The hidden treasures of the primary tumor: Extended neoadjuvant chemotherapy plus GM-CSF in locally advanced cancer

Patients with locally advanced cancers have a poor prognosis when treated by surgery and/or radiotherapy. In 1989 we selected locally-advanced breast cancer (LABC) as a model for a new multidisciplinary approach of advanced tumors and aimed to study immunological and anti-angiogenic aspects during treatment. Usually two to four cycles of neoadjuvant chemotherapy (NCT) prior to local therapy improves survival in patients with LABC. Prolonged NCT keeping the primary tumor and axillary lymph nodes in situ and/or prolonged administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) was intended to further improve survival. Patients were enrolled between 1990 and 1995. Recently we reported on 42 patients with LABC stage III, treated with doxorubicin, cyclophosphamide and GM-CSF at a three-week interval followed by mastectomy and radiotherapy. Gradually, the duration of NCT was increased from four to six cycles. Of the 42 patients, five patients received four cycles, 13 patients received five cycles, and 24 patients received six cycles. This is our first report with a median follow-up of five years (range 10-111 months). The clinical response rate was 98% and the complete response rate 50%. Although the response rate was independent of the number of cycles, the disease free and overall survival appeared to improve with increasing numbers of cycles, to 66% (p=0.0000) and 79% (p=0.0016), respectively, at five years for six cycles. No patient showed progressive disease during NCT. We are presently investigating whether NCT-induced tumor antigens are being processed by GM-CSF stimulated dendritic cells (DCs) and whether cytotoxic T-lymphocytes are triggered. The percentage of DCs (S100+ cells) in axillary lymph nodes increased significantly after NCT (0.5% before NCT; 8.9% after NCT; p=0.018). Improvement of disease free survival is observed in patients with a high number (>8%) of axillary lymph node DCs (p=0.02). NCT and GM-CSF effects on macrophages and angiogenic factors inhibiting DC functions are also studied. In conclusion, extended NCT plus GM-CSF has produced exciting results in the LABC model, both clinically and immunologically, and is now being investigated in a randomized trial (Spinoza trial) in breast cancer and other locally advanced cancers.