Primary Therapy
        Local-regional treatment
        Breast reconstruction
Adjuvant Radiation Therapy
        Post-breast conservation surgery
        Postmastectomy
        Adjuvant radiation therapy late toxic effects
Adjuvant Systemic Therapy
        Hormone therapy
        Chemotherapy
        Monoclonal antibodies
Timing of Primary and Adjuvant Therapy
        Postoperative adjuvant chemotherapy
        Preoperative adjuvant chemotherapy
        Adjuvant radiation and chemotherapy
        Timing of surgery
        Chemotherapy risks
        Chemotherapy and tamoxifen risks
Treatment Options
        Primary therapy
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage I, II, IIIA, and operable IIIC breast cancer often requires a multimodality approach to treatment. Irrespective of the eventual procedure selected, the diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures. In many cases, the diagnosis of breast carcinoma using core needle biopsy or fine-needle aspiration cytology may be sufficient to confirm malignancy. After the presence of a malignancy is confirmed and histology is determined, treatment options should be discussed with the patient before a therapeutic procedure is selected. The surgeon may proceed with a definitive procedure that may include biopsy, frozen section confirmation of carcinoma, and the surgical procedure elected by the patient. Estrogen-receptor (ER) and progesterone-receptor (PR) protein status should be determined for the primary tumor.[1] Additional pathologic characteristics, including grade, proliferative activity, and human epidermal growth factor receptor 2 (HER2/neu) status, may also be of value.[2-5]

Options for surgical management of the primary tumor include breast-conserving surgery plus radiation therapy, mastectomy plus reconstruction, and mastectomy alone. Surgical staging of the axilla should also be performed. Survival is equivalent with any of these options as documented in randomized prospective trials (including the European Organization for Research and Treatment of Cancer's trial [EORTC-10801]).[6-13] Selection of a local therapeutic approach depends on the location and size of the lesion, analysis of the mammogram, breast size, and the patient’s attitude toward preserving the breast. The presence of multifocal disease in the breast or a history of collagen vascular disease are relative contraindications to breast-conserving therapy.[14]

All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[15] The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary is debatable.[16-18] Retrospective studies have shown that certain tumor characteristics, such as large tumors (T2 lesions), positive axillary nodes, tumors with an extensive intraductal component,[19] palpable tumors, and lobular histology correlate with a greater likelihood of finding persistent tumor on re-excision. Patients whose tumors have these characteristics may benefit from a more generous initial excision to avoid the need for a re-excision.[20,21]

Radiation therapy (as part of breast-conserving local therapy) consists of postoperative external-beam radiation therapy (EBRT) to the entire breast with doses of 45 Gy to 50 Gy, in 1.8 Gy to 2.0 Gy daily fractions over a 5-week period. Shorter hypofractionation schemes achieve comparable results.[22-24] A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[25][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001), respectively.[26][Level of evidence: 1iiDiii] If a boost is used, it can be delivered either by EBRT, generally with electrons, or by using an interstitial radioactive implant.[27]

The age of the patient should not be a determining factor in the selection of breast-conserving treatment versus mastectomy. A study has shown that treatment with lumpectomy and radiation therapy in women 65 years and older produces survival and freedom-from-recurrence rates similar to those of women younger than 65 years.[28] Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is not certain. Retrospective studies indicate no difference in local failure rates or overall survival (OS) when women with strong family histories are compared with similarly treated women without such histories.[29,30][Level of evidence: 3iiiDii] The group with a positive family history, however, does appear more likely to develop contralateral breast cancer within 5 years.[29] This risk for contralateral tumors may be even greater in women who are positive for BRCA1 and BRCA2 mutations.[31][Level of evidence: 3iiiDii] Because of the available evidence indicating no difference in outcome, women with strong family histories should be considered candidates for breast-conserving treatment. For women with germ-line mutations in BRCA1 and BRCA2, further study of breast-conserving treatment is needed.

Breast-conserving surgery alone without radiation therapy has been compared with breast-conserving surgery followed by radiation therapy in six prospective randomized trials (including the National Surgical Adjuvant Breast and Bowel Project's trial [NSABP-B-06] and the Cancer and Leukemia Group B's trial [CLB-9343]) .[6,32-36] In two of these trials, all patients also received adjuvant tamoxifen.[35,36] Every trial demonstrated a lower in-breast recurrence rate with radiation therapy, and this effect was present in all patient subgroups. In some groups, for example, women with receptor-positive small tumors [35] and those older than 70 years,[37] the absolute reduction in the rate of recurrence was small (<5%). The limited impact of radiation therapy in this group of women was also reported in a confirmatory observational study looking at in-breast control rates using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.[38] The impact of radiation therapy on local control was additionally clarified by showing that healthy women aged 70 to 79 years were most likely to benefit from radiation therapy (number needed to treat [NNT] to prevent one event = 21–22 patients) when compared to women aged 80 years or older or to those who have comorbidities (NNT = 61–125 patients).[38] The administration of radiation therapy may be associated with short-term morbidity, inconvenience, and potential long-term complications.[37]

