Locally Advanced Disease
The optimal treatment for patients with locally advanced breast cancer has yet to be defined, due to the heterogeneity of this group. There are approximately 40 different substage possibilities with the different combinations of tumor size and nodal status. Between 66% and 90% of patients with stage III breast cancer will have positive lymph nodes at the time of axillary dissection, and approximately 50% of patients will have four or more positive nodes.
Patients with locally advanced breast cancer have disease-free survival rates ranging from 0% to 60%, depending on tumor characteristics and nodal status. In general, the most frequent type of treatment failure is caused by distant metastases, and the majority of them appear within 2 years of diagnosis. With the increased utilization of multimodality therapy, including chemotherapy, radiation therapy, and surgery, survival of this patient population has improved significantly.
Neoadjuvant chemotherapy is administered prior to surgery and has the same impact on disease-free and overall survival as adjuvant chemotherapy. Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed. Preoperative chemotherapy requires a coordinated multidisciplinary approach to plan for surgical and radiation therapy. A multimodality treatment approach can provide improved control of locoregional and systemic disease. When neoadjuvant therapy is used, accurate pathologic staging is not possible. The majority of patients receiving neoadjuvant chemotherapy and either breast-conservation treatment (BCT) or mastectomy will require radiation therapy following surgery.
Active regimens. Preoperative chemotherapy regimens reported to result in high clinical response rates include anthracycline-containing regimens followed by a taxane (or vice versa). The most common anthracycline-containing regimens used are CAF (cyclophosphamide, Adriamycin [doxorubicin], and fluorouracil(Drug information on fluorouracil) [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide(Drug information on cyclophosphamide)), or FEC (5-FU, epirubicin(Drug information on epirubicin) [Ellence], cyclophosphamide). The most common taxane regimens used are either weekly paclitaxel(Drug information on paclitaxel) or every-3-week docetaxel(Drug information on docetaxel) (Taxotere) (Table 1). Administration of TAC (Taxotere [docetaxel], Adriamycin [doxorubicin] and cyclophosphamide) or AT or may produce equivalently high response rates. Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response (pCR) rate for women with locally advanced disease. (The dosages of these combination chemotherapy regimens are provided in Table 1, "Stage II Breast Cancer" chapter.)
There seems to be no difference in survival in women with locally advanced disease who receive chemotherapy before or after surgery. Neoadjuvant chemotherapy results in complete clinical response rates ranging from 20% to 53% and partial response rates (≥ 50% reduction in bidimensionally measurable disease) ranging from 37% to 50%, with total response rates ranging from 80% to 90%. Patients with large lesions are more likely to have partial responses. However, pCRs do occur and are more likely to be seen in patients with smaller tumors that are triple-negative or which overexpress HER2. A pCR in the primary tumor is often predictive of a complete axillary lymph node response. Patients with locally advanced breast cancer who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival compared with those who have less than a pCR. However, a pCR does not eliminate the risk of recurrence.
In order to improve the prognostic information that can be obtained from evaluating pathologic response after neoadjuvant chemotherapy, Symmans et al developed the residual cancer burden (RCB) method of measuring residual disease. Pathologic slides and reports from 382 patients were reviewed in two different treatment cohorts: paclitaxel followed by FAC (n = 241) and FAC alone (n = 141). RCB was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses. RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pCR vs residual disease [RD]; hazard ratio [HR] = 2.50; 95% confidence interval [CI], 1.70–3.69; P < .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort. The investigators concluded that RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance.
Patients should be followed carefully while receiving neoadjuvant systemic therapy to determine treatment response. In addition to clinical examination, it may also be helpful to document photographically the response of ulcerated, erythematous, indurated skin lesions. Physical examination, mammography, and breast ultrasonography are best for assessing primary tumor response, whereas physical examination and ultrasonography are used to evaluate regional nodal involvement.
The role of magnetic resonance imaging (MRI) in evaluating response to preoperative chemotherapy is still evolving. Dynamic contrast-enhanced MRI performed at baseline, during chemotherapy, and before surgery has yielded more than 90% diagnostic accuracy in identifying tumors achieving a pCR and can potentially provide functional parameters that may help to optimize neoadjuvant chemotherapy strategies. Despite its high sensitivity, however, a large number of patients still may have either false-negative or false-positive results of MRI scanning.
