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German researchers report success using high-dose chemotherapy and stem cell infusion to treat women with advanced breast cancer. Writing in The Lancet, they say their experimental treatment provided better disease-free and overall survival than traditional chemotherapy.

Their results stand in contrast to those of several previous studies which found no benefit to high-dose chemotherapy, and a higher incidence of toxic side effects. The new findings suggest researchers should take another look at the possibility of using this technique against breast cancer, said lead study author Ulrike Nitz, MD, coordinator of the Breast Center at the University Hospital of Duesseldorf.

"The trials published so far are very heterogeneous," she said. "We need a closer look at each of them to identify promising strategies."

Nitz said her group may have done just that. Previous studies gave women 1 cycle of high-dose chemotherapy after a lengthy introductory treatment with regular chemotherapy. Nitz and her colleagues instead used a short introductory treatment followed by 2 high-dose cycles of chemotherapy. In addition, the women were given infusions of their own stem cells, collected before the high-dose treatment started.

They randomly assigned 201 women to the high-dose regimen, while 202 women received conventional chemotherapy. The women were between the ages of 18 and 60. Their cancer had spread to at least 9 lymph nodes but there was no evidence of distant spread. The chemotherapy was given after surgery to remove the tumor or the entire breast.

After 4 years, 60% of women in the high-dose group and 44% in the control group were still alive and cancer-free. Fifty-three women in the high-dose group had died, and 74 in the traditional chemotherapy group had died. No treatment-related deaths took place, but the high-dose group did experience more severe side effects.

Nitz said the results came as a surprise, even though the researchers had a sense that women on the experimental regimen had done well.

"After publication of the other high-dose trials, we did not expect to see such a large survival difference," she said. "As survival rates for this subgroup of patients with standard regimens have not been improved substantially over the last 20 years, we think that [our procedure] is a very good option for these patients and should be investigated further."

One important point that is sure to generate discussion is the composition of the chemotherapy regimens the researchers used, said Larry Norton, MD, deputy physician-in-chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center in New York. Neither the control arm nor the high-dose arm used a taxane, a type of drug shown to be very effective against advanced breast cancer that doesn't respond to other treatments. That means the high-dose treatment may have appeared better because the standard chemotherapy used wasn't as good as it could have been.

"This may be an issue of an inferior control arm rather than a superior trial arm," said Norton, who was not involved in the German study. "The single most active class of agents in breast cancer is absent in both treatments."

Nitz and colleagues acknowledge and address that concern in their paper. They say taxanes (paclitaxel and docetaxel) have been shown to be most effective in women with 1-3 involved lymph nodes, and less effective in women with more than 4 involved nodes. They also cite findings from the Breast Cancer International Research Group that taxanes may actually be inferior in patients with 10 or more positive nodes.

"We therefore conclude that our dose-dense anthracycline-based regimen is up to date and appropriate," they write. "Superiority of high-dose chemotherapy in this trial cannot be attributed to a weakness of the control regimen."

Nevertheless, Norton said the new study is unlikely to change practice in the United States.

"Essentially, all the well-done, well-controlled, and audited clinical trials showed high-dose chemotherapy didn't add anything except toxicity, and if it did add anything it was at enormous cost, so it did fall out of favor," he said. "I think [chemotherapy] has accomplished all it can.

"The real future is going to come from targeted biological agents combined with [chemotherapy]," he continued. "There are dozens of exciting compounds, and integrating those into the treatment regimens is something we should be focusing on."

Citation: "Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial." Published in the Dec. 3, 2005, issue of The Lancet (Vol. 366; No. 9501: 1935-1944). First author: Ulrike Anneliese Nitz, MD, University Hospital, Duesseldorf, Germany.