Treatment of locally advanced breast cancer.

It is possible to convert most patients with stage III breast cancer to the state of "no evidence of disease." The challenges now are to increase the cure rate by eradicating local and distant micrometastatic disease, and to minimize the mutilation of locoregional treatment.     

Factors affecting outcome in locally advanced breast cancer.

Patients presenting with locally advanced breast cancer (LABC) constitute a diverse group for which a variety of treatment modalities have been instituted. To assess which factors have a direct impact on outcome, we reviewed the medical records of 104 patients diagnosed with stage IIIA, stage IIIB and T3N0M0 breast carcinoma. When considered individually (univariate analysis), clinical stage, pathological stage, oestrogen receptor status and type of therapy were significant predictors for disease-free survival (DFS) and overall survival (OS). However, in a multivariate analysis, only clinical stage was a significant predictor for both DFS and OS, while ER status was a significant predictor for OS. There was a high degree of correlation between clinical and pathological staging. Nearly two-thirds of the patients developed a recurrence by 5 years. Loco-regional recurrence was the site of first recurrence in one-third of the patients by 5 years. The prognosis for patients presenting with LABC is poor, and they should be treated aggressively with loco-regional and systemic multimodality therapy. Although groups of patients with improved outcome could be identified by clinical or pathological staging, no group demonstrated an outcome good enough to be spared from multimodality therapy.     

Update on locally advanced breast cancer

Locally advanced breast cancer remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. Patients with locally advanced disease encompass a wide range of clinical scenarios including advanced primary tumors (stage T4), advanced nodal disease (fixed axillary nodes or involvement of ipsilateral supraclavicular, infraclavicular, or internal mammary nodes), and inflammatory carcinomas. The prognoses of women with locally advanced breast tumors are also heterogeneous and depend on tumor size, extent of lymph node involvement, and the presence or absence of inflammatory carcinoma. Women with locally advanced disease require multimodal therapy, and coordinated treatment planning among the medical oncologist, surgical oncologist, and radiation oncologist is necessary to optimize patient care. In this article, the epidemiology, evaluation, prognostic factors, and treatment for locally advanced breast cancer are discussed. Inflammatory cancer is also reviewed, but is considered separately due to its distinct biology and clinical behavior.     

Neoadjuvant chemotherapy in locally advanced breast cancer

Thirty-eight patients with locally advanced breast cancer (Stage III) were treated over a 3-year period. All patients initially received two cycles of CMF (cyclophosphamide, 100 mg/m² p.o. d1–14; methotrexate 40mg/m² intravenously (iv), d1 and d8., 5 Fluorouracil 500 mg/m² iv d1 and d8). They were then subjected to surgery and external beam irradiation to the chest field and drainage areas. Four more cycles of chemotherapy completed the treatment protocol. A response to initial chemotherapy was seen in 75.7% patients, with two patients achieving a complete response. No patient had disease progression while on chemotherapy. Tumor reduction of a degree to allow breast conservation procedures was seen in eight patients. The chemotherapy was well tolerated. Twelve patients failed to complete the treatment protocol. Follow-up for the remaining 26 ranges from 9–40 months (mean 18 months). Ten patients developed a recurrence. Of those, only one had isolated local recurrence, two had local and systemic recurrence, and seven had systemic disease alone. Patients with recurrence were salvaged with further chemotherapy (Adriamycin and cyclophosphamide). © 1996 Wiley-Liss, Inc.     

Clinical trials in locally advanced breast cancer

Survival after treatment of locally advanced breast cancer is poor and resembles that for untreated breast cancer. Although retrospective comparisons have suggested that the addition of systemic treatment might be beneficial, a literature survey of the controlled clinical trials failed to show consistent survival benefits of any treatment modality. The local control, or time to local progression, on the other hand seems to be improved by increasing the dose of radiotherapy, or by the addition of endocrine or cytostatic treatment. Further studies should be undertaken to find better means to subdivide patients in different treatment groups. Since the present treatment modalities are unlikely to improve survival more than marginally, clinical studies are necessary to search for the best palliative treatment, until experimental work provides us with better treatment tools.     

Hyperthermia for locally advanced breast cancer

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.     

