SAN ANTONIO--The first results of a large Intergroup study show that
adjuvant chemotherapy with CAF is superior to CMF in high-risk
node-negative patients, Laura Hutchins, MD, of the University of
Arkansas, reported at the ASCO plenary session for SWOG. The study
also suggests that S phase fraction can be used to stratify patients
into risk groups.
Patients with T1-3a node-negative invasive breast cancer were
assigned to risk group, based on prognostic groups identified in a
prior Intergroup trial, according to tumor size and hormone-receptor
status. S phase fraction was used to categorize patients in the
"uncertain" risk group (those with
hormone-receptor-positive tumors under 2 cm in size).
Of 3,977 eligible patients, 1,208 were eventually assigned to the
low-risk category and were followed with no additional adjuvant
therapy, while 2,163 high-risk patients were randomized to receive
CMF (cyclophosphamide, methotrexate, fluorouracil) or CAF
(cyclophosphamide, Adriamycin, fluorouracil) for 6 cycles, followed
by no further therapy or tamoxifen (Nolvadex) for 5 years.
Results for all patients show a "modest though significant"
benefit in estimated 5-year disease-free survival for CAF (86%) vs
CMF (84%) (P = .03). "This advantage for CAF is seen in overall
survival as well (92 vs 91%)," Dr. Hutchins said. CAF also had a
survival advantage for subgroup analyses by menopausal and
estrogen-receptor (ER) status (see Table).
Toxicity was greater in the CAF arms, with 11 patients having grade 3
or higher cardiotoxicity vs 3 for CMF. Grade 4 granulocytopenia,
grade 2 or higher nausea/vomiting, stomatitis, and alopecia were also
significantly greater with CAF.
Effects of Tamoxifen
In ER-positive patients, adding tamoxifen to chemotherapy
significantly increased 5-year survival, both disease-free (88% vs
82%) and overall (94% vs 91%). However, not only did tamoxifen not
improve survival in ER-negative patients, there was a trend toward
decreased disease-free survival in this group with tamoxifen (83% vs
86% for chemotherapy alone).
Similar results were seen when tamoxifen use was analyzed according
to menopausal status. "Although these subset analyses should not
be interpreted as conclusive in showing a negative effect for
tamoxifen in ER-negative patients, there clearly does not seem to be
a benefit in this subset," she said.
Use of S Phase Fraction
Looking at results by treatment assignment according to S phase
fraction, Dr. Hutchins said, "disease-free survival was very
similar for those patients in the initial low-risk group identified
by small tumor size and those patients assigned to low risk on the
basis of S phase fraction, despite these patients having a larger
The 5-year disease-free survival rates were 89% and 88%,
respectively. Thus, she said, "S phase fraction identified a
group of node-negative patients with 1 to 2 cm tumors that did well
without adjunctive therapy."
In her discussion, Dr. Nancy Davidson, of Johns Hopkins, emphasized
that the differences in survival between CAF and CMF were small but
came without major differences in toxicity. "The only caveat is
that we dont know if doxorubicin use would have an unpredicted
long-term cardiotoxicity in these women with reasonably good
prognosis," she said.
She believes either CMF or CAF is a reasonable choice in the setting
of node-negative breast cancer. "Presumably, patients and
physicians who are intent on maximizing anticancer effects will
select CAF, whereas those who are most concerned about toxicity will
Dr. Davidson called the findings on S phase fraction
"exciting," but warned that its use may not be practical
outside of clinical trials due to the problem of lack of laboratory standardization.