This chapter focuses on the treatment of stage II breast cancer, which encompasses malignancies with primary tumors > 2 cm in their greatest dimension that involve ipsilateral axillary lymph nodes as well as tumors up to 5 cm without nodal involvement.
Stage II breast cancer is further subdivided into stages IIA and IIB. Patients classified as having stage IIA breast cancer include those with T0-1, N1, and T2, N0 disease. Stage IIB breast cancer includes patients with T2, N1, and T3, N0 disease. Therefore, this patient population is more heterogeneous than are the populations with stages 0 and I disease. The pretreatment evaluation and type of treatment offered to patients with stage II breast cancer are based on tumor size, nodal status, status of receptors for estrogen and HER2/neu, and Oncotype Dx recurrence score.
Treatment
Surgical and Radiation Treatment
Multiple studies have demonstrated that patients with stage II breast cancer who are treated with either breast-conservation therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free survival (DFS) and overall survival (OS) rates.
Breast-conservation therapy
The optimal extent of local surgery has yet to be determined and, in the literature, has ranged from excisional biopsy to quadrantectomy. A consensus statement issued by the NCI recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. Patients should subsequently be treated with adjuvant breast irradiation.
Patients with tumors > 4 to 5 cm may not be optimal candidates for breast conservation due to the risk of significant residual tumor burden and the potential for a poor cosmetic result following lumpectomy (or partial mastectomy). Neoadjuvant chemotherapy, typically used for locally advanced breast cancer, is increasingly used in earlier stage, operable breast cancers to reduce the size of the primary tumor and allow for breast-conserving therapy.
In a study of more than 300 patients treated with neoadjuvant chemotherapy at the M D Anderson Cancer Center, promising results were reported. At a median follow-up of 60 months, the 5-year actuarial rates of ipsilateral breast tumor recurrence (IBTR)-free and locoregional recurrence-free survival were 95% and 91%, respectively. The authors concluded that breast-conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of recurrence-free survival in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of recurrence.
In some patients, preoperative chemotherapy produces a sufficient reduction in tumor size that allows patients to receive breast-conserving therapy. The NSABP B-18 trial showed that preoperative doxorubicin(Drug information on doxorubicin)-based chemotherapy decreases tumor size by > 50% in approximately 90% of operable breast cancers, resulting in a greater frequency of lumpectomy.
In a subsequent trial, NSABP B-27, women with invasive breast cancer were randomized to receive 4 cycles of preoperative AC (Adriamycin [doxorubicin] and cyclophosphamide(Drug information on cyclophosphamide)) chemotherapy followed by surgery, or 4 cycles of preoperative AC followed by 4 cycles of docetaxel(Drug information on docetaxel) (Taxotere) then surgery, or 4 cycles of preoperative AC followed by surgery then by 4 cycles of postoperative docetaxel. A higher rate of complete pathologic response was seen at surgery in patients treated with AC followed by docetaxel vs AC alone. There were no significant differences in DFS and OS between the treatment groups. However, those with a complete pathologic response in the breast had significant improvements in DFS (hazard ratio [HR] = 0.45; (P < .0001) and OS (HR = 0.33; (P < .0001) compared with those who had residual disease after preoperative chemotherapy. Because preoperative chemotherapy does not have a negative impact on survival, the preoperative approach is a reasonable option and has gained favor among many patients.
Preoperative chemotherapy had an ability to convert patients requiring mastectomy to candidates for breast-conserving surgery. However, there was an increase in local recurrence in the "converted" group vs those deemed eligibile initially for breast-conserving surgery.
Patients undergoing sentinel lymph node biopsy
The timing of sentinel node biopsy in patients undergoing preoperative chemotherapy is controversial. Preoperative chemotherapy can sterilize the axillary nodes and lead to errors in determining nodal involvement. Formal studies are currently ongoing to determine whether sentinel node biopsy can be safely performed after the patient has completed neoadjuvant chemotherapy. American College of Surgeons Oncology Group (ACOSOG) Z7015 is an on going trial posing precisely this question.
A prospective study designed to determine the survival impact of micrometastases in the sentinel nodes of patients with invasive breast cancer included 790 patients who underwent sentinel node biopsy. The investigators found no significant difference in 8-year DFS or OS among patients with micrometastatic tumor deposits in sentinel nodes defined as being pN0(i+) or pN1mic when compared with patients having negative sentinel nodes. The true significance of these micrometastatic deposits is still unclear, but it may help to better define groups of patients who should receive maximum adjuvant medical or surgical therapy or who could avoid additional therapy.
