cancer management

发布时间:2021-11-28 05:04:45

CHAPTER 10

Stage II breast cancer
Lori Jardines, MD, Bruce G. Haffty, MD, and Melanie Royce, MD, PhD
This chapter focuses on the treatment of stage II breast cancer, which encompasses primary tumors > 2 cm in 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 the populations with stage 0 and stage I disease. The pretreatment evaluation and type of treatment offered to patients with stage II breast cancer are based on tumor size, nodal status, and estrogen-receptor status.

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 and overall survival rates.

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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 National Cancer Institute (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 > 4-5 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 conservative treatment. In a recent 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 intrabreast tumor recurrence-

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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 results in sufficient reduction in tumor response that breast-conserving therapy becomes possible. The NSABP B-18 trial showed that preoperative 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 either four cycles of preoperative AC chemotherapy followed by surgery or 4 cycles of preoperative AC followed by four cycles of docetaxel followed by surgery, or 4 cycles of preoperative AC chemotherapy followed by surgery followed by four 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 disease-free and overall survival between the treatment groups. However, those who had a complete pathologic response in the breast had significant improvement in disease-free (hazard ratio [HR] 0.45; P < .0001) and overall survival (HR 0.33; P < .0001) compared with those with residual disease after preoperative chemotherapy. Since 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 compared with those deemed eligibile initially for breast-conserving surgery.

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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 as well as 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 disease-free survival have been observed in randomized trials comparing lumpectomy alone with lumpectomy and radiation therapy for patients with invasive breast cancer.
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.

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Radiation dose and protocol Radiation dose to the intact breast follows the same guidelines as are used in patients with stages 0 and I disease, described in chapter 9. Regional nodal irradiation For patients who undergo axillary lymph node dissection 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 4,500-5,000 cGy results in a high rate of regional nodal control and may improve disease-free survival in subsets of patients. Given the widespread use of systemic therapy for patients with both nodenegative and node-positive disease, the role of axillary dissection has recently come into question. In patients with clinically negative axillae who do not undergo axillary dissection, radiation therapy to the supraclavicular and axillary regions at the time of breast irradiation results in a high rate (> 95%) of regional nodal control with minimal morbidity.

Radiation therapy after mastectomy
Available data suggest that in patients with positive postmastectomy margins, 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 to consider postmastectomy radiation therapy. 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 patients 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 disease-free and overall survival advantage in selected patients. Clinical practice guidelines recently developed by the American Society of Clinical Oncology (ASCO) support the routine use of postmastectomy radiation therapy for women with stage III or T3 disease or who have four or more involved axillary lymph nodes. 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.

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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 disease-free survival. For patients with T1 or T2 tumors and one to three positive nodes, postmastectomy radiation therapy may have a benefit with respect to disease-free and overall survival. 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 toxicity Early trials employing postmastectomy radiation therapy showed that the modest improvements in breast cancer mortality were offset by an excess risk of cardiovascular deaths, presumably due to the radiation treatment techniques used, which 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 overall survival 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 4,500-5,000 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, to doses of ~6,000 cGy, may be considered. In patients who have undergone axillary lymph node dissection, even in those with multiple positive nodes, treatment of the axilla 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. MEDICAL TREATMENT Medical management of local disease depends on clinical and pathologic staging. Systemic therapy is indicated only for invasive (infiltrating) breast cancers. The sequence of systemic therapy and definitive radiation therapy in women treated with breast-conserving surgery is a subject of continued clinical research. The use of concomitant chemotherapy and irradiation is not recommended due to the radiomimetic effects of chemotherapy and the potential for increased locoregional toxicity. Delaying chemotherapy up to 8-10 weeks after surgery does not appear to have a negative impact on the development of metastasis or on survival.

