In 1962, Bloom and colleagues described the natural history of locally advanced breast cancer. (For the purposes of this manuscript, we will define locally advamced breast cancer as tumors that measure more than 5 cm, tumors that extend to the chest wall or skin, and tumors with fixed ipsilateral nodes or ipsilateral internal mammary nodes. These characteristics therefore correspond to operable disease stage IIIA (T3, N1 or any N2) and to initially inoperable stage IIIB (any N3 or any T4) disease.) Bloom et al retrospectively analyzed data from 250 untreated patients with locally advanced breast cancer (97.6% of whom had T3 or T4 disease) who were hospitalized in the Middlesex Hospital in London between 1805 and 1933. The patients, who were in the hospital for at least 6 months, died in the hospital and were autopsied. Mean survival time was 2.7 years (range, 3 months to 18 years).
Today, with the use of a consistent multimodality approach including surgical excision followed by appropriate systemic adjuvant therapy and radiotherapy, 3-year survival rates for women with locally advanced breast cancer range from 50% to 80%. However, 10-year survival rates are between 30% and 40%.
Surgical therapy has traditionally involved modified radical mastectomy, but by downstaging the primary tumor with induction chemotherapy, breast-conserving surgery becomes an option for some patients. The extent and dose of radiotherapy depends on the size of the cancer, adequacy of axillary dissection, number of axillary nodes involved, and type of primary surgery performed. The major obstacle to long-term survival for patients with locally advanced breast cancer is the development of distant metastases. Therefore, the development of more effective systemic therapies is required.
Systemic therapy has traditionally involved chemotherapy followed by hormonal agents. Recently developed cytotoxic agents (the taxanes in particular) are starting to be incorporated in clinical studies targeted to patients with locally advanced breast cancer. High-dose chemotherapy requiring stem-cell rescue is also being studied as is the use of monoclonal antibodies against breast cancer-related antigens (either individually or as vehicles to deliver chemotherapy, radioisotopes, or natural toxins). Determination of the ultimate impact of these newer agents on overall and long-term disease-free survival, local control, and quality of life will require further investigation.
In this article, we will discuss several issues relating to the optimal management of patients with locally advanced breast cancer, including the roles of combined-modality therapy; new chemotherapy agents, such as the taxanes; and high-dose chemotherapy with stem-cell transplantation. We also will describe the tools currently available to assess response to induction chemotherapy, as well as biologic correlates to predict response to treatment.
The surgical options for patients with locally advanced breast cancer include radical mastectomy, modified radical mastectomy, and breast-conserving surgery. Studies have demonstrated that radical or modified radical mastectomy as a single treatment modality leads to local relapse rates ranging from 20% to 50%, with a 5-year overall survival of only 30% to 40% and a 10-year overall survival of approximately 20% to 30%.[3-5]
Locoregional control has traditionally been achieved using mastectomy and postoperative radiotherapy. Historically, breast conservation has not been a treatment option for women with stage III disease. Recently, however, the use of induction chemotherapy has allowed increasing numbers of patients to undergo breast-conserving surgery.
Breast Conserving SurgeryNumerous investigators, including Winchester and Cox, have discussed the standards for breast-conserving surgery. The absolute and relative contraindications to breast-conserving surgery are:
- First- or second-trimester pregnancy;
- More than one malignancy in separate quadrants of the breast or diffuse malignant or indeterminate microcalcifications;
- History of prior therapeutic radiation to the involved breast;
- Large tumor in a breast in which adequate resection would cause significant cosmetic deformity; and
- Subareolar location, which may result in suboptimal cosmesis due to the removal of the nipple-areolar complex.
Clinically suspicious mobile axillary lymph nodes or microscopically involved axillary nodes are not considered contraindications to breast-conserving surgery. Beside the usual radiotherapeutic contraindications, additional surgical concerns must be considered when a patient is evaluated for breast-conserving surgery.
The surgeon should not cut the surgical specimen before the pathologist has examined it and should orient the specimen for the pathologist. Both the pathologist and surgeon should examine the specimen for adequate margins. Despite the widespread use of breast-conserving surgery for patients with breast cancer, the optimal resection margin is still not well defined. Moreover, examination of breast specimens is far from uniform.
