PHILADELPHIA—Simply giving ever higher doses of chemotherapy does not generally lead to improved survival in metastatic breast cancer. “For 20 years we’ve been exploring this approach, and the response has been uniform and uniformly disappointing,” Larry Norton, MD, of Memorial Sloan-Kettering Cancer Center, said at a symposium held at the Fox Chase Cancer Center.
He noted that with leukemia, the greater the response rate to chemotherapy, the higher the cure rate. But in breast cancer, there isn’t such a clear one-to-one correlation. Even when high-dose chemotherapy produces an objective response, mortality may not be affected.
The explanation for the failure of high-dose chemotherapy has to do with the way cells grow, he said. The growth curve is not a straight line, but rather starts out quite steep and flattens out with time.
“High chemotherapy doses kill many, many cells,” he said, “but those that are left, and there are always some left, now start their regrowth way down on the curve, where growth is most rapid.”
In other words, the closer you get to zero cells, without actually killing all of the cells, the faster they grow back. And this new lineage of cells is often resistant to further chemotherapy.
Instead of increasing the amount of a drug given, Dr. Norton recommends increasing the dose density via more frequent dosing. With the use of G-CSF (Neupogen) to speed up hematopoietic recovery, it is now possible to give doses closer together, reducing the time available for tumor regrowth.
Another way to achieve greater dose density is to give several drugs in sequence, ie, all of one agent with short intervals between doses, followed by all of the second agent and so on. “First kill the cells that are sensitive to drug A, then kill those that are sensitive to B,” he said.
In one study at Sloan-Kettering, patients with node-positive breast cancer received doxorubicin(Drug information on doxorubicin) every 2 weeks (90 mg/m2 for three doses), followed by paclitaxel (Taxol) (250 mg/m2 for three doses), then cyclophosphamide(Drug information on cyclophosphamide) (3 g/m2 for three doses). The results of this dose-dense approach have been impressive, with 81% of patients disease free at a median of 3 years’ follow-up. [For a full report on this trial, presented by Clifford Hudis, MD, see the November, 1997, issue of ONI, page 13.]
Another approach, tried with paclitaxel(Drug information on paclitaxel), is to give the drug once a week instead of once every 2 or 3 weeks. In metastatic breast cancer patients who received weekly 1-hour infusions of paclitaxel (80 to 100 mg/m2), the drug was well tolerated without cumulative neutropenia. The response rate was 50%, and some patients did not lose their hair.
Even with the best dosing schedule, patients may relapse and with cells that are resistant to most chemotherapy agents. The best hope, Dr. Norton believes, is to follow up chemotherapy with one of a number of promising approaches just now becoming available that control cell growth through mechanisms other than apoptosis, including cancer vaccines, antiangiogenesis drugs, and anti-HER-2/neu antibodies.