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The optimal timing of endocrine therapy relative to radiation therapy is still open to debate. The Southwest Oncology Group (SWOG) performed an exploratory analysis to evaluate the optimal sequencing of tamoxifen and radiotherapy after breast-conserving surgery. This study was based on data from SWOG trial 8897 (Intergroup 0102), where radiation therapy was given either before chemotherapy (and thus sequential to tamoxifen) or after adjuvant chemotherapy but concurrently with tamoxifen. Their analysis does not suggest an adverse effect on either local or systemic control with concurrent versus sequential chemotherapy and radiation therapy in node-negative breast cancer. Typically, however, endocrine therapy is started after completion of radiation therapy.

The US FDA approved docetaxel in combination with doxorubicin and cyclophosphamide for the treatment of operable, nodepositive breast cancer. The approval was based on the results of a second interim analysis of data from the Breast Cancer International Research Group (BCIRG) 001/TAX 316 trial, in which patients with node-positive early breast cancer who received docetaxel-based chemotherapy after surgery had a 25.7% reduction in their risk of relapse compared with women who received the FAC regimen. At 5-year follow-up, the reduction in the risk of relapse was maintained regardless of the patient’s hormone-receptor status (Martin M, Pienkowski T, Mackey J, et al: Breast Cancer Res Treat 82[suppl 1] [new abstract 43], 2003).

Treatment regimens Systemic adjuvant therapy has been shown to decrease the risk of recurrence and in some cases also the risk of death. Systemic therapy may be divided into chemotherapy and endocrine (hormonal) therapy. Chemotherapy often involves use of combination regimens, given for four to eight cycles. Chemotherapy is most often delivered after primary surgery for breast cancer and before radiation therapy for those who are candidates for irradiation.
Chemotherapy Multiagent therapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (5-FU, CMF regimen); cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP); doxorubicin (Adriamycin) and cyclophosphamide (AC); and sequential methotrexate and 5-FU (MF) has been used in patients with node-negative disease (see Table 2 in Chapter 9). For node-positive disease, systemic chemotherapy has changed over the past few years. Anthracycline-containing regimens are being used with greater frequency and have been shown to be of greater benefit than nonanthracyclinecontaining regimens (eg, CMF). Epirubicin (Ellence) was approved by the US Food and Drug Administration (FDA) for use in combination with cyclophosphamide and 5-FU (CEF regimen) for the adjuvant treatment of patients with node-positive breast cancer following resection of the primary tumor. In a pivotal trial conducted by the National Cancer Institute of Canada, premenopausal women with node-positive breast cancer were randomly allocated to receive either CEF or CMF, administered monthly for 6 months. With a median follow-up of 59 months, the 5-year relapse-free survival rates were 53% and 63% (P = .009), and 5-year survival rates were 70% and 77% for CEF and CMF, respectively (P = .03).
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TABLE 1: Adjuvant chemotherapy regimens in node-positive breast cancer
Regimen TAC Taxotere (docetaxel) Adriamycin (doxorubicin) Cyclophosphamide Dose and frequency

75 mg/m2 IV on day 1 50 mg/m2 IV on day 1 500 mg/m2 IV on day 1

Repeat every 21 days for six cycles. Martin M, Pienkowski T, Mackey J, et al: Eur J Cancer 2(suppl):70, 2004.

AC → T (conventional regimen) Adriamycin (doxorubicin) 60 mg/m2 IV on day 1 Cyclophosphamide 600 mg/m2 IV on day 1 × four cycles followed by Taxol (paclitaxel) 175 mg/m2 IV by 3-h infusion every 3 weeks × four cycles Dose-Dense (concurrent regimen) Adriamycin 60 mg/m2 IV on day 1 every 2 weeks Cyclophosphamide 600 mg/m2 IV on day 1 every 2 weeks × four cycles 175 mg/m2 IV by 3-h infusion every 2 weeks × four cycles 60 mg/m2 IV on day 1 every 2 weeks × four cycles 175 mg/m2 IV by 3-h infusion every 2 weeks × four cycles 600 mg/m2 IV on day 1 every 2 weeks × four cycles

followed by Paclitaxel

Dose-Dense (sequential regimen) Adriamycin followed by Paclitaxel followed by Cyclophosphamide
Citron M, Berry DA, Cirrincione C, et al: J Clin Oncol 21:1431–1439, 2003.

