Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313).
OBJECTIVE
We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).


METHODS
High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.


RESULTS
Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar.


CONCLUSIONS
The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.
Linden
Hannah M
HM
Puget Sound Oncology Consortium, Southwest Oncology Group Statistical Center, Seattle, WA, USA.
Haskell
Charles M
CM
Green
Stephanie J
SJ
Osborne
C Kent
CK
Sledge
George W
GW
Shapiro
Charles L
CL
Ingle
James N
JN
Lew
Danika
D
Hutchins
Laura F
LF
Livingston
Robert B
RB
Martino
Silvana
S
D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D011336:Probability; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013997:Time Factors
D004317:Doxorubicin; D003520:Cyclophosphamide