Optimizing adjuvant chemotherapy in early-stage breast cancer

Mortality in breast cancer has declined in the past decade, owing to advances in diagnosis, surgery, radiotherapy, and systemic treatments. Adjuvant chemotherapy has had a major effect on increasing survival in women with locoregional breast cancer. Like all treatments, adjuvant chemotherapy is a work in progress, and it has evolved from single oral agents to complex multidrug regimens. The choice of regimens is not without controversy, however, and several have been shown to be more effective than others, especially in patients who are at high risk for recurrence. The taxanes paclitaxel and docetaxel (Taxotere) have been shown to be effective in the adjuvant setting, and they have also been shown to improve the outcomes in node-positive disease. Both disease-free and overall survival are greater with doxorubicin, paclitaxel, and cyclophosphamide given in a dose-dense, every-2-week schedule with growth factor support than with the same agents given in an every-3-week schedule. Disease-free and overall survival in patients with node-positive disease are greater with docetaxel, doxorubicin (Adriamycin), and cyclophosphamide (TAC) than with fluorouracil, doxorubicin, and cyclophosphamide (FAC). Febrile neutropenia is common with the TAC regimen, but it can be minimized with growth factor support. Based on these findings, dose-dense therapy and TAC are the current adjuvant treatments of choice in patients with node-positive disease; other, less-intense regimens may be appropriate in patients with lower-risk disease. Ongoing trials are investigating the efficacy of commonly used regimens, new chemotherapeutic and biologic agents, and novel doses and schedules of currently available agents.     

Managing bone loss in women with early-stage breast cancer receiving aromatase inhibitors

Third-generation aromatase inhibitors (AIs; anastrozole, letrozole, exemestane) have replaced tamoxifen as the adjuvant treatment of choice for postmenopausal women with hormone receptor-positive early-stage breast cancer. Because bone loss is a predictable adverse event of AI therapy, early recognition, prevention, and/or treatment of AI-induced bone loss is needed. One to 5 years of AI therapy causes a bone mineral density (BMD) loss of up to 7.2% in postmenopausal women; however, current clinical guidelines do not recommend initiating bisphosphonate therapy for the treatment of BMD loss until fragility fractures or frank osteoporosis occur. Results of recent trials evaluating the use of intravenous (I.V.) zoledronic acid as prevention and treatment of AI-induced bone loss in women with early-stage breast cancer receiving letrozole suggest a potential benefit to the concurrent use of zoledronic acid and letrozole. To our knowledge, clinical trials assessing oral or other I.V. bisphosphonates for these indications have not been published. Recently, concerns of bisphosphonate-induced renal safety and osteonecrosis of the jaw have emerged. Studies evaluating bisphosphonates in women with breast cancer have reported lower rates of renal dysfunction than those reported in patients with metastatic cancer receiving bisphosphonates, and no cases of jaw osteonecrosis. The use of bisphosphonates in this population requires further study to more clearly define the most appropriate timing and length of therapy as well as the long-term efficacy and safety of these drugs. Until these data become available, balancing the safety concerns with the potential benefits of I.V. bisphosphonates to minimize or prevent AI-induced bone loss in women with early-stage breast cancer is required.     

乳腺癌相关信号转导通路的研究进展

乳腺癌的术后辅助全身化疗总是取得不断的进展。从环磷酰胺、甲氨喋呤和氟尿嘧啶的三联ＣＭＦ方案减低患者术后复发和死亡风险开始,辅助化疗方案在不断更新,蒽环类药物以及随后的紫杉醇类药物序贯或者联合应用已经成为目前主打的辅助化疗策略。患者的机体状况、肿瘤特定的生物学表型以及药物的疗效和毒性是制定辅助化疗方案必须综合考虑的因素。传统的预后指标评估患者复发风险仍然十分重要,此外新的基因组工具（如ＯｎｃｏｔｙｐｅＤＸ和Ｍａｍｍａｐｒｉｎｔ）便于我们更有选择地为不同的患者制定个体化的术后辅助治疗。     

Physical and psychologic distress associated with adjuvant chemotherapy in women with breast cancer

The incidence of physical toxicity and psychosocial effects associated with adjuvant chemotherapy for stage II breast cancer have been reported in previous studies. The purpose of this exploratory study was to quantify the degree of physical and psychologic distress experienced by patients and identify life-style changes. A semistructured interview was conducted with 78 subjects to elicit demographic data, distress, and life-style changes using the Symptoms Distress Scale (SDS), the Psychiatric Status Schedule (PSS), and questions and scales developed by the investigator. All subjects received adjuvant chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil with or without vincristine and prednisone) following primary treatment for breast carcinoma. Fifty subjects were currently on therapy and 28 had completed treatment. Fatigue was the most distressful physical symptom. Although physical distress was rated higher by subjects receiving treatment, generally all rating scores indicated only mild symptom distress. Subjects perceived more distress for the psychologic and emotional response to disease and treatment, and this persisted for women who completed therapy. Changes in role performance and daily activity were minimal.     

