TreatmentMedical Therapy
[b]TREATMENT OF INVASIVE BREAST CANCER Surgery is considered primary treatment for breast cancer, as many early stage patients are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes for providing necessary prognostic information. Several different types of operations are available for the treatment of breast cancer.
LumpectomyLumpectomy is defined as complete surgical resection of a primary tumor with a goal of achieving widely negative margins (ideally a 1 cm margin around the lesion). Other terms synonymous for lumpectomy include partial mastectomy, segmental mastectomy, and tylectomy. A quadrantectomy is a type of lumpectomy that is defined as complete removal of the entire affected breast quadrant. Lumpectomies may be performed with palpation guidance or with image guidance.
Variations on the theme of image guidance include 1) wire localization of nonpalpable image detected lesions via ultrasound, stereotactic, or MRI guidance; 2) hematoma ultrasound guidance by the operating surgeon; or 3) radioactive seed localization. Patients who undergo a lumpectomy for calcifications should always be advised to have a
mammogram following their lumpectomy to establish definitively that all calcifications were successfully removed. This mammogram should occur prior to the administration of any radiation therapy.
In general, 2 mm or greater is a reasonable definition of a clear margin. Patients with margin widths less than 2 mm are often advised to return to the operating room for re-excision to improve local recurrence rates. The rate of surgical re-excision after lumpectomy ranges from 20-60% in the published literature. Contraindications to lumpectomy include multicentric disease, adverse tumor-to-breast ratio, large primary tumor, repeated positive margins, and inability to undergo radiation therapy for invasive disease.
The NSABP-B6 was a prospective trial in which 2,163 breast cancer patients were randomized to modified radical mastectomy (the standard of care at that time), lumpectomy, and whole breast radiation therapy, or lumpectomy without radiation. All patients underwent axillary lymph node dissection. At 20-year follow-up, no significant difference was seen in overall survival, disease-free survival, or distant disease-free survival among the 3 treatment groups. However, the NSABP-B6 did find a significant difference in the rate of local recurrence between the 3 treatment arms. Patients in the lumpectomy alone without radiation therapy group had a significantly higher local recurrence rate than patients undergoing lumpectomy plus radiation therapy (39.2% vs 14.3%, respectively). Patients who underwent modified radical mastectomy had a 10.2% risk of chest wall recurrence. This landmark study established breast-conserving surgery with radiation therapy to be equivalent to modified radical mastectomy.
Oncoplastic surgery is a rapidly advancing field that uses local tissue rearrangement to reconstruct a partial mastectomy defect. Options include fasciocutaneous local tissue advancement flaps, breast parenchymal local flaps or latissimus dorsi myocutaneous flaps. The selection of aesthetically appropriate incisions also impacts the overall cosmetic result after lumpectomy. Silverstein et al reported a variety of options for oncoplastic approaches to breast conservation.
[url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]12 [/url]Kronowitz et al reported that partial mastectomy reconstruction produces superior aesthetic results and lower complication rates when performed prior to radiation therapy.
[url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]13 [/url]MastectomyA total mastectomy is defined as complete removal of all breast tissue to the clavicle superiorly, the sternum medially, the inframammary crease inferiorly, and the anterior axillary line laterally with en bloc resection of the fascia of the pectoralis major. The nipple-areolar complex (NAC) is resected along with a skin paddle to achieve a flat chest wall closure when performing a total mastectomy. A total mastectomy does not refer to removal of any axillary nodes but may be performed in conjunction with a sentinel or axillary node dissection. A modified radical mastectomy is defined as a total mastectomy with axillary lymph node dissection. In contrast, a radical mastectomy is defined as a total mastectomy plus en bloc resection of the pectoralis major and axillary lymph node dissection. Extended radical mastectomy refers to a radical mastectomy with resection of the internal mammary lymph nodes.
Two modern variations of the total mastectomy include the skin-sparing total mastectomy (SSM) and the nipple-sparing total mastectomy (NSM). These operations refer to surgical approaches designed for patients who elect to have immediate reconstruction. Both SSM and NSM are minimally invasive surgical approaches that are technically more difficult and, thus, more time-consuming than traditional mastectomy. SSM and NSM result in preservation of the patient's skin envelope and maintain the position of the infra-mammary fold. However, both SSM and NSM are intended to be complete total mastectomies with the same extent of resection as a traditional total mastectomy.
