Regimens For Early Breast Cancer Research Articles

Relationship of Ki-67 index in biopsies of metastatic breast cancer tissue and circulating tumor cells (CTCs) at the time of biopsy collection

BackgroundThe proliferation marker Ki-67 is a major pathological feature for the description of the state of disease in breast cancer. It helps to define the molecular subtype and to stratify between therapy regimens in early breast cancer and helps to assess the therapy response. Circulating tumor cells (CTCs) are a negative prognostic biomarker for progression free (PFS) and overall survival (OS) in patients with metastatic breast cancer. Therefore, the CTC count is often described as surrogate for the tumor burden. Both, decrease of Ki-67 and CTC count are considered as evidence for therapy response. The presented work analyzed the correlation between the Ki-67 indices of metastatic tissue biopsies and CTC counts in biopsy time-adjacent peripheral blood samples.Patients and methodsBlood samples from 70 metastatic breast cancer patients were obtained before the start of a new line of systemic therapy. CTCs were enumerated using CellSearch® (Menarini Silicon Biosystems, Bologna, Italy) whereas intact CTCs (iCTCs) and non-intact or apoptotic CTCs (aCTCs) were distinguished using morphologic criteria. The proportion of cells expressing Ki-67 was evaluated using immunohistochemistry on biopsies of metastases obtained concurrently with CTC sampling before the start of a new line of systemic therapy.Results65.7% of patients had a Ki-67 index of > 25%. 28.6% of patients had ≥ 5, 47.1% ≥ 1 iCTCs. 37.1% had ≥ 5, 51.4% ≥ 1 aCTCs. No correlation was shown between Ki-67 index and iCTC and aCTC count (r = 0.05 resp. r = 0.05, Spearman’s correlation index). High CTC-counts did not coincide with high Ki-67 index. High Ki-67, ≥ 5 iCTCs and aCTCs are associated with poor progression free (PFS) and overall survival (OS).ConclusionCTCs and Ki-67 are independent prognostic markers in metastatic breast cancer. High Ki-67 in metastatic tumor tissue is not correlated to high iCTC or aCTC counts in peripheral blood.

Neoadjuvant pegylated liposomal doxorubicin- and epirubicin-based combination therapy regimens for early breast cancer: a multicenter retrospective case-control study.

This study aimed to compare the effectiveness and safety of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based combination therapy regimen as neoadjuvant therapy for early breast cancer. Patients with stage I-III breast cancer who underwent neoadjuvant therapy followed by surgery between January 2018 and December 2019 were retrospectively reviewed. The primary outcome was pathological complete response (pCR) rate. The secondary outcome was radiologic complete response (rCR) rate. Outcomes were compared between treatment groups PLD-cyclophosphamide followed by docetaxel (LC-T group) or epirubicin-cyclophosphamide followed by docetaxel (EC-T group), using both propensity-score matched (matched) and unmatched data. Data were analyzed from patients who received neoadjuvant LC-T (n = 178) or EC-T (n = 181) treatment. The overall pCR rate and rCR rate were higher in the LC-T group compared with the EC-T group (unmatched pCR: 25.3% vs. 15.5%, p = 0.026; rCR: 14.7% vs. 6.7%, p = 0.016; matched pCR: 26.9% vs. 16.1%, p = 0.034; rCR: 15.5% vs. 7.4%, p = 0.044). Analysis by molecular subtype showed that compared with EC-T treatment, LC-T treatment achieved significantly greater pCR rate in triple-negative subtype and greater rCR rate in Her2 (+) subtype. Neoadjuvant PLD-based therapy may be a potential option for patients with early-stage breast cancer. The current results warrant further investigation.

EE228 Cost-Effectiveness Analysis of the 25 Fraction Versus 5 Fraction Radiotherapy Regimens for Early Breast Cancer

The study comparatively analysed the cost-effectiveness of 25-fraction versus 5 fraction radiotherapy regimens for treating early breast cancer patients. Several clinical trials have been conducted to study the efficacy and safety of newer 5- fraction radiotherapy and compared them with conventional 25-fraction regimens.

Patient-reported symptom severity, interference with daily activities, and adverse events in older and younger women receiving chemotherapy for early breast cancer.

