SAN FRANCISCOHigh-dose adjuvant chemotherapy with stem cell
support provided no overall or disease-free survival benefit over standard
chemotherapy in a randomized, multicenter Italian trial including 398
metastatic breast cancer patients.
However, an investigator presenting the study at the 37th
Annual Meeting of the American Society of Clinical Oncology (ASCO) said that a
potential progression-free survival advantage in younger women and those with
less lymph node involvement is notable and perhaps deserves further study.
In the trial, which included women 60 years of age or younger
with at least four positive nodes, overall survival rates were 77% and 76%,
respectively, for controls vs transplant at a median follow-up of 52 months.
Similarly, 5-year progression-free survival rates were 62% and 65%.
Yet there was a trend toward improved progression-free survival
for the 112 patients younger than 36 years of age, and among the 147 patients
who had between four and nine positive lymph nodes (hazard ratios of 0.66 and
0.69, respectively), said Dr. Alessandro Gianni, professor of medicine and
surgery, University of Milan, Italy.
That trend in favor of high-dose chemotherapy amounted roughly
to a 30% reduction in risk of recurrence for those who were younger or who had
fewer positive nodes. "These two groups are not negligible," Dr.
Gianni said. "They represent approximately half of the entire population
that we analyzed, so it’s not a trivial difference."
Also notable, according to Dr. Gianni, was the overall rate of
disease-free survival, which was much higher than expected, based on historical
experienceperhaps a consequence of introducing tamoxifen (Nolvadex) after
chemotherapy (90% of patients received 5 years of tamoxifen).
"This is close to 50% better than any other prior studies
we carried out in the adjuvant setting," Dr. Gianni said. "This makes
a longer follow-up necessary to consider these conclusions as final
Patients in the study were randomized to a conventional regimen
of epirubicin (Ellence) (three courses) followed by six courses of CMF (cyclophosphamide,
methotrexate, fluorouracil), or to high-dose chemotherapy with stem cell
supportone course of cyclophosphamide, then one course of methotrexate with
leucovorin rescue, then two courses of epirubicin, then one course of thiotepa
plus melphalan (Alkeran) with stem cell autografting.
All patients were scheduled to receive tamoxifen 20 mg/d for 5
years, regardless of receptor or menopausal status.
High-dose chemotherapy was deemed safe in this setting, with a
0.5% acute lethal toxicity rate (one patient died of interstitial pneumonia)
and no late adverse events. Grade 4 toxicity was represented mainly by
mucositis, Dr. Gianni said. Most other toxicities were grade 2 or grade 3 and
included infection, mucositis, and hepatic/renal toxicity. There were no cases
of myelodysplastic syndrome or secondary leukemia.
James N. Ingle, MD, professor of oncology, Mayo Clinic,
Rochester, Minnesota, said that differences in disease-free survival in patient
subsets were "interesting observations" but do not translate into
clinical practice implications. "When you start slicing and dicing, you
get down to fairly small subsets," Dr. Ingle said.
The findings of this and other studies suggest that high-dose
chemotherapy with autologous hematopoietic stem cell transplantation is not
proven to be indicated for the management of women with any stage of breast
cancer, he said.
"High-dose chemotherapy should be utilized only in the
setting of scientifically meritorious clinical trials," Dr. Ingle said,
"and, as a matter of fact, multiple trials are ongoing. Several have
completed accrual, and we look forward to the results."