The axillary lymph nodes should be staged to aid in determining prognosis and therapy. Although most authorities agree that an axillary node dissection in the presence of clinically negative nodes is a necessary staging procedure, controversy exists as to the extent of the procedure because of long-term morbidity (e.g., arm discomfort and swelling) associated with it. Data suggest that the level of lymph node involvement (stage I vs. stage II vs. stage III) does not add independent prognostic information to the total number of positive axillary nodes.[39] The standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., 6–10 at a minimum), while reducing morbidity from the procedure. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[39,40] In another series, the incidence of axillary node relapse in patients with T1a tumors treated without axillary node dissection was 2%.[41][Level of evidence: 3iiiA] Because the axillary node status remains the most important predictor of outcome in breast cancer patients, insufficient evidence is available to recommend that lymph node staging can be omitted in most patients with invasive breast cancer.

To decrease the morbidity of axillary lymphadenectomy while maintaining accurate staging, several investigators have studied lymphatic mapping and sentinel lymph node (SLN) biopsy in women with invasive breast cancer.[42-45] The SLN is defined as the first node in the lymphatic basin that receives primary lymphatic flow. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[46,47] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection.[42-45] The results of a randomized trial of 532 patients with T1 carcinomas undergoing either SLN biopsy plus complete axillary dissection or SLN biopsy alone showed, after a median follow-up of 78 months, no difference in 5-year DFS (92.9% in the SLN biopsy without routine axillary dissection group vs. 88.9% in patients having axillary dissection irrespective of SLN findings, P = .1).[48][Level of evidence: 1iiDii]

The reported false-negative rates (i.e., the number of patients with negative SLN biopsy divided by the number of patients with positive axillary nodes at the time of axillary node dissection) of SLN biopsy range from 0% to 15% with an average of 8.8%.[49] The success rate varies with the surgeon’s experience and with the primary tumor characteristics. In general, studies have restricted the use of SLN biopsy to women with T1 and T2 disease, without evidence of multifocal involvement or clinically positive lymph nodes. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy. In a randomized trial of 1,031 women that compared SLN biopsy followed by axillary dissection when the SLN was positive with axillary dissection in all patients, quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. axillary dissection groups, respectively; P = .001).[50][Level of evidence 1iiC] Arm function was also better in the SLN group. Ongoing randomized trials will help to determine if both procedures yield comparable survival rates and if a therapeutic benefit comes from complete axillary lymphadenectomy in patients with SLN metastases. Although there are no data on its impact on survival, the SLN biopsy with complete dissection after a positive result is a commonly used alternative to axillary lymph node dissection.[49,51] Prospective trials will be available soon to address the question of survival.

For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).[52-55] Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the FDA's Web site for more information on breast implants.) Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[56]

Radiation therapy is regularly employed after breast-conservation surgery. Radiation therapy also can be indicated for postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[57]

For women who are treated with breast-conserving surgery, the most common site of local recurrence is the conserved breast itself. The risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node-negative women. Thus, whole breast radiation therapy after breast conserving surgery is recommended.[58]

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, in the 2005 Early Breast Cancer Trialists' Collaborative Group's (EBCTCG) update, when all relevant trials were combined, 15-year breast cancer mortality was reduced from 35.9% to 30.5% in women receiving radiation therapy (absolute difference of 5.4%; 95% CI, 2.1%–8.7%; breast cancer death rate ratio 0.83; 95% CI, 0.75–0.91; P = .002). There was a similar effect on all-cause mortality.[57]

Although adjuvant whole-breast radiation is standard treatment, no trials have addressed the role of regional lymph node radiation therapy in this setting. The National Cancer Institute of Canada's study (CAN-NCIC-MA20) has closed, but until results are reported, decisions regarding the use of such therapy must rely on extrapolations from the postmastectomy setting and on knowledge of the local-regional recurrence rates following conservation therapy with axillary lymph node dissection for a given lesion.

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure following mastectomy. Radiation therapy can decrease local-regional recurrence in this group, even among those patients who receive adjuvant chemotherapy.[59] Patients at highest risk for local recurrence include those with four or more positive axillary nodes, grossly evident extracapsular nodal extension, large primary tumors, and very close or positive deep margins of resection of the primary tumor.[60-62]

Patients with one to three involved nodes without any of the previously noted risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting has been unclear. The 2005 EBCTCG update indicates, however, that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[57][Level of evidence: 1iiA] For women with node-positive disease postmastectomy and axillary clearance, radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain = 17%; 95% CI, 15.2%–18.8%). This translated into a significant (P = .002) reduction in breast cancer mortality, 54.7% versus 60.1% with an absolute gain of 5.4% (95% CI, 2.9%–7.9%). In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8.0%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In contrast, for women with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality in these patients (absolute gain = 1.0%; P > .1 95%; CI, -0.8%–2.8%). Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors, when axillary nodes were negative, the risk of isolated loco-regional recurrence was low enough (7.1%) that routine loco-regional radiation therapy was not warranted.[63]

Late toxic effects of radiation therapy, though uncommon, can include radiation pneumonitis, cardiac events, arm edema, brachial plexopathy, and the risk of second malignancies. Such toxic effects can be minimized with current radiation delivery techniques and with careful delineation of the target volume.