To the authors' knowledge, it is unknown whether patient-reported symptom severity and symptom interference with daily activities differ between younger (aged <65 years) and older (aged ≥65 years) women receiving similar chemotherapy regimens for early breast cancer (EBC). Study participants rated 17 side effects of chemotherapy regimens currently in use in clinical practice (2014-2019). Of 284 women with EBC (stage I-III), approximately 57% were aged <65 years and 43% were aged ≥65 years. For anthracycline-based regimens, a higher percentage of younger women reported moderate, severe, or very severe (MSVS) hot flashes (49% vs 18%) (P < .001). For nonanthracycline regimens, a higher percentage of younger women reported MSVS hot flashes (38% vs 19%) (P = .009) and a lower percentage reported MSVS arthralgia (28% vs 49%) (P = .005). With regard to symptom interference with daily activities, a higher percentage of younger women being treated with anthracycline-based regimens reported MSVS hot flashes (32% vs 7%) (P = .001) and myalgia (38% vs 18%) (P = .02). For nonanthracycline chemotherapy, a higher percentage of younger women reported MSVS interference for hot flashes (26% vs 9%) (P = .006) and lower percentages reported abdominal pain (13% vs 28%) (P = .02). Overall, there were no significant differences noted among younger versus older patients with regard to hospitalizations (19% vs 12%; P = .19), dose reductions (34% vs 31%; P = .50), dose delays (22% vs 25%; P = .59), or early treatment discontinuation (16% vs 16%; P = .9546). Older and younger women with EBC who were treated with identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events. In this study, women receiving chemotherapy for early breast cancer rated the severity of 17 symptoms and symptom interference with their activities of daily living. Older (aged ≥65 years) and younger (aged <65 years) women who received identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update.

The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab. Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.Additional information can be found at www.asco.org/breast-cancer-guidelines.

A Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide

PurposeDose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT.Materials and MethodsPatients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability.ResultsOf 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%).ConclusionDose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Clinical Value of Capecitabine-Based Combination Adjuvant Chemotherapy in Early Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

Capecitabine has consistently demonstrated high efficacy and acceptable tolerability in salvage chemotherapy for advanced breast cancer. However, there remains no consensus on its role in adjuvant chemotherapy for early breast cancer (EBC). To estimate the value of capecitabine-based combination adjuvant treatment in EBC, eight randomized controlled trials with 14,072 participants were analyzed. The efficacy and safety outcomes included disease-free survival (DFS), overall survival (OS), relapse, breast cancer-specific survival (BCSS), and grades 3–5 adverse events. Capecitabine-based combination adjuvant chemotherapy demonstrated a 16% increase in BCSS (HR = 0.84, 95% CI = 0.71–0.98, p = 0.03) in the overall analysis and a 22% improvement in DFS (HR = 0.78, 95% CI = 0.64–0.96, p = 0.02) in the hormone receptor-negative (HR−) subgroup. However, there were no significant differences in DFS (HR = 0.96, 95% CI = 0.89–1.05, p = 0.38), OS (HR = 0.91, 95% CI = 0.82–1.00, p = 0.06), or relapse between capecitabine-based and capecitabine-free combination adjuvant chemotherapy. Analogous results were observed in the subgroup analyses of HR+, HER2−, HER2+, and triple-negative EBC. Regarding safety, reduced myelosuppression and hand–foot syndrome development were observed in capecitabine-treated patients. Capecitabine-based combination adjuvant chemotherapy might provide some BCSS benefit compared with capecitabine-free regimens in EBC, but the absolute survival gain is small, and the survival benefit appears to be restricted to patients with HR− EBC, which may indicate a target population for capecitabine-based combination adjuvant chemotherapy.

Capecitabine in Combination with Standard (Neo)Adjuvant Regimens in Early Breast Cancer: Survival Outcome from a Meta-Analysis of Randomized Controlled Trials.