Neoadjuvant docetaxel in locally advanced breast cancer

Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast conserving therapy. Pathologic response rate, though generally low, is an important outcome as it is presumably associated with eradication of micrometastatic disease and may likely result in improved outcomes. Anthracyclines have long been considered the most efficacious chemotherapy agents for neoadjuvant therapy of early breast cancer. Unfortunately, not all patients respond to neoadjuvant anthracycline-based chemotherapy. In an effort to improve primary tumor response, docetaxel, an active agent in breast cancer, has been evaluated in the neoadjuvant setting. Several randomized trials, including the NSABP B-27, GEPAR-duo, and the Aberdeen trial, evaluating docetaxel in sequence with a doxorubicin-based neoadjuvant regimen have been reported, with encouraging findings. We designed the Aberdeen trial with two primary aims: (1) to evaluate primary docetaxel in patients that initially fail a neoadjuvant anthracycline-based polychemotherapy regimen, and (2) to compare a docetaxel-based neoadjuvant regimen with a standard anthracycline-based regimen in patients who do respond to the first four cycles of the anthracycline-based regimen. Eligible patients (n = 162) had previously untreated large (> or = 3 cm) or locally advanced (T3, T4, T x N2) breast cancer. All received four cycles of CVAP, after which clinical response was assessed. Responding patients were then randomized to four additional cycles of CVAP or to docetaxel 100 mg/m2 every 3 weeks for four cycles. Patients failing to respond to CVAP received the docetaxel regimen. After the first four cycles of CVAP, the overall response rate (ORR) was 67%. Ultimately, responses were higher in the group randomized to docetaxel compared with those continuing CVAP (cCR: 94% vs. 66%; p = 0.001; pCR 34% vs. 16%; p = 0.04). The addition of docetaxel improved overall survival and disease-free survival for patients responding to four cycles of CVAP as compared with those receiving eight cycles of CVAP. Relative dose intensity was higher and the incidence of severe leukopenia was lower in the group randomized to docetaxel. These data and data from the NSABP B-27 and GEPAR-duo trials strongly support a combined anthracycline/docetaxel regimen in the neoadjuvant setting.     

Combined sequential approach in locally advanced breast cancer

Background: The interaction between primary and adjuvant chemotherapy is a crucial point in the treatment of locally advanced breast cancer.Objective: To evaluate the therapeutic efficacy of a sequential treatment with primary anthracyclines and adjuvant CMF in this patient subset.Design: Prospective cohort study.Patients: Eighty-eight breast cancer patients, stage T3b-T4 abc, N0–2, M0.Results: From February 1991 to July 1994, 88 consecutive patients with locally advanced breast cancer were treated at the Istituto Nazionale Tumori, Milano, with full-dose doxorubicin (75 mg/m2) or epirubicin (120 mg/m2) for three cycles followed by surgery, adjuvant chemotherapy with i.v. CMF for six cycles and local radiotherapy ± Tamoxifen. A high rate of objective responses (70%), but a low incidence of pathologic complete remission (2%), were observed following primary treatment with single-agent anthracyclines. Frequency of responses was not associated with tumor estrogen or progesterone receptors status, Mib-1 or grading. In 28 patients (32%) conservative surgery could be performed. At a median follow-up of 52 months, relapse free survival and overall survival are 52% and 62%, respectively. A multivariate analysis demonstrated a significant favorable prognosis in patients with limited nodal involvement at surgery and negative Mib-1 values. This drug sequence failed to significantly ameliorate the long term results in this unfavorable patient subset and more effective drug regimens and innovative therapeutic strategies are needed.     

Dose-intensive chemotherapy for locally advanced breast cancer

The availability of hematopoietic growth factors has allowed a range of feasibility and uncontrolled studies with high-dose chemotherapy (with or without stem-cell support) to take place. Preliminary data from some randomized studies are now available as well. Dose-intensive chemotherapy appears to be effective in downstaging the tumor. Only a minority of patients achieve a pathologic complete remission and additional therapeutic options to control minimal residual disease are urgently needed. There are few indications that highdose chemotherapy is superior to conventional dose therapy in terms of relapse-free or overall survival. Although the results of most randomized studies are premature or unknown at this time, a modest but clinically significant survival advantage may still emerge.     