In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.[64] The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[64][Level of evidence: 3iii]

Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, had an association with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.[59,65-67] This was probably caused by the radiation received by the left myocardium.

Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left breast radiation was used. Cardiac mortality decreased accordingly.[68,69] At this time, cardiac mortality was also decreasing in the United States.

An analysis of SEER data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate due to ischemic heart disease in women who received left chest wall or breast radiation was found.[70,71][Level of evidence: 3iB]

Lymphedema consequent to cancer management remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. Axillary radiation therapy can increase the risk of arm edema in patients who received axillary dissection from 2% to 10% with dissection alone to 13% to 18% with adjuvant radiation therapy.[72-74] (Refer to the PDQ summary on Lymphedema for more information.)

Radiation injury to the brachial plexus following adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were followed for 5.5 years to assess the rate of brachial plexus injury.[75] The diagnosis of such injury was made clinically with computerized tomography to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0% compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

The rate of second malignancies following adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with the long-term risk at 0.2% at 10 years.[76] One report suggests an increase in contralateral breast cancer for women younger than 45 years who have received chest wall radiation therapy after mastectomy.[77] No increased risk of contralateral breast cancer occurs for women 45 years and older who receive radiation therapy.[78] Techniques to minimize the radiation dose to the contralateral breast should be used to keep the absolute risk as low as possible.[79] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.[80]

If ER status is used to select adjuvant treatment, the study should be performed in a well-established, skilled laboratory. Immunohistochemical assays appear to be at least as reliable as standard ligand-binding assays in predicting response to adjuvant endocrine therapy.[81]

The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. The most recent analysis, which included information on 80,273 women in 71 trials of adjuvant tamoxifen, was published in 2005.[82] In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors. In these women, the 15-year absolute reductions in recurrence and mortality associated with 5 years of use were 12% and 9%, respectively.[82][Level of evidence: 1iiA]

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50 to 69 years, ≥70 years), progesterone receptor status, or other tumor characteristics.[82] This EBCTCG meta-analysis also confirmed the benefit of adjuvant tamoxifen in ER-positive premenopausal women.[82] Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the latter group (5.3% vs. 12.5% with 5 years of use).[82][Level of evidence: 1iiA] Similar results were found in the International Breast Cancer Study Group-1393 trial.[83] Of 1,246 women with stage II disease, only the women with ER-positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[82,84-86] Results from the EBCTCG meta-analysis show a highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction 15.2%; P < .001) and a less significant advantage with respect to mortality (proportionate reduction 7.9%; P = .01).[82] Results from the NSABP-B14 study, which compared 5 years of adjuvant tamoxifen to 10 years of adjuvant tamoxifen for women with early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[84][Level of evidence: 1iA] Another trial that included both node-positive and node-negative women also demonstrated the equivalence of 5 years and 10 years of therapy.[85][Level of evidence: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment. In one trial, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation.[86] In the ER-positive subgroup, a longer time-to-relapse was associated with continued tamoxifen use, but no improvement in OS was observed. The current recommendation is that adjuvant tamoxifen be discontinued after 5 years in all patients as current standard therapy.[87] Clinical trials, such as the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment--Offer More? (CRC-TU-ATTOM ) trial are addressing different durations of adjuvant tamoxifen, and results are pending.

(Refer to the Letrozole section in the Aromatase inhibitors section of this summary for more information.)

That chemotherapy should add to the effect of tamoxifen in postmenopausal women has been postulated.[88,89] In a trial (NSABP-B16) of node-positive women older than 50 years with hormone receptor–positive tumors, 3-year DFS and OS rates were better in those who received doxorubicin, cyclophosphamide, and tamoxifen versus tamoxifen alone (DFS was 84% vs. 67%; P = .004; OS was 93% vs. 85%; P = .04).[90][Level of evidence: 1iiA] The NSABP-B20 study compared tamoxifen alone with tamoxifen plus chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU] [CMF] or sequential methotrexate and 5-FU) in women with node-negative, ER-positive breast cancer.[91] After 12 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 89% DFS and 87% OS compared with an 79% DFS and 83% OS with tamoxifen alone.[91][Level of evidence: 1iiA] In another study of postmenopausal women with node-positive disease, tamoxifen alone was compared with tamoxifen plus three different schedules of CMF. A small, DFS advantage was conferred by the addition of early CMF to tamoxifen in women with ER-positive disease.[92][Level of evidence: 1iiDii] However, another study in a similar patient population, in which women were randomized to receive adjuvant tamoxifen with or without CMF, showed no benefit in the chemotherapy arm; in this study, intravenous (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[93][Level of evidence: 1iiA] The overall results of the available evidence suggest that the addition of chemotherapy to tamoxifen in postmenopausal women with ER-positive disease results in a significant, but small, survival advantage.

