West Midlands Oncology Association trial of adjuvant chemotherapy in node-negative breast cancer.

Between 1976 and 1984, 574 patients with operable breast cancer and histologically negative axillary lymph nodes were randomly assigned after mastectomy to receive either no further treatment or chemotherapy with oral LMF (fluorouracil, 500 mg, methotrexate, 25 mg, and chlorambucil, 10 mg, on day 1; fluorouracil, 500 mg, and chlorambucil, 10 mg, on day 2). There is no overall survival or relapse-free survival benefit at a median follow-up of 10 years and 8 years, respectively. There are significantly more local relapses in the control group (P less than .01), but an excess of distant relapses in the treated group is not statistically significant (P = .24). A positive treatment effect in small tumors (relapse-free survival, odds ratio = 0.55, P = .01) and a negative effect in progesterone receptor-positive tumors (survival, odds ratios = 2.04, P = .04) is probably ascribable to chance. Analysis of various prognostic factors shows that tumor size and histological grade have a clear effect on both relapse-free interval and survival.     

Selection criteria for epirubicin-based adjuvant chemotherapy in node-negative breast cancer

The management of node-negative breast cancer is problematic due to the lack of reliable prognostic para-meters that distinguish patients who benefit from adjuvant chemotherapy. Since surgery alone is curative in approximately 70% of these patients, clinicians are faced with the dilemma of possible overtreatment or undertreatment. As a compromise, traditional cyclophosphamide/methotrexate/fluorouracil (CMF) is administered rather than newer, potentially more effective regimens containing anthracyclines or taxanes. Invasion and metastasis of solid tumors require tumor-biologic factors that promote the dissolution of the surrounding tumor matrix and the basement membranes, and the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator-inhibitor type 1 (PAI-1), play major roles in these invasive processes. Our laboratory and others have reported that determinations by enzyme-linked immunosorbent assay (ELISA) of uPA and PAI-1 concentrations in tumor tissue extracts reliably separate patients with node-negative breast cancer at very low risk of relapse even without chemotherapy from high-risk patients who urgently need intensive effective treatment in order to reduce increased mortality. By eliminating low-risk patients from study entry, these markers permit unbiased evaluation of newer anthracycline-containing regimens in high-risk patients with node-negative disease. A multicenter, transnational European study is currently underway to compare the efficacy of a regimen combining epirubicin and cyclophosphamide with the traditional CMF regimen in these patients, whose risk of relapse and death is similar to that of many patients with node-positive disease.     

Attitudes and practices regarding adjuvant chemotherapy in node-negative breast cancer

Eight months after an NCI "Clinical Alert" was issued a survey was conducted to examine attitudes and practices regarding the use of adjuvant chemotherapy for node-negative breast cancer among Connecticut physicians most experienced in the care of such patients. Respondents (N = 66) indicated that the communication prompted change in case management practices; 65% reported increased use of adjuvant chemotherapy in treatment of women with node-negative disease. Seventy-seven percent of physicians who responded now consider adjuvant chemotherapy for node-negative patients to be the standard of care in their community. Opinions regarding the NCI strategy were more equivocal, with 44% of respondents terming the issuance of the Clinical Alert "inappropriate." Our findings suggest that real change in the treatment of breast cancer may have been precipitated by the NCI's action.     