A-CMF Adriamycin (doxorubicin) 75 mg/m2 IV on day 1 Repeat every 3 weeks for four courses. Cyclophosphamide 600 mg/m2 IV on day 1 Methotrexate 40 mg/m2 IV on days 1 and 8 5-FU 600 mg/m2 on day 1
Repeat every 3 weeks for eight courses. Buzzoni R, Bonadonna G,Valagussa P, et al: J Clin Oncol 9:2134–2140, 1991.

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Several trials have also shown the benefit of incorporating taxanes (paclitaxel and docetaxel [Taxotere]) in the adjuvant treatment of node-positive breast cancer, and they are now routinely used in this setting. Taxanes can either be given in combination with an anthracycline or sequentially, either before or after an anthracycline. The Breast Cancer International Research Group (BCIRG) compared Taxotere, Adriamycin, and cyclophosphamide (TAC regimen) with 5-FU, Adriamycin, and cyclophosphamide (FAC regimen) in 1,480 women with node-positive breast cancer (BCIRG 001). The median disease-free survival at 3 years was 82% for TAC vs 74% for FAC. The relative risk reduction for the entire group was 32%, with the most benefit seen in women with one to three positive lymph nodes (50% risk reduction). A statistically significant difference in overall survival was also noted for TAC in this same group of women but not for those with four or more positive nodes. Although febrile neutropenia was greater with TAC, it was ameliorated with growth factor support. In another study by the Cancer and Leukemia Group B (CALGB 9344), 3,121 women with operable, node-positive breast cancer were randomly assigned to receive three doses of doxorubicin with standard dose cyclophosphamide followed by either no further therapy or four cycles of paclitaxel (175 mg/m2). This study did not show any substantial benefit from dose escalation of doxorubicin. However, the addition of four cycles of paclitaxel improved the disease-free and overall survival. At 5 years, the disease-free survival was 65% and 70%, and overall survival was 77% and 80% after AC vs AC plus paclitaxel, respectively. An unplanned subset analysis showed that the majority of the benefit was seen in those with estrogen receptor-negative tumors. Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. Toxicity was modest with the addition of four cycles of paclitaxel. In a similar study by the National Surgical Adjuvant Breast and Bowel Project (NSABP B-28), the addition of paclitaxel (225 mg/m2) did not initially result in improvement of either disease-free or overall survival. However, with longer follow-up (median 67 months), improvement in disease-free survival in favor of AC followed by paclitaxel has emerged. Dose-dense treatment CALGB 9741 tested two novel concepts: dose density and sequential therapy. Dose density refers to the administration of drugs with a shortened interval between treatments, whereas sequential therapy refers to the delivery of treatments one at a time rather than concurrently. A total of 2,005 women with operable, node-positive breast cancer were randomly assigned to receive one of the following regimens: (1) sequential Adriamycin (A) × 4 (doses) followed by Taxol (T) × 4 followed by cyclophosphamide (C) × 4, with doses every 3 weeks; (2) sequential A × 4 followed by T × 4 followed by C × 4, every 2 weeks with filgrastim (Neupogen); (3) concurrent AC × 4 followed by T × 4, every 3 weeks; or (4) concurrent AC × 4 followed by T × 4, every 2 weeks with filgrastim. At a median follow-up of 36 months, there was an improvement in disease-free (risk ratio = 0.74; P =.010) and overall survival (risk ratio = 0.69; P =.013) in favor of dose density. Four-year disease free survival was 82% for the

