Dose-dense Chemotherapy More Effective Than Sequential Chemotherapy in Node-Positive Breast Cancer Patients

Data from a clinical trial reported in the April 1, 2003 issue of the Journal of Clinical Oncology indicates that dose dense chemotherapy in node-positive breast cancer patients significantly improves clinical outcomes. Sequential chemotherapy was found to be as effective as concurrent chemotherapy.

Dose dense chemotherapy consists of administering therapy more frequently than the conventional 3-week interval. It has been hypothesized that the more frequent administration of cytotoxic therapy would be a more effective way of minimizing tumors. However, the drawbacks to this approach include increased toxicity and side effects which may lead to dose-reduction or delays in drug administration, thereby removing the benefit of the regimen. To counteract the particularly debilitating side effect of suppressed blood cell production, researchers have administered a granulocyte colony-stimulating factor, such as filgrastim, a drug that stimulates growth of blood cells. This approach has allowed the completion of a dose-dense regimen of chemotherapy, consisting of treatments every 2 weeks, rather than the conventional 3-weeks.

Sequential therapy refers to the application of treatments one at a time rather than concurrently. Previous trials have shown that adding new, effective drugs sequentially to adjuvant treatment regimens can improve survival in patients with early-stage breast cancer. In addition, sequential chemotherapy has proven superior to a strictly alternating pattern.

The current clinical trial compared dose-dense chemotherapy to the conventional 3-week chemotherapy, and sequential with concurrent administration. The same agents at the same dose levels and the same dose densities were used. Patients consisted of women with primary adenocarcinoma of the breast (including metaplastic and bilateral lesions) and metasteses other than axillary lymph nodes. The median age was 50 years, median number of involved lymph nodes was three, and 65% had estrogen receptor-positive tumors. A total of 2005 patients were included in this study. All were administered doxorubicin, paclitaxel, and cyclophosphamide. The patients were randomly assigned to receive treatments either sequentially or concurrently, and at either a 2-week (dose-dense) or the conventional 3-week interval:

Results indicate that disease free survival (DFS) was significantly prolonged for the dose-dense regimen, compared to conventional 3-week schedule, as follows:

1 year 2 years 3 years 4 years
Dose-dense 97% 91% 85% 82%
Conventional 95% 87% 81% 75%

Dose-dense therapy reduced the risk of recurrence by 19% for ER-positive tumors and 32% for ER-negative tumors. This difference by ER status was not statistically significant. There was no difference in either DFS or overall survival (OS) between the concurrent and sequential schedules. There was no interaction between density and sequence.

Futhermore, the increases in DFS and OS were not accompanied by an increase in toxicity. Severe neutropenia (low white blood cell count) was less frequent in patients who received the dose dense regimens. The use of filgrastim in the dose-dense regimens did result in a statistically significant decrease in granulocyte toxicity. But, there was still a low rate of hospitalization and no mortality during the chemotherapy regimens.

Given the findings of this clinical trial, patients may wish to speak to their doctor about the risks and benefits of dose-dense chemotherapy treatments. Drawbacks to filgrastim treatment may include mild/moderate muscular and joint pain as well as the inconvenience of 7 days of injections per course. Furthermore, the cost/benefit ratio should be carefully considered, as filgrastim adds considerable expense, perhaps thousands of dollars.

Reference: Citron ML, Berry DA, Cirrincione C, Hudis C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C9741/Cancer and Leukemia Group B trial 9741. Journal of Clinical Oncology 2003; 21: 1-9.