Feasibility of adjuvant chemotherapy for breast cancer patients

To evaluate the feasibility of adjuvant chemotherapy, we analyzed the toxicities of chemotherapy for primary breast cancer in Japanese women. Since the opening of the National Cancer Center Hospital East, 180 female breast cancer patients have received adjuvant chemotherapy or chemo-hormonal therapy following surgical treatment between June 1992 and December 1995. On the basis of informed consent about prognosis and adjuvant therapy, most patients decided to choose the type of cytotoxic chemotherapy themselves. Adjuvant chemotherapy consisted of oral fluoropyrimidine compounds (OFP), cyclophosphamide + adriamycin +/- 5-fluorouracil [CA(F)] or cyclophosphamide + methotrexate + 5-fluorouracil (CMF). Toxicity was determined using the Toxicity Grading Criteria of the Japan Clinical Oncology Group (JCOG). Sixty-six patients received OFP, 59 CA(F) and the rest 55 CMF. The toxicity grading of leukocytes and neutrophils was significantly higher in patients treated with CA(F) or CMF than in those treated with OFP. Similar results were also seen relating to the toxicity of nausea/vomiting and alopecia. There was no statistical difference in the toxicity grading of hemoglobin, glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) and stomatitis/ gastritis between the three groups of patients. Interestingly, the number of patients that were forced to discontinue chemotherapy was higher in those receiving OFP than in those receiving CA(F) or CMF. Cytotoxic chemotherapy of CA(F) or CMF results in greater toxicity than OFP, but is tolerated and feasible in the adjuvant setting used in Japanese breast cancer patients from the viewpoint of toxicities by anticancer chemotherapy.      

Helping patients make informed choices: a randomized trial of a decision aid for adjuvant chemotherapy in lymph node-negative breast cancer

BACKGROUND: In recent years, patients have indicated a desire for more information about their disease and to be involved in making decisions about their care. We developed an aid called the "Decision Board" to help clinicians inform patients with lymph node-negative breast cancer of the risks and benefits of adjuvant chemotherapy. We determined whether adding the Decision Board to the medical consultation improved patient knowledge and satisfaction compared with the medical consultation alone. METHODS: Between October 1995 and March 2000, 176 women with lymph node-negative breast cancer who were candidates for adjuvant chemotherapy were randomly assigned to receive the Decision Board plus the medical consultation (83 patients) or the medical consultation alone (93 patients). One week after the consultation, patients completed a questionnaire assessing their knowledge about breast cancer and chemotherapy. Satisfaction with decision making was assessed 1 week and 3, 6, and 12 months after randomization, and differences between groups were analyzed by a repeated measures analysis of variance. All statistical tests were two-sided. RESULTS: Patients in the Decision Board arm were better informed about breast cancer and adjuvant chemotherapy than patients in the control arm (mean knowledge score = 80.2 [on a scale of 0-100], 95% confidence interval [CI] = 77.1 to 83.3, and 71.7, 95% CI = 69.0 to 74.4, respectively; P<.001). Over the entire study period, satisfaction with decision making was higher for patients in the Decision Board arm than for patients in the control arm (P =.032). There was no statistically significant difference between the two groups in the number of patients who chose adjuvant chemotherapy (77% and 70% for patients in the Decision Board arm and those in the control arm, respectively; P =.303). CONCLUSION: When making decisions regarding adjuvant chemotherapy, patients with early breast cancer who had been exposed to the Decision Board had better knowledge of the disease and treatment options and greater satisfaction with their decision making than those who received the standard consultation.     