These operations may not be appropriate for cancers near the skin or nipple. Additionally, SSM or NSM are not appropriate for locally advanced or inflammatory breast cancer. Multiple retrospective single institution studies have reported excellent results with SSM and NSM. No randomized clinical trials compare survival results for SSM, NSM, and total mastectomy. However, most surgical oncologists accept that as long as SSM and total mastectomy are carefully performed and patients are carefully selected, these are reasonable oncologic choices for prophylactic mastectomy and for the treatment of selected early stage breast cancers. Complications after total mastectomy include risk of local recurrence (5-10%), wound infection, seroma, mastectomy skin flap necrosis, hematoma, chronic pain, incisional dog ears, lymphedema, and fibrosis.
Breast ReconstructionBreast reconstruction for mastectomy may be performed in the immediate or the delayed setting. Most patients undergoing mastectomies for prophylaxis or early stage breast cancer are candidates for reconstruction. Immediate reconstruction, when feasible, generally provides superior cosmetic results because a SSM or NSM may be offered to selected patients, resulting in preservation of the native skin envelope and infra-mammary crease. However, when postmastectomy radiation is likely or a reconstructive surgeon is unavailable, delayed reconstruction following all adjuvant therapies may be recommended.
Reconstruction may be performed via implant-based methods, autologous tissue-based (termed flaps) method, or a combination of the two. Implant-based approaches include tissue expanders and saline or silicone implants. Tissue-based approaches include the
transverse rectus abdominus myocutaneous flap (TRAM),
latissimus dorsi flap, and the
deep inferior epigastric perforator flap (DIEP).
Although federal law protects the rights of patients to have reconstruction by mandating that insurance companies support reconstruction, most patients undergoing mastectomy do not undergo breast reconstruction. Reasons for this include provider biases, patient preferences and lack of available specialty services. Patients and physicians should have realistic expectations for breast reconstruction. Although excellent results may be achieved, often multiple operations are required for revisions, symmetry procedures, and
nipple reconstruction. Complications related to reconstruction include infected prosthetic implant, implant rupture, capsular contracture, flap necrosis, flap loss, fat necrosis, asymmetry, and scarring.
Management of the Contralateral BreastPatients diagnosed with breast cancer that are not known carriers of a deleterious
BRCA mutation are predicted to have a 0.7% annual risk of contralateral breast cancer. Patients who are known
BRCA mutation carriers have a 3% annual risk of a contralateral breast cancer. The decision for contralateral prophylactic mastectomy (CPM) is a personal decision for the patient and impacted by cancer stage, desire for symmetry, comorbidities, histologic risk factors, family history, potential difficult surveillance, and degree of risk aversion. Patients with locally advanced breast cancers should be discouraged from a contralateral prophylactic mastectomy, as potential surgical complications could compromise their oncologic treatments. Mastopexy and reduction mammoplasty for the contralateral breast are potential alternatives to contralateral prophylactic mastectomy as symmetry procedures.
Sentinel Lymph Node DissectionSentinel lymph node (SLN) dissection is a minimally invasive procedure designed to stage the axilla in breast cancer patients who have clinically negative nodes. Sentinel nodes are the first node or first group of nodes that drain from the breast to the axilla. Lymphatic mapping may be performed with radioisotope (technetium
99 sulfur colloid) alone or radioisotope plus a patent blue dye (Lymphazurin or methylene blue). With sentinel lymph node dissection, typically 1-3 lymph nodes are removed and tested for nodal metastasis with hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) with an anticytokeratin cocktail.
Sentinel lymph nodes may be checked intraoperatively by imprint touch preparation, frozen section, or RT-PCR. Intraoperative evaluation allows for immediate axillary lymph node dissection to be performed if the sentinel lymph node is unequivocally positive for nodal metastasis. The American Society of Clinical Oncology (ASCO) Guideline Recommendations for Sentinel Lymph Node Biopsy in early stage breast cancer recommends axillary lymph node dissection after detection of a positive sentinel lymph node. However, isolated tumor cells detected by specialized techniques such as immunohistochemistry and RT-PCR remain of uncertain significance. When sentinel lymph node mapping is not successful, complete axillary lymph node dissection is recommended. Absolute contraindications for sentinel lymph node dissection include clinically suspicious axillary nodes, which should be evaluated by ultrasound-guided (FNA), and biopsy-proven node-positive disease.