The use of adjuvant tamoxifen has been associated with certain toxic effects. The most important effect is the development of endometrial cancer which, in large clinical trials, has been reported to occur at a rate that is two times to seven times greater than that observed in untreated women.[94-97] Women taking tamoxifen should be evaluated by a gynecologist if they experience any abnormal uterine bleeding. Although one retrospective study raised concern that endometrial cancers in women taking tamoxifen (40 mg/day) had a worse outcome and were characterized by higher-grade lesions and a more advanced stage than endometrial cancers in women not treated with tamoxifen, other larger studies using standard tamoxifen doses (20 mg/day) have not supported this finding.[94,98,99] Similar to estrogen, tamoxifen produces endometrial hyperplasia, which can be a premalignant change. In a cohort of women without a history of breast cancer who were randomly assigned to receive tamoxifen or placebo on the British Pilot Breast Cancer Prevention Trial, 16% of those on tamoxifen developed atypical hyperplasia at varying times from the start of treatment (range, 3–75 months; median, 24 months), while no cases occurred on the control arm.[100] The value of endometrial biopsy, hysteroscopy, and transvaginal ultrasound as screening tools is unclear.[101,102] Of concern is an increased risk of gastrointestinal malignancy after tamoxifen therapy, but these findings are tentative, and further study is needed.[103]

Tamoxifen use is also associated with an increased incidence of deep venous thrombosis and pulmonary emboli. In several adjuvant studies, the incidence ranged from 1% to 2%.[84,90,104-106] Clotting factor changes have been observed in controlled studies of prolonged tamoxifen use at standard doses; antithrombin III, fibrinogen, and platelet counts have been reported to be minimally reduced in patients receiving tamoxifen.[107] The relationship of these changes to thromboembolic phenomena is not clear. Tamoxifen use may also be associated with an increased risk of strokes.[106,108,109] In the NSABP Breast Cancer Prevention Trial (NSABP-P1), this increase was not statistically significant.[108]

Another potential problem is the development of benign ovarian cysts, which occurred in about 10% of women in a single study.[110] The relationship between tamoxifen and ovarian tumors requires further study.[111] Short-term toxic effects of tamoxifen use may include vasomotor symptoms and gynecologic symptoms (e.g., vaginal discharge or irritation).[112]

Opthalmologic toxic effects have also been reported in patients receiving tamoxifen; patients who complain of visual problems should be assessed carefully.[113-115] Because the teratogenic potential of tamoxifen is unknown, contraception should be discussed with patients who are premenopausal or of childbearing age and are candidates for treatment with this drug.

Tamoxifen therapy may also be associated with certain beneficial estrogenic effects, including decreased total and low-density lipoprotein levels.[116,117] A large controlled Swedish trial has shown a decreased incidence of cardiac disease in postmenopausal women taking tamoxifen. Results were better for women taking tamoxifen for 5 years than for women taking it for 2 years.[118] In another trial, the risk of fatal myocardial infarction was significantly decreased in patients receiving adjuvant tamoxifen for 5 years versus those treated with surgery alone.[117] In the NSABP-B14 study, the annual death rate due to coronary heart disease was lower in the tamoxifen group than in the placebo group (0.62 per 1,000 vs. 0.94 per 1,000), but this difference was not statistically significant.[119] To date, three large controlled trials have shown a decrease in heart disease.[117-119]

Controlled studies have associated long-term tamoxifen use with preservation of bone mineral density of the lumbar spine in postmenopausal women.[120-122] In premenopausal women, decreased bone mineral density is a possibility.[123]

The EBCTCG meta-analysis included almost 8,000 premenopausal women who were randomly assigned to undergo ovarian ablation with surgery or radiation therapy (4,317) or ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists (3,408). Overall, ovarian ablation or suppression reduced the absolute risk of recurrence at 15 years by 4.3% (P < .001) and the risk of death from breast cancer by 3.2% (P = .004).[82] No evidence showed that the relative benefit of suppression differed from that of ablation, but the benefit of either was less in patients who received chemotherapy.[124][Level of evidence: 1iiA]

A single study of more than 300 patients that compared cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP) with the same chemotherapy regimen plus surgical oophorectomy showed no additional survival benefit from oophorectomy.[125][Level of evidence: 1iiA] Three trials (including the International Breast Cancer Study Group's trial [IBCSG-VIII] and the Eastern Cooperative Oncology Group's trial [EST-5188]) involving more than 3,000 patients assessed the impact on DFS and OS from the use of an LHRH analogue (in one trial, 50% of the patients had radiation oophorectomy rather than an LHRH analogue) in addition to chemotherapy.[124,126,127][Level of evidence: 1iiA] None of the trials identified a statistically significant benefit in OS or DFS from ovarian suppression.