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dose-dense regimens and 75% for the others. There was no difference in diseasefree or overall survival between the concurrent (dose-dense) and sequential schedules. The dosages, schedules, and frequencies of chemotherapy regimens used for node-positive breast cancer are detailed in Table 1. Other regimens also used in node-negative (Chapter 9) and/or metastatic disease (Chapter 11) are listed in their respective chapters. Recommendations All patients with stage II breast cancer should be considered for systemic adjuvant therapy. Adjuvant chemotherapy in node-positive breast cancer improves disease-free and overall survival by 24% and 15%, respectively. Risk reductions for multiagent chemotherapy are proportionately the same in patients with node-negative and node-positive disease. Chemotherapy for women 50 years of age and older is similar to that for younger women. However, multiagent chemotherapy affords the greatest benefit in women younger than age 50 with respect to reductions in the risk of recurrence and death from breast cancer. For instance, CMF or AC chemotherapy improves disease-free survival in women aged 50 to 69 by 18%, vs 33% for women younger than age 50. Limited data are available from randomized trials regarding women aged 70 and older. However, in the absence of comorbidity, such as heart, renal, or liver disease, systemic adjuvant therapy can be offered to women > 70 years old.

Endocrine (hormonal) therapy
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview analyses demonstrated a significant advantage with the addition of tamoxifen (20 mg/d PO) for 5 years to the adjuvant therapy regimen of women with estrogen receptor-positive breast cancer regardless of age. Treatment with tamoxifen reduced the risk of death by 14% in women younger than age 50 and by 27% in those 50 years of age and older. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years.

Premenopausal women
Approximately 60% of premenopausal women with primary breast cancer have estrogen receptor-positive tumors. For this group of patients, the benefit of adjuvant endocrine therapy, either tamoxifen or ovarian ablation, was established in the EBCTCG overview. Endocrine therapy has comparable efficacy to that of chemotherapy. For premenopausal women, however, the long-term morbidity associated with permanent ovarian suppression may be significant. Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) analogs offers an alternative to permanent ovarian ablation, which is potentially reversible on cessation of therapy. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial is a randomized trial directly comparing goserelin (Zoladex) monotherapy with CMF

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in premenopausal women 50 years of age and younger with node-positive, stage II breast cancer. The primary efficacy population included 1,614 patients: 797 randomized to receive goserelin and 817, CMF. Estrogen-receptor status was known for 92.5% of patients; 80% had estrogen receptor-positive tumors. At a median follow-up of 6 years, the estrogen receptor-positive patients treated with goserelin fared comparably to those who received CMF in terms of disease-free survival (HR = 1.01; P = .94) and overall survival (HR = 0.99; P = .92). Not surprisingly, CMF was superior to goserelin in patients with estrogen receptor-negative tumors. The onset of amenorrhea occurred sooner with goserelin; by 6 months, more than 95% of patients on goserelin were amenorrheic, vs 59% for CMF recipients. Reversibility of amenorrhea was also greater for goserelin; 1 year after cessation of goserelin treatment, 23% remained amenorrheic, vs 77% for CMF recipients. Several studies have compared adjuvant chemotherapy with combined endocrine therapies in premenopausal women, consisting of tamoxifen for 5 years and an LHRH agonist for 2 to 3 years. Overall, combination endocrine treatment yielded better results than chemotherapy alone. Whether a strategy of combined endocrine therapy is better than tamoxifen alone, either with or without chemotherapy, in premenopausal patients with hormone receptor-positive tumors is the subject of several ongoing clinical trials. In the Suppression of Ovarian Function Trial (SOFT), following adjuvant chemotherapy, tamoxifen alone is compared with tamoxifen plus ovarian function suppression/ablation vs ovarian function suppression plus an aromatase inhibitor (exemestane [Aromasin]). The role of ovarian suppression and aromatase inhibitors in this setting is further investigated by the complementary Tamoxifen and Exemestane Trial (TEXT) comparing ovarian suppression with the LHRH analog triptorelin (Trelstar) plus tamoxifen vs triptorelin plus exemestane. Currently, almost all premenopausal women with lymph node-positive, hormone receptor-positive breast cancer receive chemotherapy. Whether combined endocrine therapies alone may be sufficient to achieve excellent outcomes without chemotherapy is a question being investigated in the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial. This trial is comparing ovarian function suppression with an LHRH agonist plus chemotherapy followed by tamoxifen or exemestane vs ovarian function suppression and tamoxifen or exemestane without chemotherapy for premenopausal patients with hormone receptor-positive tumors.