Capecitabine has been investigated in early breast cancer in several studies, but it was undefined that whether it could improve survival. To investigate whether the addition of capecitabine affected survival in patients with early breast cancer, a meta-analysis was conducted and overall survival (OS), disease-free survival (DFS), and toxicity were assessed. The PubMed, Embase databases and the Cochrane Central Register of Controlled Trials were searched for studies between January 2006 and April 2016. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CI were derived. Seven trials with 9097 patients, consisted of 4 adjuvant and 3 neoadjuvant studies, were included in this meta-analysis. Adding capecitabine showed no improvement in DFS (HR = 0.93; 95% CI, 0.85–1.02; P = 0.12), whereas a significant improvement in OS was observed (HR = 0.85; 95% CI, 0.75–0.96; P = 0.008). A sub-analysis of DFS showed that benefit of capecitabine derived from patients with triple negative subtype and with extensive axillary involvement. Safety profiles were consistent with the known side-effects of capecitabine, but more patients discontinued scheduled treatment in the capecitabine group. Combining capecitabine with standard (neo)adjuvant regimens in early breast cancer demonstrated a significantly superior OS, and indicated DFS improvement in some subtypes with high risk of recurrence. Selection of subtypes was a key to identify patients who might gain survival benefit from capecitabine.

Selection of Optimal Adjuvant Chemotherapy Regimens for Early Breast Cancer and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline Summary

Selection of Optimal Adjuvant Chemotherapy Regimens for Early Breast Cancer and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline Summary

Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.

A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

Abstract P5-09-04: Consensus and disagreement between experts and community practitioners asked to make therapeutic recommendations for early breast cancer (EBC)

Abstract Intro. Most patients with stage II BC will receive surgery along with systemic therapy, but no consensus exists among experts on optimal use of neoadjuvant vs adjuvant therapy in many cases. Furthermore, treatment guidelines list multiple reasonable regimens for EBC, but lack patient-specific recommendations. We have shown previously that online decision support tools can affect treatment decisions of community practitioners. In this study, we sought to determine areas of consensus and disagreement among expert faculty providing treatment recommendations for a 2015 decision support tool on EBC as well as those using the online tool. Methods. An online decision support tool was developed with input from 5 experts on systemic therapy recommendations for 235 patient scenarios in EBC. Tool users were asked to enter specific patient criteria and their intended management for each case before displaying the 5 expert recommendations for the user-entered case. Users were asked to indicate if the expert recommendations changed their intended approach. Results. At interim analysis, 406 individuals used this tool, with 674 patient scenarios entered. Among users reporting on the tool's clinical impact, 88% indicated expert recommendations either confirmed or changed their intended therapy. Expert recommendations in the tool showed areas of consensus and disagreement in treating patients with EBC. For example, expert recommendations varied in the choice of systemic therapy prior to surgery and when to continue directly to surgery before systemic treatment. Expert recommendations for initiating systemic neoadjuvant therapy in HER2-, HR+ EBCcNcTExpert 1Expert 2Expert 3Expert 4Expert 5NCCN GuidelinesNegativecT1a cT1b cT1c Recommend cT2 RecommendConsider cT3ConsiderRecommendConsiderPositivecT1a RecommendConsider cT1b RecommendConsider cT1c RecommendConsider cT2ConsiderRecommendConsider cT3ConsiderRecommendConsider Experts did agree on starting with surgery in patients with node-negative, T1a disease; however, only 30% of tool users agreed. Both experts and users agreed in recommending systemic neoadjuvant therapy for patients with HER2+, node-positive T2 disease. In patients with HER2+ EBC, experts always chose to include dual HER2-targeted therapy in neoadjuvant systemic therapy but only included trastuzumab in adjuvant regimens. However, only 51% of tool users selected dual HER2-targeted therapy as part of neoadjuvant therapy and 13% use dual HER2-targeted therapy in the adjuvant setting. Expert opinion varied on when to use adjuvant chemotherapy in patients with HR+, HER2- EBC, particularly for those with intermediate or unknown recurrence scores and no lymph node involvement. Detailed comparison of expert consensus and disagreement, analysis of practice pattern information from user responses, and perceived impact of the expert recommendations will be presented. Conclusions. This EBC tool highlights specific clinical scenarios having either consensus or disagreement among experts and community practitioners. Education that includes online decision support tools may increase the number of clinicians making optimal treatment decisions for patients with EBC. Citation Format: Obholz KL, Rosenthal KM, O'Regan RM, Swain SM, Yardley DA, Brady ED. Consensus and disagreement between experts and community practitioners asked to make therapeutic recommendations for early breast cancer (EBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-09-04.