As an adjuvant strategy, ovarian ablation has also been compared with chemotherapy in premenopausal women. In a direct comparison of surgical or radiation ablation and CMF, DFS and OS rates were identical in 332 premenopausal women with stage II disease.[128][Level of evidence: 1iiA] A Danish trial compared ovarian ablation or suppression to CMF (nine cycles intravenously every 3 weeks) in premenopausal, ER-positive women and found no difference in OS or DFS in the two study groups.[129,130] The study did not have tamoxifen as an adjuvant arm and also did not use taxanes or anthracyclines. Results may have been different with these two contemporary modifications to the study. A trial of CMF versus tamoxifen plus ovarian ablation (e.g., by surgery, radiation therapy, or gonadotropin-releasing hormone [GnRH]) in premenopausal or perimenopausal women with receptor-positive tumors has been reported.[131][Level of evidence: 1iiA] In this small trial, which did not meet its target accrual, the combination of tamoxifen and ovarian ablation provided comparable DFS and OS rates. In three larger trials in which medical ovarian ablation with goserelin was used, the impact of goserelin alone on DFS was found to be comparable to CMF in the subgroup of ER+ patients,[124,132][Level of evidence: 2Dii] whereas the combination of goserelin and tamoxifen was associated with prolonged DFS compared with CMF alone.[133][Level of evidence: 1iiDii] Whether tamoxifen or aromatase inhibitors add to ovarian ablation, and the elucidation of the optimal roles for endocrine manipulation and chemotherapy in receptor-positive premenopausal women, require further evaluation.[134] These issues are the subject of several trials.

Based on disease-free survival advantage as described below, aromatase inhibitors have become the first-line adjuvant therapy for postmenopausal women; however, because there is no demonstrated survival advantage to aromatase inhibitors, tamoxifen remains a reasonable alternative.

A large randomized trial of 9,366 patients has compared the use of the aromatase inhibitor anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative and node-positive disease.[135,136] Most (84%) of the patients in the study were hormone-receptor positive. Slightly more than 20% had received chemotherapy. With a median follow-up of 33.3 months, no benefit was observed for the combination arm relative to tamoxifen. Patients on anastrozole, however, had a significantly longer DFS (hazard ratio [HR] = 0.83) than those on tamoxifen. In an analysis conducted when all but 8% of the patients had completed protocol therapy at a follow-up of 68 months,[136] the benefit of anastrozole relative to tamoxifen with respect to DFS was slightly less (HR = 0.87; 95% CI, 0.78–0.96; P = .01). A greater benefit was seen in hormone receptor-positive patients (HR = 0.83; 95% CI, .73–0.94; P = .05). There was an improvement in time to recurrence (HR = 0.79; 95% CI, 0.70–0.90; P = .005), distant DFS (HR = 0.86; 95% CI, 0.74–0.99; P = .04) and contralateral breast cancer (42% reduction; P = .01) in patients who received anastrozole.[136][Level of evidence: 1iDii] No difference was shown in OS (HR = 0.97; 95% CI, 0.85–1.12; P = .7 ). Arthralgia and fractures were reported significantly more often in patients who received anastrozole, whereas hot flushes, vaginal bleeding and discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic and deep venous thromboembolic events were more common in patients who received tamoxifen.[136] An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[137,138]

Three trials examined the effect of switching to anastrozole to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[139-141] One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR = 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS.[139][Level of evidence: 1iiA] The other two trials (including the Austrian Breast and Colorectal Cancer Study Group's trial [ ABCSG trial 8]) were reported together.[140] A total of 3,224 patients were randomized after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR = 0.61; 95% CI, 0.42–0.88; P = .007) was observed.[141]

A meta-analysis of these three studies showed that patients who switched to anastrozole had significant improvements in DFS (HR = 0.59; 95% CI, 0.48–0.74; P < .001), EFS (HR = 0.55; 95% CI, 0.42–0.71; P < .001), distant DFS (HR = 0.61; 95% CI, 0.45–0.83; P= .002), and OS (HR = 0.71; 95% CI, 0.52–0.98; P = .04) compared with the patients who remained on tamoxifen.[142]

A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole versus tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years.[143] In an updated analysis from the Breast International Group (BIG-1-98) including only the 4,922 women who received tamoxifen or letrozole for 5 years, at a median follow-up time of 51 months, DFS was significantly superior in patients treated with letrozole (HR = 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS = 84.0% vs. 81.1%).[144][Level of evidence: 1iDii] OS was not significantly different (HR = 0.91; 95% CI, 0.75–1.11; P = .35). Patients on letrozole had significantly fewer thromboembolic events, endometrial pathology, hot flashes, night sweating, and less vaginal bleeding. Patients on tamoxifen had significantly fewer bone fractures, arthralgia, hypercholesterolemia, and cardiac events other than ischemic heart disease and cardiac failures.[144]

A large double-blinded randomized trial (CAN-NCIC-MA17) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who had received tamoxifen for approximately 5 (4.5–6.0) years.[145] After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR = 0.57) favoring the letrozole arm.[145][Level of evidence: 1iDii] After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Women on letrozole had significantly more hot flashes, arthritis, arthralgia and myalgia, but less vaginal bleeding. New diagnoses of osteoporosis were more frequent on letrozole (5.8% vs. 4.5%), though the difference was not statistically significant (P = .07). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[146,147] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis.[148] In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR = 0.60; 95% CI, 0.43–0.84; P = .002). Although no significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR = 0.61; 95% CI, 0.38–0.98; P = .04), though the P value was not corrected for multiple comparisons. An ASCO Technology Assessment panel has commented on the implications of these results.[137,138]