临床淋巴结阴性乳腺癌新辅助化疗与腋窝降阶梯处理的研究

背景与目的：前哨淋巴结活检（sentinel lymph node biopsy,SLNB）是临床淋巴结阴性（clinically nodenegative,cN₀）早期乳腺癌患者诊断的标准,但对于新辅助化疗（neoadjuvant chemotherapy,NAC）的cN₀患者行SLNB的时机仍存在争议。本研究旨在探讨cN₀患者接受NAC与SLNB的最佳时机,评估其NAC后选择性避免腋窝手术的可行性。方法：回顾性分析2010年10月—2018年4月山东大学附属山东省肿瘤医院乳腺病中心收治的809例行NAC患者的临床病理学资料,分析138例cN₀患者的不同临床病理学特征与NAC后腋窝淋巴结阴性（即ypN₀）的相关性。结果：cN₀患者NAC后81.9%（113/138）为ypN₀。激素受体（hormone receptor positive,HR）阳性（+）/人表皮生长因子受体2（human epidermal growth factor receptor-2,HER2）阴性（-）、HR⁺/HER2⁺、HR-/HER2⁺,以及三阴性乳腺癌（triple-negative breast cancer,TNBC）患者NAC后ypN₀率分别为75.4%（46/61）、81.0%（17/21）、79.2%（19/24）和96.9%（31/32）（P<0.001）。HER2⁺患者接受靶向治疗、TNBC患者接受NAC后,ypN₀率分别为94.1%（16/17）、96.9%（31/32）,较HR⁺/HER2^-患者显著增高（均P<0.05）。乳房肿瘤的分子分型、临床分期、影像学完全缓解及病理完全缓解（breast pathologic complete response,bpCR）与NAC（行全疗程化疗）后ypN₀显著相关（P均<0.05）,其中乳房肿瘤的分子分型（OR=0.454, P=0.049）、临床分期（OR=3.174,P=0.029）和bpCR（OR=0.337,P=0.016）是NAC后ypN₀的独立预测因素。结论：不同分子分型cN₀患者NAC与SLNB的最佳时机不同：HR⁺/HER2^-患者接受NAC前行SLNB可降低腋窝淋巴结清扫（axillary lymph node dissection,ALND）的风险,而HER2⁺患者接受靶向治疗和TNBC患者NAC后行SLNB能更好地避免ALND。鉴于cN₀患者NAC后的高ypN₀率,尤以HER2⁺行靶向治疗及TNBC患者为著,使其NAC后选择性避免腋窝手术成为可能。     

Current status of Milan adjuvant chemotherapy trials for node-positive and node-negative breast cancer

This report summarizes the most important clinical results achieved at the Milan Cancer Institute through various randomized trials with systemic adjuvant chemotherapy. In the study testing surgery versus surgery plus 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in node-positive patients, the reduction in failure rate (34%) significantly favored CMF-treated patients (P less than 0.001). Despite a reduction in the death rate of 23%, the overall survival showed only a trend for CMF compared to surgery alone (P = 0.10). In a second study, the 8-year results confirmed the lack of difference in relapse-free survival and total survival rates between patients who received 12 and 6 cycles of CMF. The third study indicated that at 6 years, postmenopausal women who had 1-3 positive lymph nodes and were treated with full-dose sequential non-cross-resistant combinations had rates of relapse-free survival and total survival that were superior to those previously achieved with CMF in the same menopausal subset. In a limited series of patients with negative axillary nodes as well as negative estrogen receptors, there was clear evidence of very poor prognosis in women given only local-regional therapy, compared to women treated with adjuvant CMF. Within the node-negative subset, the proliferative activity (labeling index) of the primary tumor appears to be a more effective prognostic discriminant than estrogen receptor status. The proportion of primary drug-resistant tumor cells as well as the lack of relative dose intensity in the drug programs tested so far probably represent the two most important causes for the failure of adjuvant chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sentinel lymphadenectomy for the staging of clinical axillary node-negative breast cancer before neoadjuvant chemotherapy

Background

Several authors reported sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NC). Nevertheless, the ideal time of SLNB is still a matter of debate.

Methods

We evaluated the feasibility and the accuracy of SLNB before NC using a combined procedure (blue dye and radio-labelled detection) before NC. Axillary lymph node dissection (ALND) was performed after completion of NC in a homogeneous cohort study with clinically axillary node-negative breast cancer.

Results

Among the 20 women who had metastatic SLNB (65%), 4 (20%) had additional metastatic node on ALND. By contrast, all the 11 women who had no metastatic SLNB had no involved nodes in the ALND. The SLN identification rate before NC was 100% with any false negative.

Conclusions

SLNB before NC is a feasible and an accurate diagnostic tool to predict the pre-therapeutic axilla status. These findings suggest that ALND may be avoided in patients with a negative SLNB performed before NC.     

Treatment decisions in axillary node-negative breast cancer patients.