Pathologists need to reach a better consensus about the definition of a positive margin, since positive or unknown margins of excision are associated with a significantly greater incidence of residual tumor on reexcision[8-10] and a higher risk of local recurrence after radiation therapy.
Despite the precautions taken at initial biopsy, reexcision of a previous biopsy site may be necessary to ensure negative margins. Proper orientation of the original biopsy specimen will help avoid reexcision of already clear margins, and thus the unnecessary removal of normal breast tissue. When the site of the positive margin is unknown, a rim of tissue around the entire biopsy cavity will need to be removed. Placing clips to outline the breast cavity may aid in marking the tumor bed and in planning radiation therapy.
Axillary DissectionThe prognosis of patients with locally advanced breast cancer is related to nodal status, size of the primary lesion, and estrogen/progesterone receptor status. Axillary node status, the single most important prognostic indicator, still requires axillary dissection with histologic examination for definitive diagnosis. With breast-conserving surgery, axillary dissection is generally done through a separate axillary incision for better cosmesis.
The extent of the axillary dissection depends on the extent of disease. A level I and II dissection is appropriate for most invasive tumors, with a minimum of six lymph nodes required to adequately sample the axilla. Levels I, II, and III lymph nodes that contain obvious disease are removed. The long thoracic, thoracodorsal, and medial pectoral nerves are preserved routinely.
Axillary dissection has the potential morbidity of arm edema (reported incidence, 2% to 22%), upper extremity cellulitis (which often aggravates arm edema), and sensory disturbance in the distribution of the intercostal brachial nerve.
The length of hospitalization necessary following these surgical proceduresie, mastectomy, breast-conserving surgery, and axillary dissectionhas decreased significantly over the last few years, with outpatient surgery being technically possible for an increasing number of patients.[13,14]
Surgery Following Induction ChemotherapyThe role of surgery following induction chemotherapy has been debated recently.[15-17] Investigators from British Columbia evaluated the impact of mastectomy in patients with locally advanced breast cancer who received induction chemotherapy (three cycles of doxorubicin(Drug information on doxorubicin) [Adriamycin] and cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan] on day 1 and methotrexate(Drug information on methotrexate) and 5-fluorouracil [5-FU] on day 14) followed by radiotherapy between 1979 and 1983.[Joseph Ragaz, md, personal communication, December, 1996] If patients were deemed to have operable disease, the physician could recommend mastectomy or continued observation.
Ten-year results document a statistically significant improvement in overall survival for the mastectomy group compared with the observation group. However, when a subset of patients who achieved either a complete or partial response to induction chemotherapy was analyzed, no statistical difference in overall survival emerged.
The role of breast-conserving surgery (lumpectomy) for patients who have undergone induction chemotherapy for locally advanced breast cancer has also been evaluated recently.[18-20] Touboul and co-workers examined three different locoregional approaches based on response to induction chemotherapy. Patients who had residual tumors > 3 cm or multifocal tumors underwent a mastectomy; patients deemed to have no residual disease received radiation therapy alone; and patients who had small tumors (defined as £ 3 cm) after induction chemotherapy underwent wide excision and radiation therapy. Between 1982 and 1990, 97 patients were enrolled.
At a median follow-up of about 8 years, the 5-year locoregional relapse rate was 16% in patients treated with radiation alone, 16% in those given radiation plus wide excision, and 5.4% in those who had mastectomy (P = .04 for mastectomy vs radiation alone or with wide excision). However, the 5-year breast-conservation rate was 52%, and the 5-year overall and disease-free survival rates were identical for all three arms with 5- and 10-year overall survival rates of 80% and 69%, respectively. (Five-year and 10-year survival rates after conservative local treatment were 85.5% and 67.8%, respectively, vs 75.7% and 71.9% after nonconservative treatment, P = .9). The study concluded that local treatment does not influence 5- and 10-year overall survival and that preoperative chemotherapy and radiation therapy do allow conservative surgery to be used more often.