A large double-blinded randomized trial (BIG-9702) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[149,150] After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR = 0.68) favoring the exemestane arm.[149][Level of evidence: 1iDii] After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[151] At 2.5 years after randomization, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).[151][Level of evidence: 1iA] Women on exemestane had significantly more arthralgia, diarrhea, hypertension, fractures, arthritis, musculoskeletal pain, carpal tunnel syndrome, insomnia, and osteoporosis, but women on tamoxifen had significantly more gynecologic symptoms, muscle cramps, vaginal bleeding and discharge, thromboembolic disease, endometrial hyperplasia, and uterine polyps.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which meets every 5 years to review data from global breast cancer trials. The year 2000 overview analysis (published in 2005) summarized the results of randomized adjuvant trials initiated by 1995.[82] The analyses of adjuvant chemotherapy involved 28,764 women participating in 60 trials of combination chemotherapy (polychemotherapy) versus no chemotherapy, 14,470 women in 17 trials of anthracycline-containing versus CMF-type chemotherapy, and 6,125 women in 11 trials of longer versus shorter chemotherapy duration.

For women younger than 50 years, polychemotherapy reduced the annual risk of disease relapse and death from breast cancer by 37% and 30%, respectively. This translated into a 10% absolute improvement in 15-year survival (HR = 42% vs. 32%). For women aged 50 to 69 years, the annual risk of relapse or death from breast cancer was decreased by 19% and 12%, respectively. This translated into a 3% absolute gain in 15-year survival (HR = 50% vs. 47%). The absolute gain in survival for polychemotherapy versus no adjuvant therapy in women younger than 50 was twice as great at 15 years as it was at 5 years (10% vs. 4.7%), while the main effect on disease recurrence was seen in the first 5 years.[82] The 15-year cumulative reduction in mortality from 6 months of an anthracycline-based regimen (e.g., fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, epirubicin, cyclophosphamide [FEC]) was 38% in women younger than 50 years, and 20% in those aged 50 to 60 years. The meta-analysis also showed that the reduction in risk of recurrence was similar in the presence or absence of tamoxifen, irrespective of age (<50 years vs. 50 to 69 years), though the result did not attain statistical significance in those randomly assigned women younger than 50 years. This finding, however, is most likely due to the relatively small number of younger women in trials of combined chemoendocrine therapy. Few women older than 70 years had been studied, and specific conclusions could not be reached in this group. Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to ER status, and they were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[82] As a result, they may not reflect treatment outcomes based on evolving treatment patterns.

Results of individual trials are generally in agreement with the conclusions of the meta-analysis. The NSABP-B13 study demonstrated a benefit for chemotherapy with sequential methotrexate and 5-FU versus surgery alone in patients with node-negative, ER-negative tumors.[90,91,152,153][Level of evidence: 1iiA]

The EBCTCG meta-analysis assessed data from five trials comparing durations of at least 6 months with longer durations of 9 to 24 months. No survival benefit was demonstrated for durations greater than 6 months.[154][Level of evidence: 1iiA]

The EBCTCG meta-analysis analyzed 11 trials that began in 1976 through 1989 in which women were randomized to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) versus CMF alone. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of FEC or FAC) with CMF (either oral or IV) in approximately 14,000 women, 64% of whom were under 50 years.[82] Compared to CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[154][Level of evidence: 1iiA]

The largest direct comparison of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) (six cycles) versus CMF (six cycles) occurred in a U.S. Intergroup study (INT-0102), which was not included in the meta-analysis.[155] In this study, 2,691 patients were randomized to receive CAF or CMF with a second randomization to 5 years of tamoxifen versus no tamoxifen. Ten-year follow-up estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% vs. 75%; HR = 1.09; 95% CI, 0.94–1.27). CAF had slightly better OS than CMF (85% vs. 82%, HR = 1.19 for CMF vs. CAF; 95% CI, 0.99–1.43), though values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with tamoxifen. Overall, tamoxifen had no benefit (DFS, P = .16; OS, P = .37), but the tamoxifen effect differed by high-risk groups. For high-risk node-positive patients, tamoxifen was beneficial (DFS, hazard ratio [HR] = 1.32 for no tamoxifen vs. tamoxifen; 95% CI, 1.09–1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99–1.61; P = .03) but not for high-risk node-negative patients (DFS, HR = 0.81 for no tamoxifen vs. tamoxifen; 95% CI, 0.64–1.03; OS, HR = 0.79; 95% CI, 0.60–1.05). The conclusion of this trial was that CAF did not improve DFS compared with CMF; and, there was a slight effect on OS. Given greater toxicity, CAF cannot be concluded to be superior to CMF. Tamoxifen is effective in high-risk node-positive disease but not in high-risk node-negative disease.[155][Level of evidence: 1iiA]

