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Edited comments by Dr Mamounas
NSABP B-27 neoadjuvant trial
The main goal of this trial was to determine whether the addition
of docetaxel to AC would improve disease-free or overall survival.
Additionally, the trial assessed whether the addition of preoperative
docetaxel resulted in improved clinical and pathologic response
rates and whether postoperative docetaxel improved the outcomes
of patients with pathologically positive nodes.
Docetaxel was selected in light of the phase II data demonstrating
response rates around 47% in anthracycline-resistant breast cancer.
Phase III data, which became available after the trial began, indicated
that docetaxel was actually more active than doxorubicin.
Response rates in NSABP B-27
Preoperative doxorubicin/cyclophosphamide followed by docetaxel
increased both the clinical and pathologic response rates compared
to preoperative doxorubicin/cyclophosphamide alone. The clinical
response rate increased from 85% to 91%, with the complete response
rate improving from 40% to 65%. Of even greater importance, the
pathologic response rate essentially doubled from 13.5% to 25.6%
in patients with ER-positive and ER-negative tumors.
The median tumor size in B-27 was 4.5 cm; whereas, the median
tumor size in our previous neoadjuvant trial B-18 was about 2.2
cm. Since B-27 involved eight cycles of therapy, there may have
been a natural selection to enroll higher-risk patients with larger
tumors. Surprisingly, the pathologic response rate (~13%) for doxorubicin/cyclophosphamide
was the same in both trials, indicating that a tumor will respond
to neoadjuvant chemotherapy regardless of its size.
Sentinel node biopsy in patients on NSABP B-27
In about 400 cases, we performed a sentinel node biopsy off-protocol.
We were then able to compare those results to the axillary dissection,
which was part of the protocol. We were able to identify the sentinel
node in about 85% of the cases. The success rate was higher (~90%)
for the cases in which we used radioisotope and blue dye together.
The false-negative rate was about 11% for node-positive patients,
which is comparable to the results obtained in the multicenter trial
by Krag.
Survival in NSABP-27
The disease-free and overall survival analyses require enough
observed events, and it may still be another couple of years before
we perform the final analyses. Although B-18 did not demonstrate
a disease-free or overall survival difference, B-27 may or may not
support this result.
Neoadjuvant capecitabine/docetaxel trial
In light of the B-27 trial results, we are designing a neoadjuvant
trial that will compare doxorubicin/cyclophosphamide followed by
docetaxel with or without capecitabine. This trial is based on Dr
O’Shaughnessy’s study, which demonstrated that capecitabine/docetaxel
improved survival in patients with metastatic breast cancer. Since
B-27 established that preoperative docetaxel almost doubled the
pathologic response rate, we want to see if adding capecitabine
will further increase the pathologic response.
This trial will also assess many biomarkers, both before and after
chemotherapy, with sequential core biopsies. We will attempt to
identify molecular biomarkers with DNA microarray and high throughput
technology that can predict the response to chemotherapy. We will
also measure thymidine phosphorylase to determine if it is upregulated
by docetaxel. Based on data from B-18 and B-27, sentinel node biopsy
alone will be allowed for patients with a pathologic complete response.
We will evaluate whether neoadjuvant chemotherapy can reduce the
extent of surgery, not only in the breast but also in the axilla.
Because hand-foot syndrome is associated with higher doses of
capecitabine, we plan to decrease the dose to 2 gm/m2 (in two divided
doses for two weeks with one week off). There are some data to suggest
that the efficacy is not reduced by this dose reduction. In fact,
the majority of the patients in Dr O’Shaughnessy’s trial
had this dose reduction. In the adjuvant setting, it is reasonable
to reduce the dose of a drug from its maximum tolerated dose.
Sequential versus combination chemotherapy in
the adjuvant setting
NSABP B-30 is an important trial since it will answer whether
sequential chemotherapy is better than combination chemotherapy
in the adjuvant setting. Patients with node-positive breast cancer
are randomized to doxorubicin/cyclophosphamide followed by docetaxel
versus doxorubicin/docetaxel versus docetaxel/doxorubicin/cyclophosphamide.
The rationale for selecting docetaxel is related to the issue of
cardiac toxicity. Initial phase II trials from Europe reported over
a 90% response rate for paclitaxel when given in combination with
doxorubicin. However, there was an increase in cardiac toxicity
when paclitaxel was given in combination with doxorubicin and cyclophosphamide.
Although cardiac toxicity may be attenuated by either changing the
length of the infusion or separating paclitaxel from doxorubicin
by several hours to a day, these maneuvers may also decrease efficacy.
In phase II trials, docetaxel when given in combination with doxorubicin
did not increase cardiac toxicity. This difference in cardiac toxicity
may be related to the different vehicles used to dissolve paclitaxel
and docetaxel. Paclitaxel is dissolved in cremophor, which is known
to increase doxorubicin’s area under the concentration curve
(AUC). Docetaxel, on the other hand, is dissolved in polysorbate,
which does not increase doxorubicin’s AUC.
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