Outcomes of women with early-stage breast cancer receiving adjuvant trastuzumab

Introduction

Large randomized trials assessing the benefit of adjuvant trastuzumab in early-stage breast cancer positive for the human epidermal growth factor receptor 2 (her2) have demonstrated a significant improvement in survival. The objective of the present study was to describe the outcomes of women who received adjuvant trastuzumab for her2-positive breast cancer in British Columbia since publicly funded population-based use was initiated in July 2005.

Methods

Women from British Columbia, newly diagnosed with stage i–iii breast cancer between July 2004 and December 2006, who were positive for her2 overexpression by immunohistochemistry (3+) or amplification by fluorescence in situ hybridization (ratio ≥ 2.0) were included in the study. Data were collected from the prospectively assembled BC Cancer Agency Outcomes Unit, with cases linked to the provincial pharmacy data repository to determine the proportion of women who received adjuvant trastuzumab.

Results

Our retrospective study identified 703 her2-positive patients, of whom 480 (68%) received trastuzumab. In patients receiving trastuzumab, the 2-year relapse-free survival was 96.1% [95% confidence interval (CI): 93.6% to 97.7%] and the overall survival was 99.3% (95% CI: 97.9% to 99.8%). Among node-negative and -positive patients, the 2-year relapse-free survival was 97.8% and 94.8% respectively (p = 0.09) for the trastuzumab-treated group and 90.9% and 77.3% (p = 0.01) for the group not receiving trastuzumab (n = 223). Site of first distant metastasis was the central nervous system in 19.5% of the entire cohort and in 37.5% of patients treated with trastuzumab.

Discussion

This population-based analysis of adjuvant trastuzumab use among Canadian women demonstrates highly favorable outcomes at the 2-year follow-up.     

Gray matter density reduction associated with adjuvant chemotherapy in older women with breast cancer

Purpose

The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer.

Methods

We recruited 16 women aged ≥?60 years with stage I–III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry.

Results

The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (p_{FWE(family-wise error)-corrected}?<?0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (p_{FWE-corrected}?<?0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (p_{FWE-corrected}?<?0.05).

Conclusions

Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).

     

Routine cardiac evaluation in patients with early-stage breast cancer before adjuvant chemotherapy

IntroductionThis population-based study of women diagnosed with early-stage breast cancer aimed to (i) determine the current utilization pattern of multigated acquisition (MUGA) scans before adjuvant chemotherapy (AdjC) treatment, and (ii) examine the impact of MUGA scan results on AdjC decision making.MethodsAll women who underwent curative-intent surgery for stage I-III breast cancer between October 2005 and September 2006 in Nova Scotia, Canada, were identified through the provincial cancer registry. A retrospective chart review was performed to abstract all relevant clinical-pathologic variables, including baseline cardiac risk factors. The association between MUGA scan utilization and clinical-pathologic variables, as well as receipt and type of AdjC, was examined through univariate and multivariate analyses.ResultsThe study included 593 women, of whom 238 (40%) received AdjC (94% anthracycline vs. 6% nonanthracycline) and 198 (33%) underwent baseline MUGA scans. Of those received AdjC, 80% underwent MUGA scans. MUGA scan utilization was associated with AdjC treatment (yes vs. no; P < .0001), Her-2/neu status (positive vs. negative vs. not tested; P < .0001), and AdjC regimen (anthracycline vs. nonanthracycline; P < .0001). Abnormal MUGA results were observed in 5 (2.5%) of 198; all were smokers, and 4 were >65 years of age. In the 1 patient <50 years old, subsequent echocardiograms indicated normal cardiac function.ConclusionsRoutine baseline MUGA scans before AdjC were abnormal and changed the AdjC treatment decision in only 2.5% and 2.0% of patients, respectively. Routine MUGA scans before anthracycline-based AdjC without trastuzumab, however, did not influence AdjC decisions for younger patients <65 years of age without underlying cardiac risk factors.     