Several investigators have attempted to improve outcomes by combining CMF and anthracycline-containing regimens. Two Italian studies have evaluated these regimens.[156,157] In one study, 490 premenopausal and postmenopausal women with one to three axillary lymph nodes were randomized to receive CMF (12 cycles) or CMF (eight cycles) followed by doxorubicin (four cycles).[156] After a median observation of 17.5 years, no statistically significant difference was documented in the first study (relapse-free survival [RFS], HR = 1.06; total survival, HR = 1.03). In contrast, the delivery of doxorubicin first, followed by CMF significantly reduced the risk of disease relapse (HR = 0.68; 95% CI, 0.54–0.87; P =.0017) and death (HR = 0.74; 95% CI, 0.57–0.95; P = .018) compared with the alternating regimen. In the other study, 403 premenopausal and postmenopausal women with four or more positive axillary lymph nodes were randomized to receive doxorubicin (four cycles) followed by CMF (eight cycles) or CMF (two cycles) alternating with doxorubicin (one cycle) for a total of 12 cycles.[157] Women who received doxorubicin followed by CMF had better RFS (42% vs. 28%; P = .002) and OS (58% vs. 44%; P = .002).[157][Level of evidence: 1iiA]

The NSABP-B15 trial randomized 2,194 patients with axillary node-positive breast cancer and tumors determined nonresponsive to tamoxifen to doxorubicin and cyclophosphamide (AC) (four cycles), CMF (six cycles), or AC (four cycles) followed after a 6-month delay by CMF (three cycles).[158] No differences were seen in DFS or OS among the three groups.[158][Level of evidence: 1iiA] This study has also shown no difference in survival rates between four cycles of AC and six cycles of CMF.

The results of these various studies comparing and combining CMF and anthracycline-containing regimens suggest a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal patients. Uncertainty remains, however, about whether there is an advantage to combining both regimens.

Evidence suggests that particular tumor characteristics may predict anthracycline-responsiveness. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant CAF,[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA] A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[159][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods. The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in RFS and OS. In patients with HER2/neu amplification, the RFS and OS was increased by CEF. In the absence of HER2/neu amplification, CEF and CMF were similiar to RFS (HR for relapse = 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HR for death = 1.06; 95% CI, 0.83–1.44; P = .68).

Four randomized trials (including CLB-9344, NSABP-B28, and the Programmes d'Actions Concertées Sein trial [PACS-01]) have examined the benefit of adding taxanes (either paclitaxel or docetaxel) to anthracycline-based adjuvant chemotherapy regimens for more than 8,000 node-positive breast cancer patients.[160-163][Level of evidence: 1iiA] The benefits of adding paclitaxel or docetaxel to standard anthracycline-based adjuvant chemotherapy have been demonstrated in patients with node-positive disease. All four trials showed a benefit in 5-year DFS, with a range of absolute benefits of 4% to 5%. HRs from each of the trials range from 0.73 to 0.83, and all P values were less than .03. Three of the trials showed a benefit in 5-year OS, with a range of absolute benefits of 3% to 5%. HRs from each of the trials range from 0.72 to 0.80, and all P values were less than .01.[160,162,164] A retrospective subset analysis of one trial suggested that treatment with paclitaxel resulted in a greater benefit in DFS (P = .0093) and OS (P = .0056) in HER2-positive patients versus HER2-negative patients.[165] No OS advantage was found for the docetaxel plus cyclophosphamide (TC) regimen versus standard-doseAC,[166] and the doxorubicin plus docetaxel (AT) regimen in the Eastern Cooperative Oncology Group's trial (E-2197) was found to be excessively toxic in regards to septicemic deaths compared with standard-dose AC.[167]

Retrospective and some prospective data support the view that physicians should avoid arbitrary reductions in dose intensity.[168,169] The data for the benefit of dose escalation in breast cancer, however, are more controversial. The CALGB-8541 trial compared three dose intensities of CAF in 1,550 patients with node-positive breast cancer. Patients received either CAF (300/30/300 mg/m² every 4 weeks for four cycles; low-dose arm), CAF (400/40/400 mg/m² every 4 weeks for six cycles; moderate-dose arm), or CAF (600/60/600 mg/m² every 4 weeks for four cycles; high-dose arm). The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had 66% of the dose intensity as the high-dose arm but the same total drug dose. At a median follow-up of 9 years, DFS and OS on the high-dose and intermediate-dose arms were superior to the corresponding survival measures on the low-dose arm (P = .001) with no difference in these measures between the high-dose and intermediate-dose arms.[168][Level of evidence: 1iiA] The higher dose levels used in this trial are currently considered standard, so it is unclear whether this trial is supportive of the value of dose intensity or, rather, supportive of the concept of a threshold level below which treatment becomes ineffective.