Although helpful in prognosis and treatment planning, completion axillary dissection after a positive sentinel node biopsy may not be required for small tumors and in the absence of lymphovascular invasion. Factors affecting the rate of positive nonsentinel nodes and the necessity of axillary dissection following a positive sentinel lymph node resection were evaluated in NSABP B-32. Women with operable invasive breast cancer and clinically negative nodes were randomized to undergo sentinel node resection with immediate conventional axillary dissection (group 1) or without axillary dissection (group 2). Patients in group 2 who had positive sentinel nodes underwent axillary dissection. Data from 1,166 patients with positive sentinel nodes that were available for multivariate analysis (595 from group 1; 571 from group 2) indicated that a significantly higher percentage of patients in group 2 had positive nonsentinel nodes than did those in group 1 (41.5% vs 35.5%; P = .032). Clinical tumor size was a significant predictor for positive nonsentinel nodes P = .0010). Percentages of patients having positive nonsentinel nodes were significantly increased by the number of positive sentinel nodes, and lymphovascular invasion was a significant predictor for positive nonsentinel nodes. The percentages of patients with positive nonsentinel nodes significantly decreased with increases in the number of hot spots identified and the number of sentinel nodes removed.
The ACOSOG Z0011 trial is a randomized, multicenter trial designed to determine the effects of completion axillary node dissection on survival of patients with clinical T1 or T2 N0 M0 breast cancer who have one to two positive sentinel nodes. Patients were treated with lumpectomy with whole breast irradiation and adjuvant systemic therapy. Clinical and tumor characteristics were similar between 445 patients randomized to axillary lymph node dissection (ALND) and 446 randomized to sentinel lymph node dissection (SLND) alone. At a median follow-up of 6.3 years, locoregional recurrences were uncommon, occurring in 3.1% of ALND and 1.6% of SLND patients (P = .11). Only age (≤ 50 years) and higher Bloom-Richardson scores were associated with locoregional recurrence by multivariate analysis. Number of positive sentinel nodes, size of the sentinel node metastasis, and number of lymph nodes removed were not associated with locoregional recurrence. The omission of ALND in this group of patients did not result in inferior survival. The 5-year OS was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year DFS was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. A drawback of this study is its early closure and accrual of less than one-half of the targeted enrollment population; nonetheless, its findings could have important implications for clinical practice. It is important to note that the Z0011 trial did not include patients undergoing mastectomy, lumpectomy without radiotherapy, partial-breast irradiation, or neoadjuvant therapy. In those patients, ALND remains standard practice when SLND identifies a positive SLN.
Radiation therapy after breast-conserving surgery
For patients with stages I and II breast cancer, radiation therapy following lumpectomy remains an acceptable standard of care. Randomized trials and single-institution experiences have consistently demonstrated a significant reduction in local relapse rates for radiotherapy following breast-conserving surgery. Furthermore, small but significant differences in distant metastasis and DFS have been observed in randomized trials comparing lumpectomy alone with lumpectomy and radiation therapy for patients with invasive breast cancer.
An EBCTCG meta-analysis that included more than 7,300 women from 10 trials who were treated with breast-conserving surgery and randomized to receive observation or radiation showed a highly significant benefit for radiation therapy. There was a threefold reduction in local relapse with radiation, with a 5-year local relapse risk of 7% in those allocated to radiation as compared with 26% in the nonirradiated cohorts. The 15-year risk of death from breast cancer was 30.5% among those allocated to radiotherapy and 35.9% among those who were not.
Based on the results of a number of retrospective, single-institution experiences as well as several prospective, randomized clinical trials, breast-conserving surgery followed by radiation therapy to the intact breast is now considered standard treatment for the majority of patients with stage II invasive breast cancer.
Radiation dose and protocol
Radiation dose to the intact breast follows the same guidelines used in patients with stages 0 and I disease, described in Chapter 6.
Regional nodal irradiation
For patients who undergo ALND and are found to have negative lymph nodes, regional nodal irradiation is no longer employed routinely. For patients with positive lymph nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.
