Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy.
OBJECTIVE
The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin-->CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel-->CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate.


METHODS
A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C.


RESULTS
Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P<0.0001). PTS induced a significant axillary downstaging (P<0.001), and breast sparing surgery was feasible in 65% versus 34% (P<0.001).


CONCLUSIONS
Doxorubicin/paclitaxel-->CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.
Gianni
Luca
L
Istituto Nazionale Tumori, Milan, Italy, and Hospital Vall d'Hebron, Barcelona, Spain. gianni@istitutotumori.mi.it
Baselga
José
J
Eiermann
Wolfgang
W
Guillem Porta
Vicente
V
Semiglazov
Vladimir
V
Lluch
Aña
A
Zambetti
Milvia
M
Sabadell
Dolores
D
Raab
Günther
G
Llombart Cussac
Antonio
A
Bozhok
Alla
A
Martinez-Agulló
Angel
A
Greco
Marco
M
Byakhov
Mikhail
M
Lopez Lopez
Juan Josè
JJ
Mansutti
Mauro
M
Valagussa
Pinuccia
P
Bonadonna
Gianni
G
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D015999:Multivariate Analysis; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011300:Preoperative Care; D016896:Treatment Outcome
D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil; D008727:Methotrexate