Other trials have clearly escalated doses beyond the standard range. The NSABP-B22 and NSABP-B25 trials escalated the dose of cyclophosphamide to 1,200 mg/m² (without granulocyte-colony stimulating factor [G-CSF]) and 2,400 mg/m² (with G-CSF), respectively, with no significant advantage observed in DFS or OS compared with the standard dose of 600 mg/m².[170,171][Level of evidence: 1iiA]

U.S. Intergroup study CLB-9344 randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m²). Following treatment with doxorubicin, a second randomization occurred to paclitaxel or to no further therapy. After chemotherapy, patients with ER-positive tumors were offered a planned course of tamoxifen for 5 years. No difference in DFS related to the dose of doxorubicin was found.[160] In contrast, a Canadian trial (CAN-NCIC-MA5) in which cyclophosphamide, epirubicin, and 5-FU (CEF) were given to a total dose of 720 mg/m² for a period of six 4-week cycles demonstrated at a median follow-up of 10 years for live patients, a 10-year RFS of 52% for patients who received CEF compared with 45% for CMF patients (HR for CMF vs. CEF = 1.31; stratified log-rank, P = .007).[172] The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF vs. CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher (four patients [1.1%] in the CEF group vs. one patient [0.3%] in the CMF group).[172][Level of evidence: 1iiA] The design of the trial does not allow a determination of whether anthracycline or dose-intensity or both is responsible for the improved outcome. A French trial showed that higher doses of epirubicin led to a high survival rate in women with poor-prognosis disease.[173] A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.[174]

U.S. Intergroup trial CLB-9741 compared, in a 2 × 2 factorial design, the use of adriamycin, cyclophosphamide, and paclitaxel concurrently (adriamycin and cyclophosphamide followed by paclitaxel) versus sequentially (adriamycin followed by paclitaxel followed by cyclophosphamide), given every 3 weeks or every 2 weeks with filgrastim, in 2,005 node-positive premenopausal and postmenopausal patients.[175] At a median follow-up of 68 months, dose-dense treatment improved the primary end point, DFS in all patient population (HR = 0.80; P =.018) but not OS (HR = 0.85; P =.12). There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens.[175,176] Grade 2 anemia (hemoglobin <10g/dL) was more frequent in the adriamycin and cyclophosphamide followed by paclitaxel every 2 weeks' arm (P < .001). At cycle five, this same arm had the lowest nadir hemoglobin of 10.7 g/dL, 0.9 g/dL lower than the other arms. Also, epoetin alpha use was highest in this arm compared with the three other arms (P = .013). In conclusion, dose-dense adriamycin and cyclophosphamide followed by paclitaxel every 14 days in C2 was associated with a greater incidence of moderate anemia, higher use of epoetin alpha, and more red cell transfusions than the other arms.[177][Level of evidence: 1iiA]

Several clinical trials (including EST- 2190) have tested high-dose chemotherapy with bone marrow transplant (BMT) or stem cell support in women with more than ten positive lymph nodes and in women with four to nine positive lymph nodes.[178-185] A prospective randomized trial of 403 patients testing the use of two tandem high-dose chemotherapy courses demonstrated a statistically significant (P = .02) difference in 5-year survival (75% vs. 70%) with a 49-month median follow-up.[184][Level of evidence: 1iiA] The remaining trials comparing conventional chemotherapy to high-dose chemotherapy with BMT or stem cell support in high-risk patients in the adjuvant setting indicated no OS or EFS benefit from the high-dose chemotherapy with BMT or stem cell support.[178-183,185-187][Level of evidence: 1iiA] The information to date does not support the use of high-dose chemotherapy outside the context of a randomized clinical trial.

Also, a systemic review of nine randomized controlled trials comparing the effectiveness of high-dose chemotherapy and autograft with conventional chemotherapy for women with early poor prognosis breast cancer was performed.[185] In total 1,758 women were randomly assigned to receive high-dose chemotherapy with autograft, and 1,767 women were randomly assigned to receive conventional chemotherapy. There were 48 noncancer-related deaths on the high dose arm and four on the conventional dose arm (RR = 7.74; 95% CI, 3.43–17.50). There was no statistically significant difference in OS between women who received high-dose chemotherapy with autograft and women who received conventional chemotherapy, either at 3 years (RR = 1.02; 95% CI, 0.98–1.06), or at 5 years (RR = 0.98, 95% CI, 0.93–1.05). There was a statistically significant benefit in EFS at 3 years for the group who received high dose chemotherapy (RR = 1.11; 95% CI, 1.05–1.18). However, this significance was lost at 5 years (RR = 1.00; 95% CI, 0.92–1.08).[185]

The NSABP-B19 trial compared CMF to sequential methotrexate followed by 5-FU in 1,095 women with node-negative, ER-negative tumors. After 13 years of follow-up, an overall benefit was seen for CMF relative to methotrexate plus 5-FU (MF) (RFS: HR = 0.59, 95% CI, 0.45–0.77, P < .001; OS: HR = 0.71; 95% CI, 0.55–0.92; P = .01). All age and menopausal groups demonstrated an RFS benefit, and most demonstrated an OS benefit.[152][Level of evidence: 1iiA] Serious toxicity (≥grade 3), especially febrile neutropenia, was more frequent among CMF-treated patients. With no outcome advantage in older women and more toxic effects from the CMF regimen, the results of this study suggested that methotrexate followed by 5-FU was a reasonable substitute for CMF for older women.

U.S. Intergroup study CLB-9344 randomized women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m²) and a fixed dose of cyclophosphamide (600 mg/m²) every 3 weeks for four cycles. After AC chemotherapy, patients underwent a second randomization to paclitaxel (175 mg/m²) every 3 weeks for four cycles, and women with ER-positive tumors also received tamoxifen for 5 years. Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).[160][