Treatment decisions must be made on 9000 axillary node-negative breast cancer patients each month in the United States. Which of these patients will benefit from adjuvant therapy is a major question. Valid methods are needed to distinguish those patients who are "cured" from those who will suffer a cancer recurrence. A complex network of prognostic variables enters into the treatment decision, together with a risk-versus-benefit assessment. We are using a neural-network-based form of artificial intelligence that, once "trained" with data representing an event and its outcome, can identify subsets of patients with low recurrence risks. Larger data sets are being evaluated with the hope of introducing the neural-network technique to routine clinical practice.     

Ten-year results of FAC adjuvant chemotherapy trial in breast cancer

Two hundred twenty-two patients with stage II or III breast cancer were treated in the first adjuvant trial from M.D. Anderson Hospital. At a median follow-up of 133 months, estimated 10-year disease-free survival was 58 and 36% for stage II and III disease, respectively. Estimated 10-year survival was 62% for patients with stage II disease and 40% for those with stage III disease. The fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC) regimen was effective in improving disease and overall survival regardless of age of the patient, stage of disease, or extent of nodal involvement in comparison with the historical control patients treated with similar local therapy. The treatment was not associated with increased risk of other malignancies, and doxorubicin-related cardiotoxicity was observed in 1% of patients. Long-term follow-up of this study confirms the earlier observation that the FAC regimen is effective in reducing the risk of recurrence and prolonging the survival of high-risk patients.     

Clinical relevance of prognostic factors in axillary node-negative breast cancer

In node-negative breast cancer, advices for adjuvant therapy are based on traditional factors like age, tumour size, grade of differentiation, and steroid hormone receptor status. Several new factors that may better describe tumour behaviour, like proliferation rate (determined by thymidine labelling index, S-phase fraction, mitotic index, or Ki-67), presence of disseminated tumour cells, as well as expression of invasion factors (urokinase-type plasminogen activator uPA and its inhibitor PAI-1) and of cell cycle genes (cyclin E), as well as gene expression patterns ('genomic profiling') are currently discussed as future methods of risk assessment and also as tools for prediction of response to specific therapy modalities. Recommendations for routine use should be based on criteria of evidence-based medicine and on their impact on clinical decision making. Among the aforementioned factors, only the invasion factors uPA and PAI-1 have reached the highest levels of evidence and are mature enough to be transferred into clinical routine: their prognostic impact has been shown in several retrospective and prospective studies and in a pooled analysis of almost 3,500 node-negative patients. Their clinical impact was demonstrated in a prospective therapy trial. In addition, a predictive value with regard to chemotherapy efficacy has recently been supposed. Thus, in order to correctly assess the individual risk and to design an adequate adjuvant treatment plan for node-negative breast cancer patients, we recommend to use uPA and PAI-1 as additional criteria together with grading and age.     

Postmastectomy radiotherapy and concomitant adjuvant chemotherapy versus adjuvant chemotherapy alone in premenopausal breast cancer patients with positive axillary nodes

