Cancer researchers theorized in the 1980s that "dose-dense" chemotherapy -- given at two-week instead of conventional three-week intervals -- would be a more effective way of killing cancer cells and extending patients' lives. But there was a problem: chemotherapy, which suppresses the immune system, usually made patients too prone to infections to tolerate treatment every two weeks.

In the 1990s, however, a drug called filgrastim became available. Filgrastim promotes the growth of white blood cells and helps patients receiving chemotherapy to withstand infections. With support from filgrastim, researchers thought patients might better tolerate dose-dense chemotherapy.

Researchers also wanted to know whether concurrent chemotherapy -- giving more than one drug at a time -- resulted in better outcomes than sequential chemotherapy -- giving one drug after another. They designed a large phase III, controlled and randomized clinical trial for women with breast cancer to try to answer two questions: Is dose-dense chemotherapy superior to conventional chemotherapy? And is concurrent therapy superior to sequential therapy?

Like all clinical trials, this one was both prospective -- it followed patients forward in time -- and experimental -- it tested an intervention: schedules of chemotherapy that were more intense than the standard of care.

Between 1997 and 1999, the trial enrolled 2,005 women whose breast cancer had spread to their lymph nodes. After surgery to remove the tumor either by mastectomy (removal of the entire breast) or lumpectomy (removal of the tumor and some nearby breast tissue), participants were assigned at random to one of four treatment groups.

• Group I received the conventional sequential therapy: the drug doxorubicin every three weeks for four cycles, followed by paclitaxel (also called Taxol) every three weeks for four cycles, followed by cyclophosphamide every three weeks for four cycles. All together, this treatment lasted 36 weeks.
• Group II received the same regimen as Group I, but at two-week intervals, along with filgrastim to reduce infection risk. This dose-dense sequential therapy lasted 24 weeks.
• Group III, the control group, received the conventional concurrent therapy every three weeks for four cycles, followed by paclitaxel every three weeks for four cycles. This treatment lasted 24 weeks.
• Group IV received the same regimen as Group III, but at two-week intervals with the support of filgrastim. This dose-dense, concurrent therapy lasted 16 weeks.

In June 2002, after three years of following how patients fared post-treatment, the researchers were able to report statistically significant findings: Patients in the two dose-dense chemotherapy groups lived longer, and experienced fewer recurrences of their cancer, than women in the conventional dose groups. This was true regardless of whether the dose-dense therapy was given sequentially or concurrently.

Specifically, 85 percent of the women who received dose-dense chemotherapy were alive and disease-free after three years, compared with 81 percent of those treated at the conventional three-week intervals. At three years, overall survival (i.e., whether disease-free or not) was 92 percent in patients who received the dose-dense regimen, compared with 90 percent in conventionally treated patients.

Concurrent therapy produced no better results than sequential therapy, but women receiving sequential therapy suffered slightly fewer side effects. These findings were eventually published in the April 15, 2003, issue of the Journal of Clinical Oncology (see the journal abstract of the study).

Cancer researchers generally prefer to have five-year follow-up data before they consider a study's results to be definitive enough to change the standard of care. If this study's findings are confirmed after two more years of follow-up, sequential dose-dense chemotherapy is likely to become the new standard of care for breast cancer patients whose disease has spread to the lymph nodes.

Glossary Terms

Treatment with drugs that kill cancer cells.

A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all.

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered experimental in other diseases or conditions. Also called investigational.

Monitoring a person's health over time after treatment. This includes keeping track of the health of people who participate in a clinical study or clinical trial for a period of time, both during the study and after the study ends.

The complex group of organs and cells that defends the body against infections and other diseases.

A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Lymph nodes filter lymph (lymphatic fluid), and they store lymphocytes (white blood cells). They are located along lymphatic vessels. Also called lymph gland.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

In medicine, a study or clinical trial in which participants are identified and then followed forward in time.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

In medicine, treatment that experts agree is appropriate, accepted, and widely used. Health care providers are obligated to provide patients with standard therapy. Also called best practice and standard of care.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.