SAN FRANCISCO—High-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 experience—perhaps a consequence of introducing tamoxifen(Drug information on 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 conclusions."
Randomization
Patients in the study were randomized to a conventional regimen of epirubicin(Drug information on epirubicin) (Ellence) (three courses) followed by six courses of CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil)), or to high-dose chemotherapy with stem cell support—one course of cyclophosphamide(Drug information on cyclophosphamide), then one course of methotrexate with leucovorin rescue, then two courses of epirubicin, then one course of thiotepa plus melphalan(Drug information on 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."