A multimodality treatment plan for locally advanced breast cancer is shown schematically in Figure 1. This approach has been shown to result in a 5-year survival rate of 84% in patients with stage IIIA disease and a 44% rate in those with stage IIIB disease. The most striking benefit has been seen in patients with inflammatory breast cancer, with 5-year survival rates of 35% to 50% reported for a multimodality treatment approach including primary chemotherapy followed by surgery and radiation therapy and additional adjuvant systemic therapy. The same chemotherapy drugs, doses, and schedules used for single-modality therapy are employed in the multimodality approach.
Surgery. Traditionally, the surgical procedure of choice for patients with locally advanced breast cancer has been mastectomy. In recently published studies, some patients with locally advanced breast cancer who responded to treatment with neoadjuvant chemotherapy became candidates for BCT and were treated with limited breast surgery and adjuvant breast irradiation. Patients who have been downstaged using neoadjuvant chemotherapy should be evaluated carefully before proceeding with conservative treatment. It may be helpful to mark the site of the primary tumor with the placement of a clip during the course of percutaneous biopsy prior to beginning adjuvant therapy. There can sometimes be a complete clinical and/or radiographic response after neoadjuvant chemotherapy or hormonal therapy, and this may facilitate a wide local incision.
The role of sentinel node biopsy in the treatment of breast cancer after neoadjuvant chemotherapy has yet to be defined. Pathologically positive axillary lymph nodes can be sterilized when neoadjuvant chemotherapy is utilized. There are other biologic concerns with sentinel node biopsy after neoadjuvant chemotherapy. The lymphatics may undergo fibrosis or may become obstructed by cellular debris, making the mapping procedure unreliable, with false-negative rates of up to 25%. The rate of conversion from positive to negative nodes can be enhanced when 4 cycles of a doxorubicin(Drug information on doxorubicin)-based regimen are followed by 4 cycles of paclitaxel or docetaxel. Sentinel lymph node biopsy will only be accurate if all the metastatic deposits within the axilla respond in a similar fashion to chemotherapy. Preliminary data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial demonstrated an 11% false-negative rate in women who underwent sentinel node biopsy after receiving 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel. However, patients with clinically positive nodes prior to neoadjuvant chemotherapy should have a full lymph node dissection.
Radiation therapy. Radiotherapy remains an integral component of the management of patients with locally advanced breast cancer. For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000-6,000 cGy) is usually employed, as discussed in the "Stage II Breast Cancer" chapter. Randomized trials suggest that postmastectomy patients with any number of positive nodes derive a disease-free survival and/or overall survival benefit from postmastectomy irradiation.
In a retrospective review, more than 500 patients in six prospective trials who were treated with neoadjuvant chemotherapy, mastectomy, and radiation were compared with 134 patients treated with the same chemotherapy and mastectomy, but no radiation. Despite the more unfavorable characteristics, the radiated patients had a lower rate of local-regional relapse than did the unirradiated group (11% vs 22%). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pCR to neoadjuvant chemotherapy still had a high rate of locoregional response, which was significantly reduced with radiation (10-year rates: 33% vs 3%; P = .006). Radiation improved cause-specific survival in the subsets of patients with stage IIIB disease, clinical T4 tumors, and ≥ 4 positive nodes. The authors concluded that radiation should be considered for these patients regardless of their response to initial chemotherapy.
Available data do not suggest a problem in delaying radiation therapy until the completion of systemic chemotherapy. Even in patients undergoing high-dose chemotherapy with autologous bone marrow or stem-cell transplantation, irradiation is generally indicated following mastectomy for patients with locally advanced disease (primary tumors ≥ 5 cm and/or ≥ four positive axillary nodes).
For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery. Formenti et al achieved a promising 20% pCR rate with concomitant 5-FU and RT in patients who presented with T3/T4 tumors that could not be resected with primary wound closure. The patients were treated with preoperative continuous infusion 5-FU at 200 mg/m2/day with radiotherapy of 50 Gy in 2 Gy fractions to the breast and regional nodes, followed by mastectomy. A total of 35 women completed the protocol; 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1 patient, and patient choice in 1 patient. No grade 3/4 skin toxicities were seen. Objective clinical response rate before mastectomy was 71% (25 of 35 patients; 4 complete responses [CRs], 21 partial responses [PRs]). In all 35 patients, however, tumor response was sufficient to make them resectable with primary wound closure.
High-dose chemotherapy. To date, available clinical trials investigating the role of adjuvant high-dose chemotherapy (HDC) with autologous stem cell transplant in breast cancer have not shown superiority over conventional adjuvant chemotherapy, in terms of disease-free or overall survival. Furthermore, in some HDC trials, study design, power, and strategy have been questioned. Thus, currently HDC cannot be recommended for patients with primary or metastatic breast cancer outside the context of a clinical trial.