AIMS: To evaluate the efficacy of postmastectomy radiotherapy (RT) combined with adjuvant chemotherapy compared to adjuvant chemotherapy alone as regards overall survival (OS), overall disease-free survival (ODFS), local disease-free survival (LDFS) and distant disease-free survival (DDFS). METHODS: We reviewed retrospectively two non-randomized groups of premenopausal high-risk breast cancer patients treated from 1985 to 1990 in the following Institutions: Department of Radiation Oncology of Brescia University, "Istituto del Radio O. Alberti" (IRA), and Department of Oncology of Brescia Hospital "Beretta Foundation" (BF). A total of 163 patients was found to satisfy the criteria of the current analysis: 81 patients received adjuvant chemotherapy alone [6 cycles CMF(1-8)] at BF and 82 patients received postoperative radiotherapy and chemotherapy [8 cycles CMF(1-21)] at IRA. A modified CMF schedule was chosen at IRA to avoid the feared increase in toxicity due to the association with RT. Primary surgical treatment was modified radical mastectomy with axillary node dissection in both cases. RESULTS: A statistically significant improvement in OS was found in systemic adjuvant therapy patients compared to those also given RT (77.6% vs 59%; P = 0.0025). No statistically significant improvement in ODFS was found in the CMF(1-8) arm compared to the RT and CMF(1-21) stm: 51.6% vs 43.6%; P = 0.46. A statistically significant improvement in LDFS at 5 years was found in irradiated patients (89.3% vs 76.2%; P <0.05). The DDFS was also improved, although without evidence of statistical significance, in the CMF(1-8) group: at 5 years 65% vs 44% (P = 0.059). CONCLUSIONS: The study confirmed that RT reduces the risk of local recurrence but without a statistically significant reduction in mortality. The lack of a survival benefit may somehow reflect the dose reduction in CMF(1-21). The evidence that CMF(1-8) offers undoubtable advantages over the CMF(1-21) regimen in OS and, perhaps, in distant control suggests that the dose intensity of CMF in this setting may also be important. In fact, although many CMF(1-8) patients received a dose intensity lower than 100%, 95% of them received a dose intensity higher than the maximum one of the CMF(1-21) patients. Although our results should be interpreted with caution, they seem to provide further rationale for testing the association of postoperative radiotherapy and the CMF(1-8) regimen in stage II breast cancer with positive nodes and treated with demolitive surgery, as already done in the conservative management of breast cancer, also in view of the new support therapies now available (i.e. hematologic growth factors).     

淋巴结阴性乳腺癌辅助疗法适应证的分析

目的：探讨淋巴结阴性（N0）乳腺癌辅助疗法的适应证。方法：以233例乳腺癌根治术切取20个以上淋巴结转移阴性的乳腺癌的患者为对象,对N0乳腺癌的复发因素和术后辅助疗法的适应证进行分析。结果：N0乳腺癌的术后复发率为17／233（7．3％）;年龄、月经史、部位、肿瘤直径及病理学因素与预后相关。在有意义的病理学预后因素中将浸润性小叶癌、组织学恶性度Ⅲ级（高度恶性）及淋巴细胞浸润阴性癌3项进行组合分析,其复发率具有3项者为28％,2项者为16％,1项者为7％。结论：对具有高危复发因素的N0乳腺癌需要进行辅助疗法。     

淋巴结阴性乳腺癌患者辅助治疗的研究进展

淋巴结阴性乳腺癌患者中有20%～30%经手术治疗后复发和转移.本文综述了如何选择需要内分泌治疗和/或化疗的淋巴结阴性乳腺癌患者,以及如何选择正确的治疗模式.     

Should women with node-negative breast cancer receive adjuvant chemotherapy? — Insights from a decision analysis model

Summary The use of adjuvant chemotherapy in women with node-negative breast cancer has been controversial and actively debated since the 1988 National Cancer Institute Clinical Alert. We developed a decision analysis model that used the results of available randomized controlled trials to assess the potential clinical and financial effects of using adjuvant chemotherapy for groups of 45-year-old and 60-year-old women. Using the baseline assumptions, we found that chemotherapy increases quality adjusted life expectancy and survival by a substantial amount at a cost comparable to most accepted medical interventions. The model highlights the uncertainties in duration of benefit from therapy, the need for refinements in risk stratification, the importance of patient preferences about toxicity and benefit, and the need for accurate cost-accounting for oncologic therapies. Decision analysis complements other methods for information gathering, analysis, and synthesis used in clinical research. With the increasing focus on the effectiveness of medical interventions, decision analysis will be an important tool for oncologists to understand.     

Randomized clinical trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide chemotherapy for patients with fast-proliferating, node-negative breast cancer.

