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Current Cooperative Group Phase III Clinical Trials in Early-Stage Breast Cancer

Current Cooperative Group Phase III Clinical Trials in Early-Stage Breast Cancer

The 4th National Institutes of Health
(NIH) Consensus Conference on Adjuvant Therapy of Breast
Cancer,held November 1-3,
2000, concluded that decreasing breast cancer mortality rates in the United
States were due, at least in part, to advances made in adjuvant treatment. This
fact lends credence to the importance of incremental improvements that have
resulted from randomized, controlled clinical trials of adjuvant therapy, and
underscores the value of this approach. With 185,000 new diagnoses of breast
cancer expected in the United States in 2000, over 100,000 women may be
candidates for some form of adjuvant therapy each year.[1]

The Consensus Conference Statement (www.consensus.nih.gov)
noted several new important research directions for adjuvant therapy. These
included the study of new hormonal therapies in lieu of, or in addition to,
tamoxifen (Nolvadex); the integration of trastuzumab (Herceptin) and
bisphosphonates into adjuvant regimens; further study of the appropriate use of
taxanes; and the evaluation of sentinel node biopsy and postmastectomy adjuvant
radiotherapy in women with one to three axillary nodes.

Hormonal Therapy

Some current trials of the US Cooperative Groups are addressing
these questions. Randomized studies testing the optimal duration of tamoxifen
have not yet demonstrated a benefit for extending tamoxifen beyond 5 years.
While ongoing studies are testing 5 years of tamoxifen vs longer durations, a
Canadian-led international collaborative study (JMA.17), which includes the US
Intergroup (Cancer and Leukemia Group B [CALGB], the Eastern Cooperative
Oncology Group [ECOG], the North Central Cancer Treatment Group [NCCTG], and the
Southwest Oncology Group [SWOG]) is comparing letrozole (Femara; a
third-generation aromatase inhibitor) to placebo in women who are disease-free
after 5 years of adjuvant tamoxifen.[2,3] It is anticipated that about 20% of
study patients who are disease free after 5 years will relapse within the first
4 years following cessation of tamoxifen. Crossover to an aromatase inhibitor—which
has been shown to be beneficial in the metastatic setting—may be beneficial in
this setting. However, there are concerns about increases in osteoporosis and
heightened lipid levels. The frequency of these adverse factors is being studied
in a selected subset of patients (MA.17B and MA.17L).

Monoclonal Antibody

Two large adjuvant trials (the National Surgical Adjuvant Breast
and Bowel Project [NSABP] B-31 and N9831) have recently begun to integrate
trastuzumab (a humanized monoclonal antibody against the HER2/neu oncoprotein)
into standard adjuvant regimens. The inclusion of trastuzumab is based on the
impressive results shown in the metastatic disease setting where trastuzumab
combined with chemotherapy demonstrated a survival advantage.[4]

To be eligible for these two trials, patient tumors must test
positive for HER2/neu, either 3+ by immunohistochemistry (IHC) or positive by
fluorescent in situ hybridization (FISH). As patients in both trials receive
doxorubicin before trastuzumab, there is careful cardiac monitoring of all
patients via multiple-gated acquisition (MUGA) scans. Both trials are divided
into two phases: An initial cohort of 1,000 patients will be entered to evaluate
toxicity and feasibility; if toxicity is acceptable, a larger cohort
(approximately 2,000 patients) will then be entered to evaluate efficacy.


The bisphosphonates represent a novel approach to breast cancer
therapy. They target the microenvironment of bone—a frequent metastatic site—rather
than the tumor itself.[5] These pyrophosphate analogs inhibit bone resorption
and have a proven role in preventing osteoporosis. In patients with advanced
breast cancer, they have been shown to reduce the incidence of hypercalcemia and
pathologic fractures.[6]

The NSABP has just commenced a trial (NSABP B-34) comparing an
oral bisphosphonate, clodronate, to placebo, with each being administered daily
for 3 years. Prior chemotherapy or tamoxifen is permitted, and patients of all
ages and nodal and receptor statuses are eligible. The trial—which utilized a
large, simple trial design—represents the largest adjuvant study performed
with bisphosphonates to date. Three previous trials have produced mixed results,
and this NSABP trial will likely provide a more definitive answer.[7-9]