A recent study evaluated the accuracy of 4 nomograms in patients with sentinal lymph node-positive breast cancer. The authors found the Memorial Sloan-Kettering Cancer Center nomogram to be more predictive than the other nomograms.
[url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]14 [/url]Axillary Lymph Node Dissection Axillary lymph node dissection for breast cancer is a complete en bloc removal of the level I and II lymph nodes. level I nodes are lateral to the pectoralis minor, level II are beneath the pectoralis minor, and level III are medial to the pectoralis minor. The level III nodes are not removed surgically unless there is suspicious or palpable adenopathy present. Skip metastasis to the axillary apex of level III without lower axillary involvement is very rare. Axillary lymph node dissection removes all nodal tissue defined by the borders of the axillary vein superiorly, the latissimus dorsi muscle laterally, the medial border of the pectoralis minor muscle medially, and the subscapularis muscle posteriorly.
Care is taken to preserve the long thoracic and thoracodorsal nerves along their course through the axilla. Injury to the long thoracic nerve results in a winged scapula, while injury to the thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90 degrees. The median and lateral pectoral nerves may also be injured during axillary lymph node dissection. The antecostobrachial nerves run directly through the resection specimen and are typically sacrificed, resulting in a predictable pattern of cutaneous numbness in the inner arm region for most patients after this procedure.
Axillary lymph node dissection was previously considered to be the standard of care for all patients diagnosed with invasive breast cancer. However, axillary lymph node dissection carries a high rate of surgical morbidity (lymphedema rates of about 25%, shoulder dysfunction, wound infection, seroma, nerve damage, numbness, chronic pain, and, rarely, brachial plexus injury). Lymphedema is the abnormal accumulation of protein-rich edema fluid in the upper extremity following axillary lymph node dissection. This occurs because a portion of the lymphatics that drain from the breast to the axilla, and those that drain from the arm are shared within the axilla. Early detection of lymphedema is paramount as lymphedema is potentially reversible when treated in its earliest stage. Compression garments and physical therapy with lymphatic massage are still the backbone for the treatment of lymphedema.
Patients who have an axillary lymph node dissection should be cautioned about the risk of lymphedema and should take precautions to avoid breaks in the skin or infections in the affected extremity. Lymphedema may develop at any time after lymph node dissection but most commonly occurs within the first 2 years of the surgery. Risk factors for developing lymphedema include obesity and radiation therapy. Although patients are commonly advised to avoid taking blood pressures or inserting IV's in the affected arm after axillary lymph node dissection, no level I or level II evidence supports that recommendation.
Breast-Conserving Radiation Therapy (RT)The purpose of radiation therapy following breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. Based on results from several randomized controlled studies, radiation to the intact breast is considered standard of care even in the lowest risk disease with the most favorable prognostic features. There are two general approaches used to deliver radiation therapy: conventional external beam radiotherapy (EBRT) and partial breast irradiation (PBI). Whole breast radiotherapy (WBRT) is comprised of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed.
Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting 6 mo or longer following treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%).
Partial breast irradiation is employed in early stage breast cancer following breast-conserving therapy as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Several techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]). Treatment is typically for 5 days, twice daily. These techniques have shown low local recurrence rates comparable to EBRT in several nonrandomized studies. The American Society of Breast Surgeons recommends the following selection criteria when considering patients for treatment with accelerated partial breast irradiation.
- Age 45 years and older
- Invasive ductal carcinoma or DCIS
- Total tumor size (invasive and DCIS) 3 cm or smaller
- Negative microscopic surgical margins of excision
- Axillary lymph node/sentinel lymph node negative
Potential complications of partial breast irradiation are catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence.
Postmastectomy Radiation TherapyClinical practice guidelines developed by the American Society of Clinical Oncology along with several prospective randomized clinical trials recommend postmastectomy radiation therapy be performed using the following criteria.
- Positive postmastectomy margins
- Primary tumors larger than 5 cm
- Involvement of 4 or more lymph nodes
Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 4500-5000 cGy to the axillary and supraclavicular regions. For patients who undergo axillary lymph node dissection and are found to have no lymph node involvement, axillary radiation therapy is not recommended. Meta-analyses have shown postmastectomy combined with regional nodal radiation therapy significantly decrease the rate of local relapse and breast cancer mortality. Currently, the benefit of radiation therapy for women with 1-3 positive axillary lymph nodes is uncertain and studies are ongoing.