Cost-effectiveness analysis of trastuzumab in the adjuvant treatment for early breast cancer.

Background:Evidence from randomized controlled trials (RCTs) has shown a significant survival advantage of trastuzumab. Although extant work in developed countries examined economic evaluation of trastuzumab in adjuvant treatment for early breast cancer based on the 1-year treatment, there is uncertainty about cost-effectiveness of trastuzumab in the Adjuvant Treatment of early breast cancer in developing countries. This study aimed to estimate cost-effectiveness of adjuvant trastuzumab therapy compared to AC-T regimen in early breast cancer in Iran.Methods:A cost-effectiveness analysis was performed using a Markov model to estimate outcomes and costs over a 20-year time period using a cohort of women with HER2 positive early breast cancer, treated with or without 12 months trastuzumab adjuvant chemotherapy. Transition probabilities were derived mainly from the BCIRG006 trial. Costs were estimated from the perspective of the Iranian health care system. Both costs and outcomes were discounted by 3%. One-way sensitivity analysis was undertaken to assess the associated uncertainties in the expected output measures.Results:On the basis of BCIRG006 trial, our model showed that adjuvant trastuzumab treatment in early breast cancer, yield 0.87 quality-adjusted life-years (QALY) compared with AC-T regimen. Adjuvant trastuzumab treatment yielded an incremental cost-effectiveness ratio (ICER) of US$ 51302 per QALY.Conclusion:By using threshold of 3 times GDP per capita, as per World Health Organization (WHO) recommendation, 12 months trastuzumab adjuvant chemotherapy is not a cost-effective therapy for patients with HER2-positive breast cancer in Iran.

Cardiac safety results from a phase II, open-label, multicenter, pilot study of two docetaxel-based regimens plus bevacizumab for the adjuvant treatment of subjects with node-positive or high-risk node-negative breast cancer

PurposeAdding antiangiogenic therapy to standard chemotherapy has improved response rates and progression-free survival in metastatic breast cancer (BC) patients. This phase II study evaluated cardiac safety of bevacizumab with/without trastuzumab with two docetaxel-based regimens in early BC.Methods127 women with non-metastatic node-positive or high-risk node-negative BC were enrolled. Women with human epidermal growth factor receptor 2 (HER2)-negative BC (n = 93) received docetaxel/doxorubicin/cyclophosphamide (TAC) + bevacizumab, while women with HER2-positive disease (n = 34) received docetaxel/carboplatin/trastuzumab (TCH) + bevacizumab, every 3 weeks for six cycles. Maintenance therapy with bevacizumab alone or bevacizumab plus trastuzumab, respectively, was given every 3 weeks for 52 weeks. The primary objective was to evaluate cardiac safety, as measured by the incidence of ≥ grade 3 clinical congestive heart failure (CHF); the secondary objective was assessment of safety and toxicity.ResultsAt least one cardiac adverse event (AE; CHF, cardiomyopathy, or left ventricular dysfunction) was reported in 26.1% of TAC (n = 92) and 17.6% of TCH subjects (n = 34); there were no cardiac deaths. ≥ Grade 3 clinical CHF was observed in 4.3% in the TAC plus bevacizumab stratum and 0% in the TCH plus bevacizumab stratum. A ≥ grade 3 treatment-emergent AE (any kind) related to study treatment was observed in 59.8% in the TAC with bevacizumab and 52.9% in the TCH plus bevacizumab stratum.ConclusionAdding bevacizumab to a docetaxel-based regimen with trastuzumab did not appear to increase cardiotoxicity.Trial registrationClinicalTrials.gov Identifier: NCT00446030, registered March 8, 2007.

Benefit risk assessment and update on the use of docetaxel in the management of breast cancer

The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo-adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling.

Epiphora and Canalicular Stenosis Associated With Adjuvant Docetaxel in Early Breast Cancer: Is Excessive Tearing Clinically Important?

