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Educational Supplement: Appendix
Recent
NSABP Adjuvant Studies in Primary
(Stage One) Breast Cancer
Bernard
Fisher, M.D.
Data on the
effects of adjuvant chemotherapy and endocrine therapy on breast
cancer obtained from randomized trials conducted during the 1970s
and early 1980s were evaluated at a consensus development conference
convened by the National Institutes of Health (NIH) in 1985. The
conference concluded that there was inadequate information to recommend
therapy other than surgery for women with negative nodes (Consensus
Conference, 1985).
By 1990, however,
findings from trials conducted by the National Surgical Adjuvant
Breast Project (NSABP) and by other investigators warranted a new
conference to reconsider the treatment of early-stage breast cancer.
Participants at the 1990 meeting concluded that the rate of
local and distant recurrence following local therapy for node-negative
breast cancer is decreased by both adjuvant combination of cytotoxic
chemotherapy and by adjuvant tamoxifen (NIH Consensus Conference,
1991). The conference also concluded that patients with tumors equal
to or less than 1 cm now had an excellent prognosis and did not
require adjuvant therapy outside of clinical trials. The participants
noted, however, that studies so far were not large enough, nor followup
long enough, to estimate accurately the interactions between menopausal
status or steroid receptor positivity and adjuvant therapy in node-negative
patients. They also noted that there were too few patients with
estrogen receptor (ER)-negative tumors to permit evaluating the
benefit of treatment with tamoxifen, that the followup period had
been too short to obtain meaningful data on the mortality of women
with breast cancer, and that no information was available to aid
in determining the effects of combination chemotherapy plus tamoxifen
in node-negative breast cancer patients. In the years since the
1990 conference, information on these issues has been obtained from
six NSABP trials involving a total of 11,620 node-negative patients
with primary breast cancer.
Findings
for Adjuvant Chemotherapy
In the NSABP
B-13 trial, women with breast cancer were randomized to receive
either surgery and no chemotherapy or surgery followed by 12 courses
(1 year) of methotrexate (M) and sequentially administered fluorouracil
(F), (M->F), followed by leucovorin
(Fisher, Dignam, Mamounas, et al., 1992). Findings through more
than 12 years of followup demonstrated that improvements in disease-free
survival (DFS) and overall survival as a result of that form of
chemotherapy, first reported after 5 years, had persisted (p=0.004
and 0.039, respectively). A second trial, B-19, was conducted to
determine if the alkylating agent cyclophosphamide (C) contributed
an additional benefit when administered along with methotrexate
and fluourouracil (CMF). Over a 6-month period, patients received
either six courses of M®F or six courses of CMF. Through an
8-year followup period, CMF produced greater DFS and overall survival
advantages (p=0.0004 and p=0.039, respectively).
The NSABP subsequently
initiated a B-23 study because of contradictory information about
the propriety of using tamoxifen with chemotherapy, and because
of uncertainty about the relative worth of doxorubicin (Adriamycin,
A), cyclophosphamide, and CMF for treatment of breast cancer (Fisher,
Anderson, Tan-Chiu, et al., in press). Women with breast cancer
(n=2,008) were randomized to receive either CMF plus placebo, or
CMF plus tamoxifen, or doxorubicin and cyclophosphamide plus placebo,
or doxorubicin and cyclophosphamide plus tamoxifen. Six cycles of
CMF were given over 6 months; four cycles of AC were administered
over a period of 63 days. No significant differences in the rates
of relapse-free survival (RFS), event-free survival (EFS), or overall
survival were observed among the four groups through 5 years of
followup, either for all patients (p=0.9, 0.8, and 0.8, respectively)
or for those =49 or =50 years of age. The study also demonstrated
that CMF was more effective than M->F for women with ER-negative
tumors. There were, however, no significant differences in outcome
between women who received 6 months of CMF and those treated with
2 months of AC. No significant advantage over that achieved from
chemotherapy alone was found when tamoxifen was given with either
regimen.
Findings
on Tamoxifen
NSABP B-14 was
initiated in 1982 to determine the effectiveness of tamoxifen in
breast cancer patients with negative nodes (Fisher, Dignam, Bryant,
et al., 1996; Fisher, Dignam, Bryant, et al., in press). In 1989,
a report on 5 years of followup on more than 2,800 randomized patients
found a significant advantage from treatment with tamoxifen. The
DFS and overall survival rates persisted for more than 12 years
(p=0.000005 and 0.0013, respectively). The therapy was also associated
with a significant reduction in contralateral and ipsilateral breast
cancer, but no additional benefit was observed from administration
of tamoxifen beyond 5 years. These benefits were obtained with a
relatively low incidence of side effects.
NSABP B-20,
a study that involved more than 2,300 women, was aimed at testing
the hypothesis that the addition of either M->F or CMF to tamoxifen
would result in a greater benefit than that which could be achieved
with tamoxifen alone (Fisher, Dignam, Wolmark, et al., 1997). After
8 years, there continue to be significant disease-free survival
and overall survival advantages from the use of tamoxifen plus chemotherapy
(44 percent versus 77 percent, p=0.002, for DFS; and 92 percent
versus 88 percent, p=0.018, for survival). The B-20 study
found no subgroup of women with breast cancer who did not benefit
from administration of CMF with tamoxifen.
Findings
on Patients with Tumors Less Than or Equal to 1 Cm and 1.1 to 2
Cm
In an attempt
to resolve uncertainty about prognosis and treatment for patients
with negative nodes and either ER-negative or ER-positive tumors
of <=1 cm, data from women in five NSABP randomized trials were
analyzed collectively (Fisher, Dignam, Tan-Chiu, et al., in press).
