Related Pages High-Dose Chemotherapy for Breast Cancer 1 A collection of material about high-dose chemotherapy with bone marrow or stem cell transplant as a treatment for breast cancer. Breast Cancer Home Page 2 NCI's gateway for information about breast cancer.

Key Words
breast cancer, high-dose chemotherapy, stem cell transplantation. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary
Two studies examined the benefits of high-dose chemotherapy with stem-cell transplantation for women at high risk of a breast cancer relapse. In both studies, a subgroup of women who underwent the experimental procedure experienced a significant delay in recurrence compared to women who received standard therapy, but they did not ultimately live any longer.

While these studies reaffirm conventional treatment as the standard of care for high-risk breast cancer, they do provide a rationale for further research to refine the technique and determine whether a subset of women might benefit from the high-dose approach.

Source
The New England Journal of Medicine, July 3, 2003.

Background
Women with high-risk breast cancer have a strong chance of relapsing and dying from their disease within 10 years. (High-risk breast cancer is generally defined as having cancer in four or more axillary lymph nodes.) Researchers have been investigating whether higher doses of chemotherapy drugs can do a better job of preventing or delaying the spread or return of breast cancer in these patients.

However, high-dose chemotherapy damages the bone marrow, which is then no longer able to produce needed blood cells. In the two studies highlighted here, researchers also performed stem cell transplantation to help repair the damage. Stem cells are able to become fully mature red blood cells.

Study 1 (Netherlands Cancer Institute)
The 885 patients in this phase III clinical trial consisted of women younger than 56 who had surgery for breast cancer, at least four cancer-positive axillary lymph nodes, and no cancer beyond the lymph nodes. Patients were randomly assigned either to receive the standard treatment (chemotherapy every three weeks for five courses, followed by radiation therapy and tamoxifen) or the same treatment but with the fifth course consisting of high-dose chemotherapy and stem-cell transplantation. The study was led by Sjoerd Rodenhuis, M.D., of the Netherlands Cancer Institute in Amsterdam.

Study 1 Results (see the journal abstract)
After a median follow-up time of 57 months, the five-year, relapse-free survival rates for all patients were 59 percent for the conventional treatment group and 65 percent for the high-dose chemotherapy and stem-cell transplantation group. However, this difference was not statistically significant – that is, it could have occurred by chance.

The researchers took a closer look at two subgroups: women with four-to-nine cancer-positive axillary nodes, and women with 10 or more positive nodes. Only women with 10 or more positive nodes had significantly improved relapse-free survival: 51 percent of the subgroup treated conventionally survived without a recurrence for five years, compared to 61 percent of the experimentally treated subgroup.

However, overall survival rates for all patients, as well as for both subgroups, were not significantly improved for those receiving high-dose therapy with stem-cell transplantation.

The authors concluded that while the results should be “interpreted with caution,” they do justify future studies in which the experimental procedure itself can be refined and researchers can select patients who may be most likely to benefit.

Study 2 (U.S. Intergroup Study)
This phase III trial consisted of 511 women no older than 60 (median age: 44) whose breast cancer had spread to at least 10 axillary lymph nodes but not beyond the lymph nodes. After surgery, the women were randomly assigned to receive six courses of standard chemotherapy or the same treatment followed by high-dose chemotherapy with stem-cell transplantation. The study was led by Martin S. Tallman, M.D., of the Northwestern University Feinberg School of Medicine in Chicago, Ill.

Study 2 Results (see the journal abstract)
After a median follow-up of 73 months, 55 percent of the experimental group had survived without a recurrence of their breast cancer, compared to 48 percent of the conventional group. This difference, however, was not statistically significant.

But when the researchers looked at the data for the 417 patients who met the trial’s strictest eligibility criteria, they found that relapse-free survival rates were significantly higher in the experimental group compared to those in the conventional group: 55 percent compared to 45 percent.

Nonetheless, overall survival rates between the two groups were not significantly different: 58 percent for the experimental group versus 62 percent for the conventional group. In addition, among those who received the high-dose chemotherapy treatment, nine died as a result of transplantation complications and nine developed preleukemia or acute myeloid leukemia.

According to the authors, these results suggest that conventional therapy for high-risk breast cancer patients should remain the standard of care.

Limitations
Jeffrey Abrams, M.D., coordinator of the NCI-sponsored U.S. Intergroup Study trial, comments that “based on the evidence from these two studies, high-dose chemotherapy with stem-cell transplantation for women with high-risk breast cancer remains an investigational treatment that should be limited to carefully controlled clinical trials.”

While attempts to refine and improve high-dose treatments are worthy of further research, he says, all the studies to date indicate that this approach is not clearly better than standard-dose chemotherapy regimens, which are less toxic and less expensive.

In an editorial accompanying the two articles, Gerald Elfenbein, M.D., concluded that “high-dose chemotherapy should best be viewed as a launching pad from which to explore new methods of post-transplantation therapy to reduce the probability of relapse."

Glossary Terms

An aggressive (fast-growing) disease in which too many myeloblasts (immature white blood cells that are not lymphoblasts) are found in the bone marrow and blood. Also called acute myeloblastic leukemia, acute myelogenous leukemia, acute nonlymphocytic leukemia, AML, and ANLL.

A lymph node in the armpit region that drains lymph from the breast and nearby areas.

The soft, sponge-like tissue in the center of most bones. It produces white blood cells, red blood cells, and platelets.

Treatment with drugs that kill cancer cells.

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.

A statistics term. The middle value in a set of measurements.

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.

A group of diseases in which the bone marrow does not make enough healthy blood cells. Also called myelodysplastic syndromes and smoldering leukemia.

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiotherapy.

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.

A drug used to treat certain types of breast cancer in women and men. It is also used to prevent breast cancer in women who have had ductal carcinoma in situ (abnormal cells in the ducts of the breast) and in women who are at a high risk of developing breast cancer. Tamoxifen is also being studied in the treatment of other types of cancer. It blocks the effects of the hormone estrogen in the breast. Tamoxifen is a type of antiestrogen. Also called tamoxifen citrate.