Postmenopausal women
For many years, tamoxifen has been the standard adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive tumors. However, demonstrable benefits of aromatase inhibitors, as from several large, randomized clinical trials, have led to increasing use of these agents in the adjuvant treatment of postmenopausal women with hormone receptor-positive tumors.

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The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was the first large randomized trial demonstrating the superiority of an aromatase inhibitor over tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer. After the initial ATAC analyses, the combination arm was closed because of low efficacy. The ATAC trial was recently updated, with a median follow-up of 68 months. In this updated analysis, only 8% of patients remain on trial treatment. Compared with tamoxifen, anastrozole (Arimidex) led to significant improvements in disease-free survival (HR = 0.87; P = .01), time to disease recurrence (HR = 0.79; P = .0005), and time to distant recurrence (HR = 0.86; P = .04). Additionally, substantial reduction in the incidence of contralateral breast cancer was observed with anastrozole compared with tamoxifen (42% reduction; P = .01). No differences have yet emerged in overall survival. The safety profile of anastrozole remains unchanged from the previous analyses. No new safety concerns have emerged with additional months of followup. In general, toxicities were less common with anastrozole than with tamoxifen, with significantly fewer cases of hot flashes, vaginal bleeding/discharge, endometrial cancer, and thromboembolic events in the anastrozoletreated patients. Arthralgias occurred more frequently with anastrozole. Fracture rates were higher with anastrozole (HR = 1.44; P < .0001); however, the low incidence of hip fractures was similar in the two groups. Other randomized trials have investigated the use of an aromatase inhibitor after tamoxifen. Two sequential strategies after tamoxifen were studied: (1) a switch to an aromatase inhibitor after 2 or 3 years of tamoxifen, to complete a 5-year course of endocrine therapy, or (2) a switch to an aromatase inhibitor after 5 years of tamoxifen, to complete 10 years of endocrine therapy, also called extended adjuvant therapy. In either strategy, the use of an aromatase inhibitor after tamoxifen provided significant reduction in events (recurrence, contralateral breast cancer, or death). In the Intergroup Exemestane Study (IES), 4,742 patients who had received 2 to 3 years of tamoxifen were randomized to receive either additional tamoxifen or a switch to exemestane, to complete a 5-year course of endocrine therapy. After a median follow-up of 30.6 months, there was a significant reduction in risk, with an HR of 0.68 (P < .001) in favor of exemestane. Disease-free survival 3 years after randomization was 91.5% in the exemestane group and 86.8% in the tamoxifen group; this represents a 32% reduction in risk, or an absolute benefit in disease-free survival of 4.7%. Distant disease-free survival was also better in the exemestane group (HR = 0.66; P = .0004). Contralateral breast cancer occurred in 9 and 20 patients in the exemestane and tamoxifen group, respectively (P = .04). Overall survival was not significantly different in the two groups. Severe toxic effects of exemestane were rare, and toxicity profiles were similar to those previously reported for aromatase inhibitors. Exemestane was associated with a higher incidence of arthralgia and diarrhea, and there was an in-

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creased trend for osteoporosis and visual disturbances. Fractures were more frequent in the exemestane group, although no significant statistical difference was noted between the two groups. Gynecologic symptoms, vaginal bleeding, and muscle cramps were more common with tamoxifen, and thromboembolic events were significantly more frequent with tamoxifen. In the MA-17 trial, 5,187 postmenopausal women who had taken tamoxifen for 5 years were randomly assigned to receive either letrozole (Femara) or placebo for an additional 5 years. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial since letrozole therapy after the completion of standard tamoxifen treatment significantly improved disease-free survival. With a median follow-up of approximately 27 months, the 4-year disease-free survival rates for letrozole and placebo were 93% and 87%, respectively (P < .001). No significant difference was noted in overall survival. However, in an updated analysis, an advantage in distant disease-free and overall survival was reported in the subset of women with node-positive disease. Toxicities associated with letrozole were similar to those seen with aromatase inhibitors in the other trials. Recent guidelines from ASCO and the National Comprehensive Cancer Network (NCCN) highlight the appropriate use of these agents in postmenopausal women with hormone receptor-positive breast cancer. Several questions remain, and we must await completion of ongoing trials and/or development of new trials for answers. For instance, neither the optimal timing nor the duration of aromatase inhibitor therapy has been established, and the role of biomarkers (such as HER-2/neu status) in selecting optimal endocrine therapy remains controversial. Furthermore, long-term effects of aromatase therapy, including osteoporosis, are not yet well characterized.

