Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer.
BACKGROUND
Neoadjuvant chemotherapy improves survival in patients with locally advanced breast cancer (LABC). Usually three to four cycles of conventional-dose neoadjuvant chemotherapy are administered prior to local therapy, and another three cycles thereafter. In an attempt to improve results, we increased the dosages and applied GM-CSF, which, besides being a hematopoietic growth factor, has become increasingly known for its immunostimulatory effects, which might enhance the antitumor effect.


METHODS
Forty-two patients with stage IIIA or IIIB breast cancer were treated with doxorubicin (A) (90 mg/m2) and cyclophosphamide (C) (1,000 mg/m2) at three-weekly intervals. In the second and fourth cycle a 10% dose reduction of both agents was applied. On the second day GM-CSF 250 micrograms/m2/day was started and given for 10 days. Initially, some patients were treated with < or = four cycles, but as the study progressed and toxicity appeared tolerable, six cycles were given whenever possible. After the chemotherapy, patients underwent surgery and postoperative radiotherapy.


RESULTS
The response rate for the whole group to AC was 98% (95% confidence interval 94%-100%), with a clinical complete response rate of 50% (95% confidence interval 35%-65%). Six patients had a pathological complete response. Median follow-up from the start of chemotherapy is 49 months (range 10-100). The disease-free survival (DFS) at three years is 57% and the overall survival (OS) at three years is 79%. There is a significant trend for improved DFS (p = 0.0000) and OS (p = 0.0002) with increasing number of cycles.


CONCLUSIONS
The results of the present study with neoadjuvant dose-intensive AC chemotherapy and GM-CSF compare favorably with previous studies in patients with LABC. This is most apparent in patients who received six cycles of neoadjuvant chemotherapy. We hypothesize that these encouraging results are probably related to the prolonged presence of the primary tumor, and to the long-term administration of GM-CSF with the primary tumor and axillary lymph nodes in situ. Therefore, a randomized study is warranted. We already initiated an international randomized trial in patients with LABC in order to answer two questions. First, does prolonged neoadjuvant chemotherapy result in an improved DFS and OS in comparison with the conventional approach, and secondly, what is the effect of GM-CSF in this approach in comparison with G-CSF?
Honkoop
A H
AH
Department of Medical Oncology, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands.
Luykx-de Bakker
S A
SA
Hoekman
K
K
Meyer
S
S
Meyer
O W
OW
van Groeningen
C J
CJ
van Diest
P J
PJ
Boven
E
E
van der Wall
E
E
Giaccone
G
G
Wagstaff
J
J
Pinedo
H M
HM
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide