Cancer Treatment Today

Since 1998, the standard of adjuvant care for patients with node-positive breast cancer in the United States and other parts of the world has been treatment with doxorubicin and cyclophosphamide followed by the taxane paclitaxel. This regimen was first administered on a schedule of once every three weeks and then, more recently, once every two weeks, after a comparative trial demonstrated improved efficacy (a 7 percent absolute improvement in disease-free survival and a 2 percent improvement in overall survival at three years) with the schedule involving more frequent administration (referred to as dose-dense therapy).

A number of phase II trials have showed that it dose dense is an aceptably tolerated approach in the neaodjuvant setting. One randomized trial looked at this question.The GEPARDUO trial of approximately 1000 patients with stage II-III breast cancer compared preoperative dose-dense doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every 2 weeks plus granulocyte colony-stimulating factor (G-CSF) for 4 cycles (dose-dense AT) with standard AC chemotherapy (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks) for 4 cycles followed sequentially by docetaxel (100 mg/m2 every 3 weeks) (sequential AC-T). While doctexel is not the same as paclitaxel. This is the approach pursued here. it is sufficiently similar to be considered identical in this setting and it has been compared to docetaxel in other studies and found essentially equivalent, in the broad sense.

The median tumor size was approximately 4 cm, and about 60% of patients had clinically negative nodes. The results indicate that the dose-dense arm was associated with a lower pathological response rate. Now, AT is not the same as AC + T, but the study suggests that the sequential AC-T regimen should remain a standard regimen against which other regimens are tested in neoadjuvant studies.

NCCN lists dose-dense therapy in the neodjuvant setting on p. BINV-K,1. The explanation for it is the statement in the NCCN guidelines that, “in general, those chemotherapy regimens recommended in the adjuvant setting may be considered in the preoperative setting” includes neoadjuvant dose dense therapy.

There is a similar regimen in clincila trials but it includes bevacizumab: Preoperative Dose-Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab in Operable Breast Cancer. NCT00546156. Of relevance, the protocol is based on the supposition that AC + T without bevacizumab is standard. It says: “Dose dense chemotherapy, which is the term for Adriamycin and Cyclophosphamide (AC) followed by Taxol chemotherapy given every two weeks, is the standard chemotherapy for the treatment of ER+ or PR+ breast cancer. In this trial, the standard chemotherapy is being combined with bevacizumab.”

In conclusion, the experts consider the proposed regimen to be standard of care in a neoadjuvant setting and it is not any longer subject to active research.

Citron ML 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(7):1-9.

Jackisch C, Von Minckwitz G, Raab G, et al. Primary endpoint analysis of the GEPARDUO study — preoperative chemotherapy comparing dose-dense versus sequential Adriamycin/docetaxel combination in operable breast cancer. Program and abstracts of the 25th Annual San Antonio Breast Cancer Symposium; December 11-14, 2002; San Antonio, Texas. Abstract 152.

NCCN, Breast Cancer 2017

Bruce E. Hillner et al, Wiser Use of Dose-Dense Adjuvant Therapy in Breast Cancer JCO March 10, 2012 vol. 30 no. 8 772-774
Schmidt M, Dose-Dense Chemotherapy in Metastatic Breast Cancer: Shortening the Time Interval for a Better Therapeutic Index.Breast Care (Basel). 2016 Feb;11(1):22-6.

Van Hoef, Marlies E.H.M. et al, Taking Advantage of , Dose Dense Chemotherapy for Breast Cancer, Oncology Times: 10 August 2003 – Volume 25 – Issue 15 – p 4–5