BETHESDA, MdThe aggregate benefit of adjuvant systemic
chemotherapy is "greater than many would think," reflecting
"real and substantial" progress, Gabriel N. Hortobagyi, MD, professor
and chairman of Breast Medical Oncology, M.D. Anderson Cancer Center, said at
the NIH Consensus Conference on Adjuvant Therapy for Breast Cancer.
Dr. Hortobagyi presented an overview of the progress made in
systemic chemotherapy, especially with combinations of agents. He said that the
2000 meta-analysis from the Early Breast Cancer Trialists’ Collaborative
Group confirms and expands upon the 1995 meta-analysis, and shows a substantial
advantage of chemotherapy over surgery alone, both for node-positive and
node-negative breast cancer, in terms of reducing the risk of recurrence and
For trials involving tamoxifen (Nolvadex), the magnitude of the
benefit in reducing the risk of recurrence is greater than the reduction in the
odds of death.
He said that "aggregate data best reflect the state of the
art." However, he reminded attendees that meta-analysis is the great
"With a meta-analysis, you don’t get the best results
but the average results. These average results are important to the generation
of hypotheses but they do not represent the best that chemotherapy has to
offer," he pointed out.
Dr. Hortobagyi said the recent meta-analysis offers the
following messages regarding adjuvant therapy:
Age is an important determinant of efficacy. Patients
younger than 50 have a substantially greater reduction in the odds of
recurrence or death than older patients. "How much of this is real and how
much is related to the adequacy of treatment is unresolved," he added.
There is a correlation between the efficacy of adjuvant
chemotherapy and estrogen-receptor (ER) status, with greater benefit seen in
the ER-negative subgroup.
Regarding duration of chemotherapy, prolonged treatment
beyond 6 months with the same regimen does not confer additional benefit above
and beyond 4 to 6 months of treatment. It is believed that 6 months is probably
as effective as 1 year of chemotherapy, but the minimum treatment duration is
not as clearly defined, and less than 6 months of treatment may be less
"With commonly employed single-therapy regimens, about 4
to 6 months of treatment will convey maximum benefit. If you use sequential
regimens, you may need to prolong the duration to deliver enough of both
regimens," he said.
The 1995 meta-analysis found that the addition of an
anthracycline to adjuvant systemic chemotherapy reduces the odds of recurrence
by about 12% and the odds of death by 11%. This "highly significant
effect" was even more pronounced in the 2000 meta-analysis, which found a
16% reduction in recurrences and a 15.7% reduction in mortality, he reported.
In a large trial of almost 4,000 patients (SWOG S8897 or INT
102) that compared CMF (cyclophosphamide, methotrexate, fluorouracil) to CAF
(cyclophosphamide, Adriamycin, fluorouracil) in node-negative breast cancer, a
substantial absolute difference3% to 4%was seen in favor of the
anthracycline-containing regimen in terms of the 5-year estimate of relapse.
But smaller randomized trials have not always shown advantages; in fact, their
results have been "all over the map," he noted.
"If you pool the data, you see a therapeutic advantage, a
significant reduction in the odds of recurrence or death," he said.
"But I have been concerned over the adoption of AC
(Adriamycin/cyclophosphamide) as a standard without having compared it to the
other two anthracycline combinations. Two-drug combinations using doxorubicin
or epirubicin [Ellence] clearly show equivalence to CMF. But our goal is not
equivalence to CMFCMF is a regimen that could use improvement."
On the other hand, he said, looking at three- or four-drug
regimens containing cyclophosphamide or fluorouracil, most of these show a
significant improvement in outcomes, both relapse-free survival and overall
survival. "This would suggest the three-drug combinations are superior to
CMF whereas the two-drug combinations are equal to CMF," he said.
Dr. Hortobagyi said that he "tentatively concludes"
that anthracycline-containing regimens are clearly more effective than regimens without
anthracyclines, that they appear particularly useful in premenopausal
patients, and that regimens that also contain 5-fluorouracil and
cyclophosphamide are more effective than AC alone."
He added, however, that there is no evidence that AC is
equivalent to FAC (fluorouracil, Adriamycin, cyclophosphamide), because these
regimens have not been formally compared. Whether FAC is superior because of
its third drug or the duration of therapy (usually 6 to 8 cycles) is unclear,
In CALGB 9344, paclitaxel (Taxol) added to AC conferred a
substantial benefit in reducing the risk of recurrence or death in
node-positive patients. This finding essentially changed the standard of
practice in the United States, but not in Europe, where oncologists remain
cautious about adopting this practice, he said.
According to Dr. Hortobagyi, the reduction in risk of
recurrence and death with chemotherapy is as follows:
Combination chemotherapy vs no combination chemotherapy
reduces the annual odds of recurrence by 23% and the odds of death by 17%,
highly significant benefits.
The addition of doxorubicin or epirubicin confers an
additional 12% benefit.
The further addition of paclitaxel conveys an
incremental benefit of 22% to 25%, highly significant (assuming the data will
Dr. Hortobagyi summarized a large body of literature on
chemotherapy dose by stating that dose reductions below optimal maximally
tolerated doses without growth factor support are "harmful."
The National Surgical Adjuvant Breast and Bowel Project (NSABP)
trials have shown that two- to fourfold increases in cyclophosphamide doses do
not improve outcome, and dose intensification studies for doxorubicin and
epirubicin suggest a dose-response correlation that is "probably a
threshold effect more than a linear correlation," he said.
In the higher dose ranges, with autologous stem cell support,
five studies have not shown a statistically significant reduction in the odds
of recurrence or death. However, a couple of trials, such as the CALGB trial
reported by Peters have shown a small (though not
significant) reduction in recurrences, which has not yet translated into a
survival benefit. Currently, more than a dozen randomized controlled trials
continue to study this issue.
For ER-positive tumors, the pairing of chemotherapy and
tamoxifen provides improved results vs either method alone, both in older and
younger women, Dr. Hortobagyi said.
"The overall benefit of systemic therapies is often
underestimated," he said. To illustrate, he described the treatment
benefit in an average 35-year-old women with a 3-cm infiltrating ductal
carcinoma, five positive nodes, and negative estrogen receptors. He calculated
her risk of recurrence at 54%. "Treatment with CMF will reduce this risk
by 37%, resulting in a residual risk of 34%. Use of CAF would further reduce
this risk to about 30%. And the addition of Taxol should bring her risk down to
about 20%," he said.
Each component is modest, but the overall aggregate is
substantial, Dr. Hortobagyi said. This patient’s maximum reduction in risk is
from 54% to 20% (about a 63% reduction). If this patient were node-negative,
with a lower baseline risk of recurrence, her risk reduction would still be
about 57%, he said.
"But this benefit does not come without toxicity," he
cautioned. "For high-risk patients, the therapeutic effect of both
tamoxifen and chemotherapy is much greater than the risk of toxicity. For
low-risk patients, the window narrows and the benefit-to-risk ratio is