Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer

A H Honkoop, S A Luykx-de Bakker, K Hoekman, S Meyer, O W Meyer, C J van Groeningen, P J van Diest, E Boven, E van der Wall, G Giaccone, J Wagstaff, H M Pinedo

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

CONCLUSION: 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?

Original languageEnglish
Pages (from-to)106-11
Number of pages6
JournalThe Oncologist
Volume4
Issue number2
Publication statusPublished - 1999

Cite this

Honkoop, A. H., Luykx-de Bakker, S. A., Hoekman, K., Meyer, S., Meyer, O. W., van Groeningen, C. J., ... Pinedo, H. M. (1999). Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. The Oncologist, 4(2), 106-11.
Honkoop, A H ; Luykx-de Bakker, S A ; Hoekman, K ; Meyer, S ; Meyer, O W ; van Groeningen, C J ; van Diest, P J ; Boven, E ; van der Wall, E ; Giaccone, G ; Wagstaff, J ; Pinedo, H M. / Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. In: The Oncologist. 1999 ; Vol. 4, No. 2. pp. 106-11.
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title = "Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer",
abstract = "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.CONCLUSION: 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?",
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author = "Honkoop, {A H} and {Luykx-de Bakker}, {S A} and K Hoekman and S Meyer and Meyer, {O W} and {van Groeningen}, {C J} and {van Diest}, {P J} and E Boven and {van der Wall}, E and G Giaccone and J Wagstaff and Pinedo, {H M}",
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Honkoop, AH, Luykx-de Bakker, SA, Hoekman, K, Meyer, S, Meyer, OW, van Groeningen, CJ, van Diest, PJ, Boven, E, van der Wall, E, Giaccone, G, Wagstaff, J & Pinedo, HM 1999, 'Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer' The Oncologist, vol. 4, no. 2, pp. 106-11.

Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. / Honkoop, A H; Luykx-de Bakker, S A; Hoekman, K; Meyer, S; Meyer, O W; van Groeningen, C J; van Diest, P J; Boven, E; van der Wall, E; Giaccone, G; Wagstaff, J; Pinedo, H M.

In: The Oncologist, Vol. 4, No. 2, 1999, p. 106-11.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer

AU - Honkoop, A H

AU - Luykx-de Bakker, S A

AU - Hoekman, K

AU - Meyer, S

AU - Meyer, O W

AU - van Groeningen, C J

AU - van Diest, P J

AU - Boven, E

AU - van der Wall, E

AU - Giaccone, G

AU - Wagstaff, J

AU - Pinedo, H M

PY - 1999

Y1 - 1999

N2 - 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.CONCLUSION: 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?

AB - 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.CONCLUSION: 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?

KW - Adult

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Breast Neoplasms/drug therapy

KW - Confidence Intervals

KW - Cyclophosphamide/administration & dosage

KW - Disease-Free Survival

KW - Doxorubicin/administration & dosage

KW - Drug Administration Schedule

KW - Female

KW - Follow-Up Studies

KW - Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use

KW - Humans

KW - Middle Aged

KW - Neoadjuvant Therapy

KW - Neoplasm Staging

KW - Neutropenia/chemically induced

KW - Thrombocytopenia/chemically induced

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JO - The Oncologist

JF - The Oncologist

SN - 1083-7159

IS - 2

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Honkoop AH, Luykx-de Bakker SA, Hoekman K, Meyer S, Meyer OW, van Groeningen CJ et al. Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. The Oncologist. 1999;4(2):106-11.