Several other trials are trying to discern the optimal schedule
of taxanes. The initial Intergroup trial, C9344, demonstrated a survival benefit
for the sequential addition of paclitaxel (Taxol) to the standard AC regimen
(doxorubicin/cyclophosphamide [Cytoxan, Neosar] in women with node-positive
breast cancer.[10] Results from NSABP B-28, a trial similar in design to the
CALGB-led Intergroup trial, were presented at the recent NIH Consensus
Conference. This trial did not find a significant survival benefit with the
addition of paclitaxel.

Additional studies in the United States and abroad are comparing
chemotherapy regimens with and without taxanes. Refinement of their role should
be forthcoming as data become available. Currently, NSABP B-30 is testing
whether combined therapy is superior to a sequential approach. This trial is
comparing ACT (doxorubicin/docetaxel [Taxotere]/cyclophosphamide) vs AT
(doxorubicin/docetaxel) vs AC-T (doxorubicin/cyclophosphamide followed by

Additionally, the Intergroup is comparing the two taxanes,
paclitaxel and docetaxel, using the established sequential regimen. This
ECOG-led study, E1199, is treating node-positive or high-risk, node-negative
patients with doxorubicin and cyclophosphamide for four cycles, followed by
randomization to docetaxel or paclitaxel given on a weekly or every-3-week

Sentinel Node Biopsy

Sentinel node biopsy is a promising new approach to stage the
axilla and reduce morbidity associated with traditional axillary lymph node
dissection. Despite several trials that demonstrate a strong correlation between
the sentinel node(s) and the status of the axillary nodes, there is concern that
no trial has yet proven that survival outcomes are equivalent only when the
sentinel node procedure is used. Trial NSABP B-32 is designed to provide such an

In this trial, surgeons are trained in the procedure via a
hands-on prestudy session, and are only permitted to randomize patients once
proficiency with the technique has been obtained. In B-32, women are randomized
to sentinel node biopsy or axillary dissection. Those who have a positive
sentinel node have a complete axillary dissection, while women with negative
axillary nodes are followed without further surgery.

The American College of Surgeons Oncology Trials Group (ACOSOG)
Z0010 and Z0011 trials are also studying the role of sentinel nodes. Patients
who desire a sentinel node biopsy may enter the Z0010 trial. Those who are found
to have a positive sentinel node are offered randomization (trial Z0011) to
axillary dissection or no further surgery. Patients with a negative sentinel
node are registered in Z0010 and followed for local recurrence and survival.
Both the NSABP and ACOSOG efforts have important laboratory components that will
compare patient outcomes with results from immunohistochemistry
on sentinel node and bone marrow specimens.

Postmastectomy Radiotherapy

An additional area under evaluation in the Cooperative Groups is
the role of postmastectomy regional radiation. For many years, the medical
oncology community had dismissed regional radiotherapy as having an impact on
local control, but no effect on overall survival. Several new clinical trials
and an updated metaanalysis of all randomized trials indicate that the effect of
regional radiotherapy on breast cancer mortality may be significant [11-14].

The recent Consensus Conference Statement concluded that the
role of postmastectomy radiotherapy was well established for women with four or
more positive axillary lymph nodes. However, controversy persists in women with
one to three nodes. In Intergroup trial, S9927, which is being led by SWOG,
women with one to three positive nodes are being randomized to regional
radiotherapy (chest wall, supraclavicular and infraclavicular nodes, and
internal mammary nodes) vs no further treatment. Eligible patients can receive
adjuvant treatment outside of a trial or in another clinical trial before entry
into this study.

Timely answers to these important research questions require the
participation of large numbers of physicians and patients. Mechanisms for
encouraging increased participation have been developed nationally by the
National Cancer Institute (NCI). In addition to the existing community clinical
oncology programs (CCOPs) and community affiliate programs of individual
Cooperative Groups, a new Cancer Trials Support Unit (CTSU) has been developed
by the NCI to permit greater access than ever before to Cooperative Group trials


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