ADJUVANT THERAPY FOR BREAST CANCERThe breast cancer mortality rate fell 24% between the years 1990 and 2000 for women aged 30-79 years. This improvement in breast cancer mortality is thought to have resulted from both improvements in early detection through screening and from advances in adjuvant treatment. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of that reduction. Adjuvant treatment of breast cancer is designed to treat micro-metastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but have not yet established an identifiable metastasis. Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality.
Adjuvant ChemotherapyCombination chemotherapy regimens are standardly recommended in the adjuvant setting. The most commonly used regimens are shown below.
Table 4. Adjuvant Chemotherapy Regimens for Breast Cancer
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Table Regimen | Dose and Schedule | Frequency | Cycles |
TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004) |
Taxotere (Docetaxel) | 75 mg/m² IV day 1 | Every 21 days | 6 |
Adriamycin | 50 mg/m² IV day 1 |
Cyclophosphamide | 500 mg/m² IV day 1 |
AC => T (conventional regimen) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]15 [/url] |
Adriamycin | 60 mg/m² IV day 1 | Every 21 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
Followed by |
Paclitaxel | 175 mg/m² IV day 1 | Every 21 days | 4 |
Dose-Dense |
Adriamycin | 60 mg/m² IV day 1 | Every 14 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
Followed by |
Paclitaxel | 175 mg/m² IV day 1 | Every 14 days | 4 |
Metronomic regimen |
Adriamycin | 20 mg/m² IV day 1 | Every week | 12 |
Cyclophosphamide | 50 mg/m² PO | Every day |
Followed by |
Paclitaxel | 80 mg/m² IV day 1 | Every week | 12 |
AC => T + H (Trastuzumab) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]16 [/url] |
4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then give 6 mg/kg IV every 3 weeks for 40 weeks; NOTE Trastuzumab to be added to a weekly Paclitaxel regimen in HER2-positive breast cancer patients |
FEC-100 [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]17 [/url] |
5-FU | 500 mg/m² IV day 1 | Every 21 days | 6 |
Epirubicin | 100 mg/m² IV day 1 |
Cyclophosphamide | 500 mg/m² IV day 1 |
FAC [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]18, 19 [/url] |
5-FU | 600 mg/m² IV day 1 | Every 21 days | 4 |
Adriamycin | 60 mg/m² IV day 1 |
Cyclophosphamide | 600 mg/m² IV day 1 |
5-FU | 500 mg/m² IV days 1 and 8 | Every 28 days | 6 |
Adriamycin | 30 mg/m² IV days 1 and 8 |
Cyclophosphamide | 100 mg/m² PO days 1-14 |
CMF (Bonadonna regimen) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]20 [/url] |
Cyclophosphamide | 100 mg/m² PO days 1-14 | Every 28 days | 6 |
Methotrexate | 40 mg/m² IV days 1 and 8 |
5-FU | 600 mg/m² IV days 1 and 8 |
Metronomic regimen [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]21 [/url] |
Cyclophosphamide | 50 mg/m² PO days 1-7 | Weekly | 24 |
Methotrexate | 15 mg/m² IV |
5-FU | 300 mg/m² IV |
TC [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]22 [/url] |
Taxotere | 75 mg/m² IV day 1 | Every 21 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
TCH [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]23 [/url] |
Taxotere (Docetaxel) | 75 mg/m² IV day 1 | Every 21 days | 6 |
Carboplatin | AUC 6 IV day 1 |
Trastuzumab | 4 mg/kg loading dose IV followed by 2 mg/kg/wk X 18 then q3wk X 12 |
Regimen | Dose and Schedule | Frequency | Cycles |
TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004) |
Taxotere (Docetaxel) | 75 mg/m² IV day 1 | Every 21 days | 6 |
Adriamycin | 50 mg/m² IV day 1 |
Cyclophosphamide | 500 mg/m² IV day 1 |
AC => T (conventional regimen) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]15 [/url] |
Adriamycin | 60 mg/m² IV day 1 | Every 21 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
Followed by |
Paclitaxel | 175 mg/m² IV day 1 | Every 21 days | 4 |
Dose-Dense |
Adriamycin | 60 mg/m² IV day 1 | Every 14 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
Followed by |
Paclitaxel | 175 mg/m² IV day 1 | Every 14 days | 4 |
Metronomic regimen |
Adriamycin | 20 mg/m² IV day 1 | Every week | 12 |
Cyclophosphamide | 50 mg/m² PO | Every day |
Followed by |
Paclitaxel | 80 mg/m² IV day 1 | Every week | 12 |
