"Since breast cancer is so common, and adjuvant drug therapy has already been found to be so effective, a way to make that treatment 31 percent more effective could potentially save thousands of lives per year in the United States alone," said Larry Norton, MD, Head of the Division of Solid Tumor Oncology at Memorial Sloan-Kettering Cancer Center, and senior author of the study.
A mathematical model called the Norton-Simon hypothesis formed the basis for the concept of dose density and another concept tested in this study, sequential therapy. The model, developed by Dr. Norton, and Richard Simon of the National Cancer Institute, was used to address the question: "Is it better to use a higher dose of a drug less often or a lower dose more frequently?" According to Dr. Norton, the answer depended upon the efficacy of the drugs and the pattern of growth of the disease, and could not be answered without a mathematical understanding of the underlying biology.
The study enrolled 2005 women with primary breast cancer that had spread to the lymph nodes, and with no other metastases. They were randomized post-operatively to one of four treatments. Two groups of patients were randomized to receive doxorubicin (A for Adriamycin®), paclitaxel (T for Taxol®), and cyclophosphamide (C for Cytoxan®) sequentially, i.e., one at a time, in two- or three-week cycles. Patients in the other two arms of the trial were randomized to receive concurrent AC followed by T, also in two- or three-week cycles. Because frequent administration of chemotherapy can result in a condition called neutropenia--the decline in the number of certain white blood cells--those on the dose-dense regimens received granulocyte colony stimulating factor (G-CSF or Filgrastim or Neupogen®) to permit administration of the drugs every two-week rather than at the conventional three-week intervals.
After four years of follow-up, researchers found that the dose-dense regimens, whether sequential or concurrent, were significantly better than the conventionally-timed three-week regimens in improving both disease-free survival and overall survival. Among patients on the dose-dense regimens, disease-free survival was 82 percent compared to 75 percent for those who received conventional therapy at four years from the start of the study. In terms of overall survival, after three years 92 percent of patients on the dose dense therapy were alive, compared to 90 percent of those on the conventionally administered regimens. The differences between the dose dense and the conventional regimens were expected to increase over time with continued patient follow-up.
Researchers also found that side effects were no more severe among patients on dose-dense regimens than among those on the conventional treatments, and that patients on the dose-dense regimens suffered fewer cases of neutropenia.
"These findings are significant because all the women received the same individual and cumulative dosage of each drug--the only difference was the interval between chemotherapy treatments--and that one difference is shown to make a positive impact on survival," said lead author Marc L. Citron, M.D., Clinical Professor of Medicine at Albert Einstein College of Medicine, and an oncologist in private practice in New York.
"The idea of dose density is really rather simple: give the drugs more often and don't give more than you need. Then, each time you treat you'll be starting with a smaller and smaller amount of cancer, because you're not giving the cancer as much time to grow between treatments," explained Clifford Hudis, Chief of the Breast Cancer Medicine Service at MSKCC, and another of the study's co-authors. "One of the exciting things about this study is that it demonstrates we are able to shorten the time patients have to be on chemotherapy, decrease the side effects, and at the same time improve outcomes."
The ability to give dose-dense regimens to patients was made possible by the addition of Filgrastim to the treatment protocol. Filgrastim is produced from G-CSF, which was discovered by researchers at Memorial Sloan-Kettering Cancer Center and provides a way to stimulate early regrowth of white blood cells in patients undergoing chemotherapy.
"If confirmed with additional research, this approach may change the standard of care in breast cancer treatment," said Dr. Norton, who added that the improved treatment is based on a concept that might also apply to other diseases.
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