Neoadjuvant chemotherapy FEC-HD in locally advanced breast cancer

The tolerance and the clinical and histological efficacy of a neoadjuvant chemotherapy FEC-HD including hematopoietic growth factors have been studied in 40 patients with stade II or III breast cancer between February 1991 and February 1997. Four courses were given, every 21 days, with 5-fluorouracil (750 mg/m2/day D1 to D4 by continuous infusion), epirubicin (35 mg/m2/day D2 to D4) and cyclophosphamide (400 mg/m2/day D2 to D4) with G-CSF (5 mug/kg/day D6 to D15). The surgery was performed 3 or 4 weeks after the end of the chemotherapy. All patients had radiotherapy. The neoadjuvant chemotherapy induced 37.5% CR, 45% PR, and 15% SD. In 40% of the patients, the surgery was conservative. An histological CR was obtained in 15% with no axillary involvement one time out of two. There was intraductal carcinoma without invasive carcinoma in 7.5%. There was no differences between the response of inflammatory and non inflammatory tumors. One hundred and fifty-eight courses have been delivered. A grade 3 or 4 leuconeutropenia, anemia and thrombopenia have been observed in respectively 34.6%, 6.3% and 8.8% of the courses. A grade 3 or 4 mucositis has been noticed in 2.5% of the courses. A febrile granulocytopenia has occurred in 3.8% of the courses. The median survival without metastatic progression was 48 months and the median overall survival was not achieved. In stade II and III breast cancer, neoadjuvant chemotherapy with FEC-HD obtains an important histological response with an acceptable toxicity. The role of the dose-intensity increase on survival remains to be determined.     

局部晚期乳腺癌的治疗进展

新辅助化疗后再手术和（或）放疗已成为治疗局部晚期乳腺癌的治疗模式。本文综述新辅助化疗的依据、疗程方案、影响疗效及预后相关因素及其优缺点，同时介绍了局部晚期乳腺癌诊断，局部治疗及内分泌治疗等方面的进展。     

Circulating tumour cells in locally advanced breast cancer

Material and methods

A prospective study was conducted to determine the value of changes in circulating tumour cell (CTC) levels prior to and after the first cycle of neoadjuvant treatment in early prediction of pathologic response in locally advanced breast cancer (LABC). Two blood samples were obtained from 72 eligible LABC patients to isolate and enumerate CTCs before neoadjuvant chemotherapy started on day 1, and on day 21, immediately before second cycle administration.

Results

Sixty patients (83.3%) had <1 CTC in the first sample and response rates in this cohort were pathologic complete response (PCR) in 2 patients (5%), partial response (PR) in 35 (87.5%), stable disease (SD) in 2 (5%) and progressive disease (PD) in 1 (2.5%). Twelve patients (16.7%) had >2 CTCs in the first sample; these patients were more likely to have triple negative tumours. All 12 had fewer CTCs in the second sample. Response rates in this second cohort of 12 patients were PCR in 4 (34%), PR in 6 (50%), SD in 1 (8%) and PD in 1 (8%). PCR rate was markedly better in this second cohort (p<0.0042; OR 14.5, 95% CI 2.3–92).

Discussion

This study suggests that the presence of CTCs prior to neoadjuvant therapy might be a predictor of response to this therapy.     

Multimodality treatment of locally advanced breast cancer

From 1976 to 1985, 61 consecutive patients with locally advanced breast cancer were treated with multimodality therapy. Overall 5-year survival was 30% with a median survival of 36 months. 50% of patients relapsed within 13 months. Other factors such as menopausal status, side of illness (right or left breast), responses to systemic or to local treatment, survival and progression-free survival in responders and non-responders have been analyzed.     

局部晚期乳腺癌的保留乳房手术

乳腺癌是女性最常见的恶性肿瘤之一,局部晚期乳腺癌(LABC)的治疗是世界范围内的临床难题,影响着乳腺癌总体生存率的提高。LABC的涵盖范围伴随着TNM分期系统的修订而不断变化。已有的研究证明,新辅助化疗后可以进行保留乳房手术(BCT),但要严格掌握适应证,保留乳房手术的指征已逐渐取得共识。开始治疗之前准确记录或定位肿瘤,要保证足够的阴性切缘。对于腋窝淋巴结手术问题仍有争议,多数主张常规进行清除手术。预后上不差于早期乳腺癌作保留乳房手术后的局部复发率。