HER-2–positive tumors
Recent results suggest that patients with HER-2/neu-expressing breast cancers associated with axillary lymph node metastasis benefit significantly from intensive, doxorubicin-containing adjuvant chemotherapy. Furthermore, studies demonstrating significant benefit for the addition of trastuzumab (Herceptin) to chemotherapy in metastatic breast cancer have prompted several groups to study this agent in the adjuvant setting. Some of these studies have completed accrual, and results should be forthcoming. At this time, use of trastuzumab in the adjuvant setting is investigational but should be considered within the setting of a clinical trial. High-dose chemotherapy Because of the higher rate of recurrence in patients with stage IIB breast cancer, high-dose chemotherapy can also be considered as part of a clinical trial. See chapter 11 for a discussion of the current status of this approach.

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TABLE 2: Follow-up recommendations for asymptomatic long-term breast cancer survivors as per NCCN guidelines
Intervention* History and physical exam Mammography Year 1 Every 4 mo Year 2 Every 4 mo Years 3-5 Every 6 mo Annually Year 6+ Annually Annually

Annually (or 6 Annually mo after post BCS irradiation) Annually? Annually Every 1 to 2 yr NRR Annually

Chest x-ray Pelvic exama Bone densityb

NRR Annually

NRR Annually

Every 1 to 2 yr Every 1 to 2 yr

NCCN = National Comprehensive Cancer Network; NRR = not routinely recomended; BCS = breast-conserving surgery a For patients with an intact uterus on tamoxifen b For patients at risk for osteoporosis * Bone scan, liver function tests, and tumor markers are not routinely recommended and are performed only if clinically indicated.

Toxic effects of medical therapy Chemotherapy The most frequent acute toxicities are nausea/vomiting, alopecia, and hematologic side effects, such as leukopenia and thrombocytopenia. Neutropenia, with its attendant risk of infection, is a potentially life-threatening complication that requires prompt medical attention and broad-spectrum antibiotics until hematologic recovery occurs.
Other toxicities may include amenorrhea, cystitis, stomatitis, myocardial failure, and nail/skin changes. Amenorrhea is drug- and dose-related and is often permanent in women over 40 years of age. Recent evidence demonstrates that chemotherapy-induced ovarian failure in the adjuvant chemotherapy setting is associated with a high risk of rapid bone demineralization in the first 6-12 months after treatment. Thus, premenopausal women undergoing adjuvant chemotherapy must be closely evaluated to prevent the development of early osteoporosis. Cardiac failure, although rare, is potentially life-threatening and may be irreversible. Endocrine therapy Toxicities with tamoxifen or aromatase inhibitors include hot flashes, menstrual irregularities, vaginal discharge, and weight gain. Thrombophlebitis and endometrial hyperplasia are more common with tamoxifen. Arthralgias, osteoporosis, and fractures are more common with aromatase inhibitors, although the incidence of hip fractures is low.