Regional nodal irradiation should be administered using careful treatment planning techniques to minimize the dose delivered to the underlying heart and lungs. Prophylactic nodal irradiation to doses of 4,500 to 5,000 cGy results in a high rate of regional nodal control and may improve DFS in subsets of patients.
Radiation therapy after mastectomy
Available data suggest that in patients with positive postmastectomy margins, chest wall fixation, primary tumors > 5 cm, or involvement of four or more lymph nodes at the time of mastectomy, the risk of locoregional failure remains significantly high enough for postmastectomy radiation therapy to be considered.
Several prospective, randomized trials have evaluated the role of postmastectomy radiotherapy in addition to chemotherapy. Most of these trials have been limited to patients with pathologic stage II disease or with T3 or T4 primary lesions. All of these trials have shown an improvement in locoregional control with the addition of adjuvant irradiation, and several recent trials have demonstrated a DFS and OS advantage in selected patients. Clinical practice guidelines developed by ASCO support routine use of postmastectomy radiation therapy for women with stage III or T3 disease or those who have four or more involved axillary lymph nodes.
The EBCTCG meta-analysis included 8,500 women who had primarily node-positive disease and were treated with mastectomy and axillary clearance. Patients were randomized to receive postmastectomy radiation vs no postmastectomy radiation. The 5-year risk of local relapse was significantly lower in the radiation group (6%) than among those randomized to no radiation (23%). Radiotherapy produced similar proportional reductions in local recurrence, regardless of patient age or tumor characteristics. The 15-year breast cancer mortality risk was also markedly lower for the radiation patients (54.7%), compared with those receiving no radiation (61.2%; P = .0002). The 5-year risk of local recurrence in patients with one to three positive nodes who received radiation therapy was 4%, compared with 16% in controls. In patients with four or more nodes, the 5-year risk of local recurrence was 12% in the radiation group and 26% in the control group.
Most ongoing trials evaluating dose-intensive chemotherapy, with or without bone marrow or stem-cell transplantation, routinely include postmastectomy radiation therapy to the chest wall and/or regional lymph nodes to minimize locoregional recurrence.
Current recommendations
There is no clearly defined role for postmastectomy irradiation in patients with small (T1 or T2) primary tumors and negative nodes. For patients with one to three positive nodes, postmastectomy radiation therapy may be considered to lower the rate of local relapse and improve DFS, although the benefit is less than that of patients with four or more positive nodes. However, based on the NCIC-CTG MA.20 trial (see sidebar), addition of regional nodal irradiation is node-positive patients is beneficial in terms of locoregional control and DFS.
For patients with four or more positive lymph nodes, with or without a large primary tumor, postmastectomy radiation therapy should be considered to lower the rate of local relapse and improve DFS. For patients who are younger, or who have T1 or T2 tumors, one to three positive nodes, poorly differentiated subtypes, or lymphovascular invasion, postmastectomy radiation therapy may have a benefit with respect to DFS and OS. However, controversies and uncertainties regarding this issue remain, and individualized decision-making based on the patient's overall condition and specific risk factors is reasonable.
Minimizing pulmonary and cardiac toxicities
Early trials employing postmastectomy radiation therapy showed that the modest improvement in breast cancer mortality was offset by an excess risk of cardiovascular deaths, presumably due to the radiation treatment techniques used, that resulted in delivery of relatively high radiation doses to the heart. Recent trials employing more modern radiation therapy techniques have not demonstrated an excess of cardiac morbidity and, hence, have shown a slight improvement in OS due to a decrease in breast cancer deaths. Thus, in any patient being considered for postmastectomy radiation therapy, efforts should be made to treat the areas at risk while minimizing the dose to the underlying heart and lungs.
Radiation dose and protocol
The available literature suggests that doses of 4,500 to 5,000 cGy should be sufficient to control subclinical microscopic disease in the postmastectomy setting. Electron-beam boosts to areas of positive margins and/or gross residual disease reaching doses ~6,000 cGy and delivered to sites of gross disease, may be considered.
In patients who have undergone axillary lymph node dissection, even in those with multiple positive nodes, treatment of the axillae does not appear to be necessary in the absence of gross residual disease. Treatment of the supraclavicular and/or internal mammary chain should employ techniques and field arrangements that minimize overlap between adjacent fields and decrease the dose to underlying cardiac and pulmonary structures.