AC => T + H (Trastuzumab) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]16 [/url] |
4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then give 6 mg/kg IV every 3 weeks for 40 weeks; NOTE Trastuzumab to be added to a weekly Paclitaxel regimen in HER2-positive breast cancer patients |
FEC-100 [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]17 [/url] |
5-FU | 500 mg/m² IV day 1 | Every 21 days | 6 |
Epirubicin | 100 mg/m² IV day 1 |
Cyclophosphamide | 500 mg/m² IV day 1 |
FAC [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]18, 19 [/url] |
5-FU | 600 mg/m² IV day 1 | Every 21 days | 4 |
Adriamycin | 60 mg/m² IV day 1 |
Cyclophosphamide | 600 mg/m² IV day 1 |
5-FU | 500 mg/m² IV days 1 and 8 | Every 28 days | 6 |
Adriamycin | 30 mg/m² IV days 1 and 8 |
Cyclophosphamide | 100 mg/m² PO days 1-14 |
CMF (Bonadonna regimen) [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]20 [/url] |
Cyclophosphamide | 100 mg/m² PO days 1-14 | Every 28 days | 6 |
Methotrexate | 40 mg/m² IV days 1 and 8 |
5-FU | 600 mg/m² IV days 1 and 8 |
Metronomic regimen [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]21 [/url] |
Cyclophosphamide | 50 mg/m² PO days 1-7 | Weekly | 24 |
Methotrexate | 15 mg/m² IV |
5-FU | 300 mg/m² IV |
TC [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]22 [/url] |
Taxotere | 75 mg/m² IV day 1 | Every 21 days | 4 |
Cyclophosphamide | 600 mg/m² IV day 1 |
TCH [url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]23 [/url] |
Taxotere (Docetaxel) | 75 mg/m² IV day 1 | Every 21 days | 6 |
Carboplatin | AUC 6 IV day 1 |
Trastuzumab | 4 mg/kg loading dose IV followed by 2 mg/kg/wk X 18 then q3wk X 12 |
A comparison of major Cancer and Leukemia Group B (CALGB) chemotherapy clinical trials from the last few decades including C8541 compared various doses of CAF, 9344 (which added paclitaxel to standard dose AC) and 9741 (which compared q3wk dosing to q2wk dosing in estrogen receptor-positive and -negative patients). In all cases, chemotherapy was enormously better in terms of improving disease-free and overall survival in patients with estrogen receptor-negative disease.
When the inferior arm of C8541 was compared to the dose dense arm of C9741, a remarkable 63% (CI 43-76%) improvement in disease-free and 59% (CI 34-74%) improvement in overall survival was observed in patients with estrogen receptor-negative disease compared to 32% (CI -7-56%) improvement in disease-free and 18% (CI -41-53%) improvement in overall survival in patients with estrogen receptor-positive disease. Overall, the advantages of chemotherapy, particularly in estrogen receptor-negative disease, were observed across all 3 trials irrespective of the chemotherapy regimen used.
Role of taxanesTaxanes are amongst the most active and commonly used chemotherapeutic agents used to treat early stage breast cancer. However, questions have lingered as to whether taxanes are the most effective chemotherapeutic agent to use in this setting and if so, what is the best dosing schedule. A recent Cochrane meta-analysis including 12 studies and more than 21,000 patients evaluated the role of taxanes in the adjuvant treatment of operable breast cancer (stage I-III). The results showed a statistically significant overall survival (HR 0.81, p< 0.00001) and disease-free survival (HR 0.81, p< 0.00001) for the taxane-containing regimens compared with the nontaxane regimens. This meta-analysis did not identify any subgroups of patients within the evaluated studies in which a taxane-containing regimen would be more efficacious.
The CALGB 9344 was one of the largest trials evaluating taxanes in the adjuvant setting for early stage breast cancer, with more than 3,000 women with node-positive breast cancer. This study demonstrated a survival benefit for the sequential use of paclitaxel following AC chemotherapy. In a recent retrospective analysis of CALGB 9344 testing for HER2 status using 1,322 original participant tumor blocks, HER2 positivity irrespective of estrogen receptor status predicted a significant benefit from paclitaxel in terms of reduced disease recurrence (HR 0.59, p= 0.01). Patients with estrogen receptor-positive, HER2-, node-positive breast cancer did not seem to benefit from the addition of a taxane.