International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer

BACKGROUND: The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer. METHODS: Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided. RESULTS: Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%). CONCLUSION: These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer.     

Delivering adjuvant chemotherapy to women with early-stage breast carcinoma: current patterns of care.

BACKGROUND: Variations in practice patterns are markers for the quality of patient care in general medicine, but little is known about variation in care delivered to cancer patients. This study's purpose was to describe chemotherapy use, variations in chemotherapy delivery, and the incidence of complications in community practice settings. METHODS: Data describing adjuvant chemotherapy for patients with early-stage breast carcinoma (ESBC) were collected from an ongoing Oncology Practice Pattern Study at 13 large managed care, academic, and community practices (1111 patients). Data collection included information about diagnoses and adjuvant chemotherapy treatments, laboratory results, supportive care, complications, and treatment modifications. RESULTS: The median patient age was 50 years, and most patients had zero to three positive lymph nodes. Chemotherapy regimens consisting of cyclophosphamide, methotrexate, and 5-fluororacil (CMF) and of doxorubicin and cyclophosphamide (AC) accounted for 76% of the adjuvant therapies used. Overall, 30% of patients had delivered average relative dose intensities 相似文献   

Ovarian protection with goserelin during adjuvant chemotherapy for pre-menopausal women with early breast cancer (EBC)

PURPOSE: Ovarian failure and infertility following adjuvant chemotherapy for early breast cancer are major concerns for some young women. Techniques for oocyte harvesting are associated with delay in starting treatment, potentially undesirable estrogen stimulation and a relatively low success rate. We report an audit of our experience with the luteinising hormone-releasing hormone agonist, goserelin, to achieve transient ovarian suppression during chemotherapy as a means of preserving ovarian function. PATIENT AND METHODS: Pre-menopausal women were offered goserelin 3.6 mg by subcutaneous injection every 28 days during chemotherapy, starting 0-14 days prior to treatment. The primary end-point was recovery of menstruation. Serum luteinising hormone, follicle stimulating hormone and oestradiol were measured at recovery of menstruation or at first year follow-up if amenorrhoea persisted. Subsequent pregnancies were recorded. RESULTS: Fifty-one evaluable women were audited. Amenorrhoea occurred in all but one. All received combination anthracycline-containing chemotherapy regimens with a mean cumulative cyclophosphamide dose of 3.9 g/m(2). Forty-five (90%) recovered menstruation during the first year of follow-up; mean time to recovery 5 months. Eight pregnancies in 10 women attempting this so far. CONCLUSION: Using goserelin concurrently with chemotherapy is associated with a high rate of ovarian function preservation.     

Functional status is well maintained in older women during adjuvant chemotherapy for breast cancer.

BACKGROUND: While adjuvant chemotherapy is known to improve survival in older women with breast cancer, there is little information about its effects on physical function and health-related quality of life. PATIENTS AND METHODS: 'Young' (<65 years of age) and 'older' (> or = 65 years of age) postmenopausal women completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30) and BR23 questionnaires and other measures prior to, during and at the completion of anthracycline-based adjuvant chemotherapy, and then 6 and 12 months later. RESULTS: Physical, role and social function decreased during chemotherapy and emotional function improved (all P <0.01). The decline in physical function was more marked in young (age range 31-64 years; n = 45) than in older women (65-80 years; n = 20) (P <0.05), despite similar baseline values and drug dose intensities. Physical and role function had recovered at 6 months post-chemotherapy. Older patients had consistently better emotional function (P <0.01). CONCLUSIONS: Physical function and other functional domains are impaired in postmenopausal women during adjuvant chemotherapy for breast cancer, but recover subsequently. Physical function appeared to be better maintained in the older women, who tolerated adjuvant chemotherapy well overall. A knowledge of these effects is important for clinical decision-making and when defining social support needs during adjuvant chemotherapy.     

Predicting early failure after adjuvant chemotherapy in high-risk breast cancer patients with extensive lymph node involvement.

