The National Cancer Institute’s Breast Intergroup INT C9741 and CALGB 9741 Trial

Published in 2003 the evaluation of combination chemotherapy for breast cancer:
- Given by both dose dense and sequential therapy
- The goal of the study was to evaluate the best way to administer the chemotherapy regimen:
  - Doxorubicin (A), cyclophosphamide (C) followed by paclitaxel (T)
- The study assessed chemotherapy administration in:
  - A dose dense fashion:
    - Two weeks vs. three weeks
  - Treatment sequence:
    - Concurrent versus sequential
- The findings of the study showed:
  - That dose density improved clinical outcomes significantly
  - Sequential chemotherapy was as effective as concurrent chemotherapy:
    - But required a longer time period of administration
Dose-dense chemotherapy:
- Refers to decreasing the interval between cycles of treatment without the need of increasing doses and toxicity
Sequential therapy:
- Refers to the administration of treatments one at a time rather than concurrently
National Cancer Institute’s Breast Intergroup INT C9741 and CALGB 9741 trial:
- Was a prospective, randomized trial designed to study adjuvant chemotherapy treatment regimens:
  - In women with axillary node-positive breast cancer conducted from September 1997 to March 1999
- Doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) were chosen for this study
- Using a 2 x 2 factorial design, patients were assigned to receive one of the following 4 regimens:
  - Sequential A then C followed by T x 4 cycles every 3 weeks
  - Dose-dense, sequential A then C then T x 4 cycles every 2 weeks with filgrastim
  - Concurrent AC x 4 cycles followed by T x 4 cycles every 3 weeks
  - Dose-dense, concurrent AC x 4 cycles followed by T x 4 cycles every 2 weeks with filgrastim

Results showed that:
- Dose-dense treatment improved the primary endpoints of:
  - Disease-free survival (DFS) and overall survival (OS):
    - Four-year DFS was 82% for dose-dense regimens and 75% for other groups (risk ratio, 0.74, P=0.01)
    - Three-year OS was 92% for dose-dense regimens and 90% in other groups (risk ratio, 0.69, P=0.013)
  - There was no difference in either DFS or OS:
    - Between the concurrent and sequential schedules
  - Severe neutropenia:
    - Was less common in patients who received the dose-dense regimens
  - As a result of this study:
    - Dose-dense and concurrent AC chemotherapy has become one of the standard components of breast cancer therapy
References:
- Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, 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. J Clin Oncol.2003;21(8):1431-1439.
- Orzano JA, Swain SM. Concepts and clinical trials of dose-dense chemotherapy for breast cancer. Clin Breast Cancer. 2005;6(5):402-411