Docetaxel, as a single agent or in combination, is widely used in the palliative treatment of many common solid tumors, including breast, lung, and prostate cancers. Docetaxel is also used in many of the adjuvant regimens in early breast cancer, including the docetaxel, carboplatin, and trastuzumab regimen, the docetaxel and cyclophosphamide combination, and those with or without an anthracycline or trastuzumab (docetaxel/doxorubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide followed by docetaxel, doxorubicin/cyclophosphamide followed by docetaxel, and doxorubicin/cyclophosphamide followed by docetaxel plus trastuzumab). Adjuvant-based docetaxel may lead to well-known acute and chronic adverse events including neutropenic fever or infection, stomatitis, hypersensitive reaction, rash, fluid retention, peripheral neuropathy, and fatigue. The safety profile of docetaxel is schedule and dose dependent. Excessive tearing (epiphora) is a common adverse event reported in patients who receive docetaxel for metastatic disease. However, there is little published information about ocular toxicity, including epiphora, in the adjuvant setting. Two large docetaxel-based adjuvant phase III studies briefly reported docetaxel-related ocular toxicity. In the Breast Cancer International Research Group (BCIRG) trial 001, lacrimal disorder was reported in 11.3% versus 7.1% of patients who received TAC versus those who received fluorouracil/doxorubicin/ cyclophosphamide, respectively. In the Eastern Cooperative Oncology Group study 1199, grade 3 and 4 lacrimation was reported in 5% of patients who received weekly adjuvant docetaxel versus less than 1% of patients who received adjuvant paclitaxel once per week, paclitaxel once every 3 weeks, or docetaxel once every 3 weeks. Other ocular symptoms such as conjunctivitis were also reported in less than 1% in patients in this trial, including those who received docetaxel once per week. In the article that accompanies this editorial, Chan et al studied the prevalence of epiphora, canalicular stenosis, and nasolacrimal duct obstruction in patients with early-stage breast carcinoma who received adjuvant docetaxel-based combination chemotherapy. This is a large prospective report evaluating ocular toxicity in patients with early breast cancer receiving adjuvant therapy, although several previous studies have reported the association between docetaxel and epiphora and its anatomic correlates, canalicular stenosis and nasolacrimal duct obstruction, in patients with metastatic breast carcinoma. Our group published several reports, some dating back to 2001, on the incidence and severity of epiphora and its anatomic correlates in patients treated with docetaxel, initially in patients treated with docetaxel once every 3 weeks, and later in patients treated with docetaxel once per week. In a prospective randomized clinical trial in patients with metastatic breast cancer, we clearly demonstrated a higher incidence of canalicular stenosis and nasolacrimal duct obstruction in patients receiving docetaxel once per week compared with those receiving docetaxel once every 3 weeks. We also showed that a delay in intervention for patients receiving docetaxel once per week leads to a need for more complicated surgery and worse outcomes. In contrast to the metastatic setting, epiphora and its anatomic correlates, canalicular stenosis and nasolacrimal duct obstruction, have not been well studied previously in patients with early breast cancer. However, it has been recognized that docetaxel given every 3 weeks (not weekly), for a short overall treatment duration (9 to 18 weeks) in patients with metastatic breast cancer is associated with only mild to occasionally moderate ocular symptoms that resolve quickly. Thus, the prospective observations reported by Chan et al using similar docetaxel dosing schedules now confirm previous results that have been observed in the metastatic setting, but in a larger number of patients with early breast cancer. Chan et al reported several important clinical observations. They described rapid onset and high incidence of epiphora (86%). Nearly 70% of patients experienced epiphora before the third cycle. However, only six patients had short-lasting grade 3 epiphora. The authors did not observe any difference between short versus long regimens. However, the majority of patient received six cycles of adjuvant therapy, and we have clearly established that it is not the patients who receive docetaxel once every 3 weeks for short periods who are the subject of greatest concern. Rather, it is the patients who receive docetaxel once per week, or once every 3 weeks for extended periods (ie, patients receiving docetaxel for metastatic disease) who are at greatest risk of canalicular stenosis. In the study by Chan et al, nearly 20% of patients had asymptomatic partial lacrimal duct obstruction at baseline according to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 17 JUNE 1

Chemotherapy regimens in early breast cancer: major controversies and future outlook

The addition of adjuvant chemotherapy in early breast cancer improves overall survival by approximately 10%. Recommendations favor the use of anthracyclines and taxanes in patients with luminal B disease, while the use of an anthracycline, taxane and alkylating agent is recommended in triple-negative disease. In luminal B disease, the addition of chemotherapy to endocrine treatment depends on estrogen receptor expression and overall risk. Chemotherapy is not recommended in most patients with luminal A (highly hormone-sensitive and low proliferation) breast cancer. A major controversy is the addition of adjuvant chemotherapy to endocrine treatment in patients with estrogen receptor-positive breast cancer. In some of these patients, multigene signatures such as the 21-gene recurrence score may be a useful addition to histopathology. The introduction of molecular subtypes and gene signatures improves the complexity of early breast cancer treatment, and individual institutes have to find their policy based on their histopathological information and the availability of gene signatures.