PURPOSE: The prospective applicability of new biologic tumor information to personalize adjuvant treatment of women with operable breast cancer remains to be demonstrated. The aim of the present study was to investigate whether patients with fast-proliferating, node-negative breast cancer could benefit from adjuvant chemotherapy with fluorouracil, epirubicin, and cyclophosphamide (FEC). PATIENTS AND METHODS: Beginning in November 1989, we analyzed the proliferative activity of primary tumors in a consecutive series of women with node-negative breast cancer to identify subgroups of patients with a worse prognosis and who were therefore suitable candidates for adjuvant systemic therapy. Proliferative activity was determined by means of the [3H]-thymidine incorporation assay using an autoradiographic technique. Women with fast-proliferating breast cancer ([3H]-thymidine labeling index, > 2.3%) were randomized to receive either six cycles of adjuvant FEC or no adjuvant therapy until disease progression. RESULTS: One-hundred twenty-five and 123 patients treated with radical surgery for pT1 to T2, N0, M0 breast cancer were randomized to the FEC and control arms, respectively. After a median follow-up of 70 months, 27 events (21.6%) were observed in the FEC arm and 39 (32.2%) in the control arm, with a significantly lower number of locoregional relapses in the FEC group. Five-year disease-free survival (DFS) was 81% in the FEC group and 69% in the control group (P <.02 by log-rank test). Cox multivariate analysis described the impact of adjuvant therapy with FEC on DFS as independent of the patients' main clinical-pathologic characteristics. CONCLUSION: FEC adjuvant polychemotherapy seems able to significantly improve the clinical outcome of patients with fast-proliferating, node-negative breast cancer.     

Feasibility and toxicity of dose-dense adjuvant chemotherapy in older women with breast cancer

Introduction The objective of this study was to examine the feasibility and toxicity of adjuvant dose-dense chemotherapy in older women with breast cancer. Methods A search of the Memorial Sloan-Kettering Cancer Center (MSKCC) breast cancer database was performed to identify all patients age 60 and older who underwent an initial consultation with a breast medical oncologist between October 1, 2002 and June 28, 2005. Inclusion criteria were: (1) age ≥ 60, (2) follow-up care obtained at MSKCC, (3) intent to treat with adjuvant dose-dense AC-T (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles followed by paclitaxel 175 mg/m² every 2 weeks for 4 cycles, with white blood cell growth factor support). Results One hundred sixty-two patients (mean age 66, range 60–76) with breast cancer, stages I (n = 5), II (n = 111), and III (n = 46) according to the sixth edition of the AJCC staging system, were included in this analysis. Forty-one percent (n = 67) experienced a grade 3 or 4 toxicity, 9% a grade 3 infection (n = 14), 6% grade 3 fatigue (n = 9), 5% neutropenic fever (n = 8), and 4% thromboembolic events (n = 7). Twenty-two percent (n = 36) did not complete the planned 8 cycles of treatment. There was no statistically significant association between age and either toxicity or treatment discontinuation. In multivariate analysis including age, pretreatment hemoglobin, and comorbidity, the presence of comorbidity (Charlson score ≥ 1) and a lower baseline hemoglobin score were associated with an increased risk of any grade 3 or 4 toxicity. Conclusions We found that the risk of toxicity depended more on comorbid medical conditions and baseline hemoglobin value than age in this cohort of older adults receiving dose-dense adjuvant chemotherapy.     

A model of chemotherapy in node-negative breast cancer.

Should all women with node-negative breast cancer receive chemotherapy? Acceptance of such a broad recommendation has been controversial due to the relatively good prognosis of these women and the lack of evidence of an improvement from chemotherapy in overall survival. We studied the question with a decision analytic model, which simulates a clinical trial of a large number of women over several decades, to calculate quality-adjusted life expectancy and the cost-effectiveness of chemotherapy in 45-year-old and 60-year-old women. The model considered a variety of scenarios about the long-term benefits of chemotherapy. The initial analysis found a lifetime benefit of 4 to 5 quality months (range, 2 to 14 months) at a cost of $15,400 to $18,800 per quality year (range, $5,100 to $56,800). If a risk-stratification protocol could identify a low-risk group, then benefit drops to about 1 quality month at a cost of $65,000 to $90,000 per year. For the average woman, chemotherapy increases the quality-adjusted life expectancy by a substantial amount at a generally acceptable cost. However, given the uncertainty of the duration of benefit and current potential for risk-stratification, a broad recommendation for chemotherapy is inappropriate.