A new clinical trial demonstrating that reducing the interval between successive doses of a commonly used chemotherapy regimen improves survival in women whose breast cancer has spread to the lymph nodes was presented at the 25th Annual San Antonio Breast Cancer Symposium in December. While previous research has evaluated the use of various forms of dose-dense chemotherapy, this is the first major controlled study to show a clear survival benefit for women with node-positive breast cancer. The first study was conducted by Cancer and Leukemia Group B (CALGB) for the Breast Cancer Intergroup, a consortium of National Cancer Institute (NCI)-sponsored Cooperative Clinical Trials Groups and enrolled 2,005 women with node positive breast cancer and randomized them to one of four regimens.

Marc L. Citron, M.D., Albert Einstein College of Medicine, who is the lead investigator of the study, has said, “This study suggests that many women with breast cancer may benefit from chemotherapy administered on a condensed schedule. With the availability of new drugs to control one of the most serious side effects of chemotherapy administration, we can further increase the chances of survival for women with breast cancer.” The newer dose dense regimen is made tolerable for patients by using the drug filgrastim (Neupogen), which helps prevent neutropenia, a serious complication of chemotherapy.

The researchers found that two dose dense regimens provided significantly higher disease-free survival rates than two regimens using conventional dosing, and that efficacy did not differ between the two dose dense regimens. Among patients on the dose dense regimens, disease-free survival was 82 percent after four years, compared to 75 percent for those who received conventional therapy. This difference corresponded to a 26 percent overall reduction in the risk of cancer recurrence. The findings confirm the predictions of a mathematical model developed in the 1980s that suggested the value of increased dose density, and which were the impetus for the study.

“The improvement in outcome could well represent an important advance in our knowledge of the biology of breast cancer and how best to treat it,” said Larry Norton, M.D., of Memorial Sloan-Kettering Cancer Center, senior investigator for the study and one of the developers of the original model. “If confirmed and extended by additional research, this finding could positively affect the care of thousands of patients throughout the world with breast cancer and perhaps, eventually, other diseases.”

The study tested both dose dense and conventional chemotherapy regimens in 2,005 women with node-positive primary breast cancer and no other metastases. Following surgical removal of their tumors, the women were assigned to one of four treatment regimens involving the standard chemotherapy drugs doxorubicin (A), paclitaxel (T), and cyclophosphamide (C):

Sequential administration (A followed by T, followed by C) in three-week intervals (conventional)
Sequential administration in two-week intervals, with filgrastim (dose dense)
Concurrent administration (A and C together, followed by T) in three-week interval
Concurrent administration in two-week intervals, with filgrastim (dose dense)

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,” according to Dr. Marc Citron.

Frequent administration of chemotherapy can result in a decline in the number of a certain type of white blood cells, leading to a condition called neutropenia. Researchers administered filgrastim (Neupogen) also known as the granulocyte-colony stimulating factor (G-CSF), to dose dense treatment
helps prevent neutropenia by stimulating the formation of white blood cells called neutrophils. Without it, chemotherapy dosing frequency is limited to longer intervals.

“It is too soon to determine whether a dose dense chemotherapy regimen with filgrastim should be the new standard of care,” said Jeffrey Abrams, the oncologist in charge of breast cancer treatment trials at NCI. “However, the reduced risk of cancer recurrence and the low occurrence of side effects are encouraging, and further follow-up as well as other studies testing this approach will hopefully confirm the findings.”

Side effects were found to be no more severe among patients on the dose dense regimens than among those on the conventional treatments, and patients on the dose dense regimens suffered fewer cases of neutropenia. The study also showed that sequential administration produced slightly fewer side effects than the concurrent regimens, with equal efficacy. In addition to improved disease-free survival, the study indicated that dose dense chemotherapy may also lead to higher overall survival rates. Additional follow-up study is necessary to confirm a survival benefit.
“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 are not giving the cancer as much time to grow between treatments, “ says coauthor Clifford Hudis, from Sloan Kettering in New York. “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, decreases the side effects, and at the same time improves outcomes.”

The study will be published in the Journal of Clinical Oncology. Citron, ML et al. Superiority of dose dense over conventional scheduling and equivalence of sequential vs. combination adjuvant chemotherapy for node-positive breast cancer (CALGB 9741, INT C9741).

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