PURPOSE: There is limited knowledge of risk factors for breast cancer recurrence within 2 years. This study aimed to predict early failure and identify high-risk patients for prognostic and therapeutic purposes. EXPERIMENTAL DESIGN: We studied 739 patients from a randomized trial who were <56 years of age and had >/=4 or more positive lymph nodes, no distant metastases, and no previous other malignancies. After complete surgical treatment, patients received conventional-dose anthracycline-based chemotherapy or a high-dose scheme of anthracycline-based plus alkylating chemotherapy. We assessed clinical and (immuno)histological parameters to predict recurrence within 2 years. RESULTS: Early failure occurred in 19% (n = 137). Median survival after early failure was limited to 0.7 year. Estrogen and progesterone receptor negativity and visceral relapse predicted poor prognosis. Early failure was associated with young age, large tumors, high histological grade, angio-invasion, apical node metastasis, and >/=10 involved nodes. Estrogen receptor, progesterone receptor, and p27 negativity; HER2 overexpression; and p53 positivity also predicted early failure. The surgical or chemotherapy regimen and histological type did not. The same parameters except tumor size were associated with early death. Grade III, >/=10 involved nodes, and estrogen receptor negativity were independently associated with early failure and together identified a subset of patients (7%) with 3-fold increased early failure and 5-fold increased early death. CONCLUSIONS: Early failure is associated with poor survival. The combination of three commonly determined parameters constitutes a strong predictive model for early failure and death.     

Effect of obesity on toxicity in women treated with adjuvant chemotherapy for early-stage breast cancer: a systematic review

The purpose of this study is to provide more definite evidence regarding the role of dose modification of chemotherapy in obese women with breast cancer by systematically reviewing current literature regarding chemotherapy-induced toxicity rates in obese and non-obese women with early-stage breast cancer. A systematic search of Pubmed and EMBASE was conducted to identify original studies investigating chemotherapy-induced toxicity in obese women receiving adjuvant chemotherapy treatment for breast cancer. Ten studies were identified. We noted low rates of adjustment for confounders such as prophylactic hematopoietic growth factor use and empirical dose reductions. Seven studies found reduced toxicity in obese compared to non-obese women. Of four studies, where dose capping was precluded or statistically adjusted for, three found reduced toxicity in obese women. These outcomes include less febrile neutropenia (body mass index (BMI) >23.6; odds ratio (OR) 4.4; 95?% confidence interval (CI) 1.65?C12.01), fewer hospital admissions (BMI >35; OR 0.61, 95?% CI 0.38?C0.97), and fewer neutropenic events (BMI >25; OR 0.49; 95?% CI 0.37?C0.66). Only a single study reported higher rates of toxicity in obese women, but this study had significant methodological issues. As a conclusion, we observed that obese patients tolerate chemotherapy better than lean patients. However, this may be confounded by poorly specified dose capping practices and the use of hematopoietic growth factors. Further research should focus on improved documentation of body size, of dose, and of use of growth factors, and analysis of how these affect recurrence rates, toxicity, and survival.     

Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy

Summary p53 and p21 play an important role in G1/S checkpoint control in response to ionizing radiation. Yet the genetic polymorphisms in these genes have not been investigated with respect to radiation toxicity in patients. We therefore assessed the association between TP53 Arg72Pro, p53PIN3 and p21 Ser31Arg polymorphisms and the risk of acute skin toxicity after radiotherapy in a prospective study of 446 female breast cancer patients (average age 60.3±9.0 years) receiving radiotherapy after breast conserving surgery. The p53PIN3 polymorphism was determined by standard PCR, and TP53 Arg72Pro and p21 Ser31Arg polymorphisms using melting point analysis of sequence-specific hybridization probes. The development of acute skin toxicity (moist desquamation) was modelled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Overall, the development of acute skin toxicity, which presented in 77 patients, was not significantly associated with the polymorphisms studied. Risks were however differential by body mass index. Compared to non-carriers, TP53 72Pro carriers had a non-significantly decreased risk of acute skin toxicity in normal weight women (hazard ratio 0.46, 95% CI, 0.18–1.18) but not in overweight patients (hazard ratio 1.07, 95% CI, 0.61–1.89) (p _interaction =0.14). Haplotype analysis for the TP53 polymorphisms suggested that effect modification by TP53 72Pro may differ according to the p53PIN3 allele (p _interaction=0.06). Furthermore, in TP53 72Pro carriers with p21 Ser/Ser genotype, the occurrence of acute toxicity was reduced in normal weight but not overweight patients. In conclusion, the TP53 72Pro variant may be associated with the development of acute skin toxicity after radiotherapy in patients with normal weight. Large clinical studies are needed to clearly confirm this association.