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Follow-up of long-term survivors
There is no consensus among oncologists as to the appropriate and optimal follow-up routine for long-term breast cancer survivors. Recommendations for follow-up testing vary. The vast majority of relapses, both locoregional and distant, occur within the first 3 years. Surveillance is most intensive in the initial 5 years; thereafter the frequency of follow-up visits and testing is reduced (Table 2). History and physical examination Surveillance methods include a detailed history and physical examination at each office visit. They are performed every 4-6 months for 5 years after completion of initial therapy, then annually thereafter. Patients at higher risk of recurrence or complications of treatment may require surveillance at shorter intervals. Patients who have been treated by mastectomy can be seen in the office annually after they have been diseasefree for 5 years. Patients who were treated with breast-conserving surgery and radiotherapy can be followed at 6-month intervals until they have been disease-free for 6-8 years and then annually. Approximately 71% of breast cancer recurrences are detected by the patients themselves, and they will report a change in their symptoms when questioned carefully. In patients who are asymptomatic, physical examination will detect a recurrence in another 15%. Therefore, a patient’s complaint on history or a new finding on physical examination will lead to the detection of 86% of all recurrences. Mammography should be performed annually in all patients who have been treated for breast cancer. For patients who have undergone breast-conserving surgery, the first follow-up mammogram should be performed approximately 6 months after completion of radiation therapy. The risk of developing contralateral breast cancer is approximately 0.5%-1.0% per year. In addition, approximately one-third of ipsilateral breast tumor recurrences in patients who have been treated by conservation surgery and radiotherapy are detected by mammography alone. As the time interval between the initial therapy and follow-up mammography increases, so does the likelihood that local breast recurrence will develop elsewhere in the breast rather than at the site of the initial primary lesion. Chest x-ray Routine chest radiographs detect between 2.3% and 19.5% of recurrences in asymptomatic patients and may be indicated on an annual basis. Liver function tests detect recurrences in relatively few asymptomatic patients, and their routine use has been questioned. However, these tests are relatively inexpensive, and it may not be unreasonable to obtain them annually.

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Tumor markers There is no evidence that tumor markers, such as carcinoembryonic assay (CEA), CA-15-3, and CA57-29, provide an advantage in survival or palliation of recurrent disease in asymptomatic patients. Therefore, the use of tumor markers to follow long-term breast cancer survivors is not recommended. Bone scans Postoperative bone scans are also not recommended in asymptomatic patients. In the NSABP B-09 trial, in which bone scans were regularly performed, occult disease was identified in only 0.4% of patients. Liver and brain imaging Imaging studies of the liver and brain are not indicated in asymptomatic patients. PET scans are not routinely recommended. Their utility is primarily as an adjunct study, often to establish the extent of metastatic disease. Pelvic examinations Women with intact uteri who are taking tamoxifen should have yearly pelvic examinations because of their risk of tamoxifen-associated endometrial carcinoma, especially among postmenopausal women. The vast majority of women with tamoxifen-associated uterine carcinoma have early vaginal spotting, and any vaginal spotting should prompt a rapid evaluation. However, since neither endometrial biopsy nor ultrasonography has demonstrated utility as a screening test in any population of women, routine use of these tests in asymptomatic women is not recommended. Bone density Premenopausal women who become permanently amenorrheic from adjuvant chemotherapy and postmenopausal women who are treated with an aromatase inhibitor are at increased risk for bone fracture from osteopenia/ osteoporosis. These patients should undergo monitoring of bone health every 1 to 2 years.

SUGGESTED READING
Albain KS, Green SJ, Ravidin P, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Results from intergroup 0100 (SWOG-8814) (abstract). Proc Am Soc Clin Oncol 21:37a, 2002. ATAC (Arimidex,Tamoxifen, Alone or in Combination) Trialists’ Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131–2139, 2002. Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation after neoadjuvant chemotherapy: The M. D. Anderson Cancer Center experience. J Clin Oncol 22:2303– 2312, 2004. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia B trial 9741. J Clin Oncol 21:1431–1439, 2003.

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Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092, 2004. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802, 2003. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62, 2005. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with nodepositive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635, 2002. Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/ cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28 (abstract). Proc Am Soc Clin Oncol 22:4, 2003. Nabholtz JM, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node-positive breast cancer patients: Interim analysis of the BCIRG 001 (abstract). Proc Am Soc Clin Oncol 21:36a, 2002. Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24–29, 2005. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report. J Clin Oncol 23:619–629, 2005.

STAGE II BREAST CANCER

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