the primary tumor. The preoperative setting
provides the opportunity to evaluate serial changes in serum and
tumor biomarkers, and to correlate such changes to tumor response
and patient outcome. As part of this study, formalin-fixed and paraffin-embedded
core biopsy or fine needle aspiration have been collected for biomarker
studies. It will be possible, using the collected materials, to
evaluate the prognostic and predictive value of several biomarkers,
including HER2, p53, p-glycoprotein, Ki67, and array-based CGH (Mamounas,
1997).
Conclusions
If the correlation
between tumor response and outcome observed in B-18 can be verified
and extended in B-27, a rapid evaluation of candidates for therapeutic
intervention could become available. Although it is tempting to
speculate on the potential biologic contributions of the preoperative
setting, the practical charge of the consensus committee must be
addressed: Should preoperative chemotherapy be part of the therapeutic
standard? The data support the use of adjuvant preoperative chemotherapy
in settings where the downstaging of the primary tumor is desirable,
and in this context it should be an accepted standard of care. Updated
results of B-18 and results from other preoperative chemotherapy
trials will be reviewed during this conference. Although the information
generated so far is unlikely to represent a threat to the domain
of the surgeon, the primacy of the operative procedure has been
significantly challenged.
References
Fisher B, Brown
A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect
of preoperative chemotherapy on local-regional disease in women
with operable breast cancer: findings from National Surgical Adjuvant
Breast and Bowel Project B-18. J Clin Oncol 1997; 15:248393.
Abstract.
Fisher B, Bryant
J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative
chemotherapy on the outcome of women with operable breast cancer.
J Clin Oncol 1998; 16:267285. Abstract.
Mamounas EP.
NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide
followed by preoperative or postoperative docetaxel. Oncology 1997;
11:3740. Abstract.
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