No Survival Advantage for High-Dose vs Standard Chemotherapy

SAN FRANCISCO—High-dose chemotherapy plus stem cell rescue did not improve overall survival vs standard chemotherapy alone in women with chemotherapy-sensitive metastatic breast cancer, according to the results of a National Cancer Institute of Canada (NCIC) trial reported at the 37^th Annual Meeting of the American Society of Clinical Oncology (ASCO).

"We could not find any subgroup in our analysis that appeared to benefit from this approach," said Michael Crump, MD, medical oncologist, Princess Mar-garet Hospital, Toronto, Canada.

The toxicity of high-dose therapy was significantly greater than that of standard-dose chemotherapy. Furthermore, risk of treatment-related mortality was higher in the high-dose chemotherapy arm.

The study was one of several major breast cancer trials of high-dose chemotherapy with transplantation reported at ASCO, all of which failed to illustrate significant differences in overall survival vs conventional therapy.

In the Canadian study, women with no prior chemotherapy for metastatic breast cancer received induction therapy with an anthracycline-based regimen. If patients had previous anthracycline exposure, they received taxane-based therapy instead.

Accrual for this 397-patient trial opened in 1997, around the time breast cancer had become the most common indication in North America for high-dose therapy with stem cell support. Encouraging single-institution phase II results, according to Dr. Crump, had suggested durable disease-free survival for this approach. However, it was not clear how much results were influenced by patient selection.

After four cycles, responders were randomized to additional standard chemotherapy for up to four cycles, or to one or two cycles of standard chemotherapy followed by high-dose chemotherapy with cyclophosphamide, mitoxantrone (Novantrone), and carboplatin (Paraplatin). All estrogen-receptor-positive patients received tamoxifen (Nolvadex) or other hormone therapy after chemotherapy.

Overall response rates were assessed at 6 weeks post-transplant in the high-dose arm, and 15 weeks after day 1 of cycle 6 in the standard-dose arm. With a median follow-up of almost 2 years, there was no difference in overall survival.

There was a small but statistically significant difference in progression-free survival: a mean of 1.0 years in the high-dose arm vs 0.7 years in the standard-dose arm. But Dr. Crump advised that difference should be interpreted with caution, since regular restaging was not performed. "Some bias may have crept into this assessment," he said.

In an exploratory analysis, the three most important variables with respect to overall survival were presence or absence of visceral disease, use of an anthracycline as part of induction therapy, and response to tamoxifen. All three variables were significant. However, treatment assignment—high-dose vs standard—was not.

Investigators were concerned they would see a high rate of congestive heart failure due to the intensive use of anthracyclines and the addition of mitoxantrone, a potentially cardiotoxic agent, in the high-dose arm. However, grade 2-4 heart failure was seen in only five patients in the high-dose arm, and four in the standard-dose arm.

More grade 3-4 toxicities were seen in the high-dose arm. In addition, there were seven treatment-related deaths in the high-dose arm, for an overall toxic death rate of 6%. Most were related to infections arising during pancytopenia.