The 8-year rates of recurrence-free survival (RFS) for women with
ER-negative tumors of <=1 cm treated with surgery alone or with
surgery plus chemotherapy were 81 percent and 90 percent, respectively
(p=0.06). Survival was similar in both groups (93 percent
and 91 percent, respectively; p=0.65). The RFS rates for
women with tumors between 1.1 and 2.0 cm were 77 percent for surgery
and 81 percent for surgery plus chemotherapy (p=0.11). Overall
survival was 77 percent and 84 percent, respectively (p=0.01).
The 8-year RFS
rate for women with ER-positive tumors treated with surgery alone
was 86 percent, compared with 93 percent after tamoxifen (p=0.01).
When both tamoxifen and chemotherapy were given, the RFS was 95
percent (p=0.07). The survival rates among women in these
three treatment groups were 90 percent, 92 percent (p=0.41),
and 97 percent (p=0.01), respectively. The RFS rate for women with
tumors of 1.2 to 2.0 cm treated with surgery alone was 75 percent,
and with tamoxifen 88 percent (p<0.001). The RFS rate
was greater after chemotherapy and tamoxifen (91 percent) than after
tamoxifen administration alone (p=0.003). Overall survival
was 83 percent after surgery, 88 percent after tamoxifen was given
(p=0.001), and 93 percent after both tamoxifen and chemotherapy
(p=0.002).
Conclusion:
The prognosis for women with ER-negative or ER-positive tumors of
=1 cm and negative nodes was somewhat better than the prognosis
for women with tumors between 1.1 and 2.0 cm. The prognosis was
not sufficiently favorable, however, to dismiss systemic therapy
as a possible option for certain women with tumors of =1 cm. A cutoff
point in the array of tumor sizes below 10 mm that would justify
systemic therapy remains to be established.
Radiation
and/or Tamoxifen after Lumpectomy for Tumors of < 1 Cm
The first results
obtained from NSABP B-06 raised the question of whether there are
cohorts of women for whom radiation therapy might be replaced with
tamoxifen. NSABP B-21 was conducted to address that issue. Women
(n=1,009) were randomized to either tamoxifen alone, radiation plus
placebo, or radiation plus tamoxifen. Recently reported results
demonstrated a rate (1,000 patients per year) of local recurrence
of 23.3 for women who received tamoxifen, 11.7 for those who received
radiation plus placebo, and 3.4 for those who received radiation
plus tamoxifen (Wolmark, Dignam, Margolese, et al., 2000).
Conclusion:
Radiation and tamoxifen administered in combination prevent local
recurrence to a greater extent than does radiation alone. Tamoxifen
alone is inferior to radiation in preventing recurrence.
Comment
Although almost
all of the NSABP studies have demonstrated a benefit from therapy,
they have all engendered controversy with regard to their clinical
application. As the prognosis for both treated and untreated cohorts
of breast cancer patients becomes better, therapeutic decision-making
becomes more difficult. The question arises as to whether some proportion
of women in a cohort can be justifiably written off
because it has been decided that the groups prognosis is sufficiently
good to negate treatment of any of them despite evidence that some
of them might benefit from a therapy of demonstrated efficacy. Many
women with breast cancer die each year because they have received
either inadequate treatment or no treatment at all. Many others
die despite having received effective treatment. Under
these complex circumstances, it would be inappropriate to deny any
woman the opportunity to receive therapy from which she might benefit.
References
Consensus conference.
(No authors listed.) Adjuvant chemotherapy for breast cancer. JAMA
1985;254:3461-3. Abstract.
Fisher B, Anderson
S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary-node
negative, estrogen receptor-negative breast cancer: findings from
National Surgical Adjuvant Breast and Bowel Project B-23. J Clin
Oncol (in press). Abstract.
Fisher B, Dignam
J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus
more than five years of tamoxifen therapy for breast cancer patients
with negative lymph nodes and estrogen receptor-positive tumors.
J Natl Cancer Inst 1996;88:1529-42. Abstract.
Fisher B, Dignam
J, Bryant J, et al. Five versus more than five years of tamoxifen
for node-negative breast cancer: updated findings. J Natl Cancer
Inst (in press). Abstract.
Fisher B, Dignam
J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, et al. Sequential
methotrexate and fluorouracil for the treatment of node-negative
breast cancer patients with estrogen receptor-negative tumors: eight-year
results from National Surgical Adjuvant Breast and Bowel Project
(NSABP) B-13 and first report of findings from NSABP B-19 comparing
methotrexate and fluorouracil with conventional cyclophosphamide,
methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982-92.
Abstract.
Fisher B, Dignam
J, Tan-Chiu E, et al. Prognosis and treatment of patients with breast
tumors of <=1 cm and negative axillary nodes. J Natl Cancer Inst
(in press). Abstract.
Fisher B, Dignam
J, Wolmark N, De Cillis A, Emir B, Wickerham DL, et al. Tamoxifen
and chemotherapy for lymph node-negative, estrogen receptor-positive
breast cancer. J Natl Cancer Inst 1997;89:1673-82. Abstract.
NIH consensus
conference. (No authors listed.) Treatment of early-stage breast
cancer. JAMA 1991;265:391-5. No Abstract Available.
Wolmark N, Dignam
J, Margolese R, et al. The role of radiotherapy and tamoxifen in
the management of node-negative invasive breast cancer =1.0 cm treated
with lumpectomy: preliminary results of NSABP protocol B-21. [abstract].
Proc Am Soc Clin Oncol 2000;19,271. Abstract.
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