However, the National Cancer Institute of Canada MA.21 and UK TACT trials, which used taxane and nontaxane-based chemotherapeutic regimens in early stage breast cancer patients, did not demonstrate a benefit in using taxanes. Although the precise role of adjuvant taxane therapy remains controversial, the optimal scheduling of taxane administration has been determined.
The Eastern Coast Oncology Group (ECOG) 1199 randomized 4,950 women with lymph node-positive or high-risk lymph node-negative early stage breast cancer to 4 cycles of AC followed by 4 different taxane regimens: 1) paclitaxel at 175 mg/m
2 q3wk; 2) paclitaxel at 80 mg/m
2 weekly; 3) docetaxel at 100 mg/m
2 q3wk; and 4) docetaxel 35 mg/m
2 weekly. After a 64-month median follow-up, paclitaxel weekly and docetaxel every 3 weeks were superior to the other two regimens in terms of disease-free survival.
Similarly, the TAX 311 trial performed by the US Oncology group showed that every 3 week docetaxel at 100 mg/m
2 improved time to progression (TTP) and overall survival when compared to paclitaxel at 175 mg/m
2 given every 3 weeks. Thus, taxane-based regimens still have use in the treatment of early stage breast cancer and should be considered in treating women especially with HER2+ disease using either the weekly paclitaxel or every-3-week docetaxel dosing schedules.
Role of anthracyclinesAnthracycline-containing adjuvant chemotherapy regimens have been used in the treatment of early stage breast cancer for decades, although concerns regarding anthracycline-associated cardiotoxicity or leukemogenic potential remain. In the 2000 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview, anthracycline-based regimens were associated with an annual risk of cardiac mortality of 0.08% per year as compared with 0.06% per year in patients treated with nonanthracycline-based regimens. However, the question of long-term cardiac safety remains, particularly for older women with early stage breast cancer.
The US Oncology 9735 trial randomized 1,016 women with operable breast cancer (stages I-III) to 4 cycles of TC versus 4 cycles of standard dose AC. After a median of 7 years follow-up, both disease-free survival (81% vs 75%; HR, 0.74; p= 0.033) and overall survival (87% vs 82%; HR 0.69; p= 0.032) were superior in the TC arm. Grade 5 cardiotoxicity (resulting in death) was seen in 6 patients treated with AC (4 from myocardial infarction; 2 from congestive heart failure) versus 2 (myocardial infarction) in the TC group. This trial established TC as a viable option for treating women with early stage breast cancer, especially those at high risk of cardiotoxicity or requiring only 12 weeks of therapy.
Additionally, a recent meta-analysis of 8 trials comprised of 6,564 women with early stage breast cancer to anthracycline versus nonanthracycline-based regimens suggested a benefit with anthracycline administration only in patients with HER2+ disease. Biologically, anthracyclines inhibit topoisomerase IIa, whose gene (
TOP2A) lies adjacent to the
HER2 gene on chromosome 17 and is coamplified in approximately 35% of
HER2 -overexpressing breast cancers.
The original trials demonstrating superiority of anthracycline-based regimens over CMF did not include
TOP2A or
HER2 testing. The BCIRG 006 trial, which randomized women with HER2+ disease to AC followed by T, AC followed by TH, or TCH, did test for
TOP2A and
HER2 coamplification.
[url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]23 [/url]This group comprised only approximately 8% of the total breast cancer population and may be the only subgroup to benefit from anthracycline administration. The role of
TOP2A as a predictive marker of response to anthracyclines needs further validation. Until then, patients should not be deprived anthracycline-based adjuvant chemotherapy if their risk assessment so determines it.
A recent study compared the effectiveness of oral uracil-tegafur (UFT) with that of CMF given as a postoperative adjuvant to women with node-negative, high-risk breast cancer. Risk-free survival and overall survival were similar in the 2 groups, but the quality of life scores were higher for patients given UFT than those given CMF. The study concluded that for women with node-negative, high-risk breast cancer, UFT is a promising alternative to CMF.
[url=https://smgroup.yoo7.com/javascript:showcontent('active','references');]24 [/url]An anthracycline followed by or concurrent with a taxane is the most optimal therapy for "triple-negative" breast cancer patients with no medical contraindications. However, it remains unclear what the optimal combination chemotherapy regimen is for ER+, HER2– tumors. Currently, CMF, TC, or an anthracycline-based regimen may all be reasonable options.
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