Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial.
BACKGROUND
Although chemotherapy and ovarian function suppression are both effective adjuvant therapies for patients with early-stage breast cancer, little is known of the efficacy of their sequential combination. In an International Breast Cancer Study Group (IBCSG) randomized clinical trial (Trial VIII) for pre- and perimenopausal women with lymph node-negative breast cancer, we compared sequential chemotherapy followed by the gonadotropin-releasing hormone agonist goserelin with each modality alone.


METHODS
From March 1990 through October 1999, 1063 patients stratified by estrogen receptor (ER) status and radiotherapy plan were randomly assigned to receive goserelin for 24 months (n = 346), six courses of "classical" CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or six courses of classical CMF followed by 18 months of goserelin (CMF --> goserelin; n = 357). A fourth arm (no adjuvant treatment) with 46 patients was discontinued in 1992. Tumors were classified as ER-negative (30%), ER-positive (68%), or ER status unknown (3%). Twenty percent of patients were aged 39 years or younger. The median follow-up was 7 years. The primary outcome was disease-free survival (DFS).


RESULTS
Patients with ER-negative tumors achieved better disease-free survival if they received CMF (5-year DFS for CMF = 84%, 95% confidence interval [CI] = 77% to 91%; 5-year DFS for CMF --> goserelin = 88%, 95% CI = 82% to 94%) than if they received goserelin alone (5-year DFS = 73%, 95% CI = 64% to 81%). By contrast, for patients with ER-positive disease, chemotherapy alone and goserelin alone provided similar outcomes (5-year DFS for both treatment groups = 81%, 95% CI = 76% to 87%), whereas sequential therapy (5-year DFS = 86%, 95% CI = 82% to 91%) provided a statistically nonsignificant improvement compared with either modality alone, primarily because of the results among younger women.


CONCLUSIONS
Premenopausal women with ER-negative (i.e., endocrine nonresponsive), lymph node-negative breast cancer should receive adjuvant chemotherapy. For patients with ER-positive (i.e., endocrine responsive) disease, the combination of chemotherapy with ovarian function suppression or other endocrine agents, and the use of endocrine therapy alone should be studied.
International Breast Cancer Study Group Coordinating Center and Inselspital, Bern, Switzerland. monica.castiglione@siak.ch
Castiglione-Gertsch
Monica
M
O'Neill
Anne
A
Price
Karen N
KN
Goldhirsch
Aron
A
Coates
Alan S
AS
Colleoni
Marco
M
Nasi
M Laura
ML
Bonetti
Marco
M
Gelber
Richard D
RD
D000328:Adult; D000568:Amenorrhea / Q000139:chemically induced; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D017273:Goserelin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D015994:Incidence; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D017697:Premenopause; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D017273:Goserelin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate