Breast cancer is a major public health problem
worldwide. An estimated 40,800 women died of the disease in 2001, making breast
cancer second only to lung cancer as the leading cause of cancer death in women
in the United States. However, over the last decade, breast cancer mortality
rates decreased approximately 1.5% per year in the United States and United
Kingdom. This is due in part to the widespread use of adjuvant systemic
therapy. Adjuvant chemotherapy and hormonal therapy reduced the risk of
recurrence and the death rate in both premenopausal and postmenopausal patients
with breast cancer.
Adjuvant therapy provided the same proportional degree of benefit to both
node-positive and node-negative patients; however, the benefit of chemotherapy
is more evident in several subsets, such as younger patients and
estrogen-receptor (ER)-negative patients. Furthermore, it has been shown that
anthracycline-containing adjuvant regimens are superior to regimens that do not
include an anthracycline. Adjuvant anthracycline therapy additionally reduced
the risk of recurrence by 12% and the risk of death by 11%. In summary,
adjuvant therapy has changed the natural history of early breast cancer.
Primary chemotherapy, also known as neoadjuvant, induction, or preoperative
chemotherapy, was initially introduced as the primary treatment of patients with
operable and inoperable locally advanced breast cancer. It became an integral
component of the multidisciplinary approach to the treatment of locally advanced
breast cancer. This strategy includes primary chemotherapy; often followed by
regional therapy in the form of surgery, radiation therapy, or both; followed,
in turn, by additional postoperative chemotherapy, radiation therapy (if not
previously administered), and hormonal therapy (ER-positive).
Primary chemotherapy has dramatically transformed the natural history of
locally advanced breast cancer over the last 2 decades.[4-11] It is now a widely
accepted treatment strategy for these patients. More than 70% of patients
achieve a clinical objective response (including pathologic complete remissions
in 10%-15%) after primary chemotherapy, and most patients experience
downstaging of the primary tumor and regional lymph node metastases. As a
result, breast conservation surgery has now been established as a potential
alternative to modified radical mastectomy in 10% to 30% of patients with
locally advanced breast cancer.[7-8,10]
After multidisciplinary therapy, almost all patients are initially rendered
disease free, and more than 70% achieve long-term local control. In The
University of Texas M. D.
Anderson Cancer Center experience, the 5-year disease-free survival rates for
patients with stage IIB/IIIA and stage IIIB disease were 71% and 33%,
respectively. The 5-year overall survival rates for stage IIB/IIIA and stage
IIIB disease were 84% and 44%, respectively; the 10-year overall survival rates
were 56% and 26%, respectively.[7-8] Patients without microscopic residual
disease had better disease-free and overall survival patterns. Among patients
whose mastectomy axillary nodes specimen did not contain residual disease,
pathologic complete remission, more than 75% achieved a 5-year survival.
Primary Chemotherapy in Operable Breast Cancer
With the goal of enhancing the breast conservation rate and disease-free and
overall survival, primary chemotherapy was later introduced as induction therapy
in patients with large, operable stage II and stage IIIA breast cancer.[12-21]
Several biological and clinical advantages initially provided the rationale for
this approach rather than adjuvant chemotherapy. They included: (1) the in vivo
tumor response assessment; (2) no postsurgical growth spurt; (3) intact tumor
vasculature; (4) early initiation of systemic treatment; (5) down staging of
primary tumor and lymph node metastasis to increase the possibility of
operability (locally advanced breast cancer) and breast conservation surgery
(locally advanced breast cancer and large operable breast cancer); (6) early
biological surrogate markers to assess the efficacy of therapy; and (7) a
decrease in drug resistance by early exposure to systemic therapy.
A number of promising phase II trials were reported in patients with large
operable breast cancer.[12-13] Significant antitumor efficacy and a higher rate
of breast conservation surgery were achieved. The Milan group presented the
largest experience. Their results included data from 536 patients who had
been enrolled in several nonrandomized clinical trials. The initial series
included patients who were considered to be candidates for mastectomy because
their tumors were clinically > 3.0 cm (later trials included patients with
tumors measuring 2.5 cm or more). They received either three or four cycles of primary
chemotherapy (CMF [cyclophosphamide (Cytoxan, Neosar), methotrexate,
fluorouracil (5-FU)] or FAC/FEC [5-FU, doxorubicin (Adriamycin),
cyclophosphamide/5-FU, epirubicin (Ellence), cyclophosphamide]). The clinical
overall response rate was 76%, with a clinical complete remission seen in 16%;
however, only 3% achieved a pathologic complete response. The incidence of
breast conservation surgery was greater than 85%.
Phase III Trials of Primary Therapy
Several large randomized phase III trials of primary therapy for operable
breast cancer have been reported.[14-21] A summary of these trials is presented
in Table 1.[14-21] The largest trial was conducted by the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-18.[14,15] Approximately 1,523 women
with stage II and III breast cancer (T1-3, N0, M0) were randomized to receive
four cycles of doxorubicin, 60 mg/m², and cyclophosphamide, 600 mg/m² (AC),
either before (primary chemotherapy) or after surgery (adjuvant chemotherapy).
The administration of primary chemotherapy resulted in a clinical complete
response in 36% and a clinical partial response in 44%, for an overall clinical
response rate of 80%. Patients randomized to receive primary chemotherapy
demonstrated a pathologic complete response rate of 13%.
There was a significant improvement in the rate of breast conservation
surgery (ie, lumpectomy) in patients in the primary chemotherapy arm vs the
adjuvant therapy arm (68% vs 60%; P = .002). The 5-year disease-free survival
(67%) and overall survival (80%) in the primary chemotherapy arm and the
adjuvant therapy arm were identical. In addition, there was no difference in the
rate of ipsilateral locoregional recurrence.
Of interest, however, was the demonstration of a significant correlation
between pathologic complete response (breast only) to preoperative chemotherapy
in terms of survival outcome. Those who also achieved a pathologic complete
response had a significantly improved disease-free and overall survival (84% and
87%, respectively) compared with those who were found to have residual invasive
carcinoma at the time of surgery (72% and 78%, respectively). The results of
this correlation have persisted through 8 years of follow-up.
In summary, previously conducted phase III randomized trials failed to
demonstrate an improvement in the disease-free and overall survival rates with
primary vs adjuvant chemotherapy. However, the trials confirmed the clinical
advantage of an increase in the breast conservation surgery rate and downstaging
of both clinical and pathologic involvement of axillary nodes. Importantly, the
demonstration of a correlation between tumor response (ie, pathologic complete
response) and patient survival (disease-free and overall) provides a useful
early surrogate marker of favorable outcome. Dividing patients into groups
according to tumor response after primary chemotherapy might provide an avenue
for improved clinical management. With the development of new, highly active
chemotherapy agents over the last 10 years, it is possible to use new
strategies to improve the outcome of patients with breast cancer.
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