Local treatment with surgery and radiotherapy gives unsatisfactory results in patients with locally advanced cancer. In many cases distant metastases appear shortly after the removal of the primary tumor. Selecting breast cancer as a model for locally advanced disease, we are extrapolating our findings to other solid tumors. Neoadjuvant chemotherapy has improved survival of these patients by downstaging the primary tumors allowing local treatment and early elimination of distant micrometastases. We recently reported in this journal on a study of 42 patients with locally advanced breast cancer (LABC) who received prolonged neoadjuvant chemotherapy of doxorubicin, cyclophosphamide, and GM-CSF prior to surgery and postoperative radiotherapy. These results were promising and prompted us to initiate an international randomized phase III study in which either six neoadjuvant cycles or three neoadjuvant cycles plus three adjuvant cycles are being compared. In LABC patients treated with six neoadjuvant chemoimmunotherapy cycles, we observed a significant rise in the dendritic cell content of the axillary tumor-draining lymph nodes after therapy, associated with an encouraging disease free survival and overall survival. We hypothesize that the prolonged presence of draining lymph nodes in combination with the repeated tumor antigen release, dendritic cell recruitment, and activation may account for the observed increased survival of LABC patients. Based on our findings and the results of preclinical studies, we hypothesize that it is more effective to administer chemotherapy in an extended neoadjuvant regimen, taking advantage of the concurrent biological and immunological processes in the primary tumor and its draining lymph nodes.