Adjuvant Chemotherapy with Vinorelbine and Epirubicin versus Adriamycin and Cyclophosphamide for Treating Node Negative Breast Cancer

Objectives : Doxorubicin is the most effective chemotherapeutic drug for treating breast cancer. The efficacy of epirubicin is identical to that of doxorubicin however, epirubicin has less toxicity. And vinorelbine is a new emerging regimen in early breast cancer. The aims of this trial were to compare the toxicity and safety in combination adjuvant chemotherapy with vinorelbine and epirubicin (VE) versus adriamycin and cyclophosphomide (AC) for patients with node negative early breast cancer. Materials and Methods : The patients with node negative early breast cancer, suitable for adjuvant chemotherapy were randomly assigned to receive either vinorelbine 25mg/m 2 on days 1 and 8 and epirubicin 75mg/m 2 on day 1 intravenously (i.v.) every 3 weeks, or adriamycin 60mg/m 2 on day 1 and cyclophophomide 600mg/m 2 on day 1 i.v. every 3 weeks for 4 cycles. We checked the laboratory data on the first day of chemotherapy and on the 15 th day after chemotherapy at each cycle. Results : 69 patients were enrolled finally from seven institutions. Grade 3/4 neutropenia was significantly more frequent in the VE arm than in the AC arm. It occurred in 10 of 30 patients (33.3%) in the VE arm and in 4 of 39 patients (10.3%) in the AC arm ( p =0.032). Delayed treatment was significantly more common in the VE arm (10/30, 33.3%) than in the AC arm (3/39, 7.7%) ( p =0.011). The most common reason for delay was neutropenia in both arms. However, dose reduction tended to be more common in the AC arm (17.9%) than in the VE arm (6.7%) ( p = 0.282). There were no significant differences of non-hematologiocal toxicities in the two arms. Conclusion : Neutropenia and delayed scheduled treatment were significantly more frequent in the VE arm than that in the AC arm. However, more long term follow-up is needed to further evaluate the cardiac toxicity, overall survival and disease free survival between the two arms.

Adjuvant chemotherapy for early-stage breast cancer: Choice of regimen and associated hematologic toxicities in a metropolitan Australian hospital.

123 Background: The commonly used adjuvant chemotherapy regimens for early breast cancer include 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D), docetaxel and cyclophosphamide (TC), doxorubicin and cyclophosphamide with or without paclitaxel and/or herceptin (AC combination) and docetaxel, carboplatin and trastuzumab (TCH). Hematologic toxicity from these regimens can be life threatening as well as cause significant morbidity for the patient and major costs to the health system. Granulocyte colony stimulating factor (GCSF) is frequently used to try and reduce these complications. In Australia, GCSF is funded for use as primary prophylaxis with docetaxel in combination with an anthracycline and cyclophosphamide. Secondary prophylaxis is available only after demonstration of prolonged severe neutropenia or an episode of febrile neutropenia (FN). Methods: Patients treated with adjuvant chemotherapy for early breast cancer at Gold Coast Hospital, Qld, Australia from February 2010 to February 2012 were identified. Patient charts were reviewed for incidence of neutropenia (neutrophil count &lt;1.0 x 109/L), FN (temp ≥38°C), dose reductions or delays and use of GCSF. Results: 102 patients were treated over this time. Incidence of neutropenia, FN and use of GCSF are summarised below. 30 patients receiving FEC-D had a dose delay or reduction with the majority due to non-haematologic toxicities. 96% patients completed 6 cycles of treatment. Of the patients with FN in the TC group, half had received primary GCSF. No patients who were given primary GCSF experienced a dose delay. Similar trends were observed in the other treatment groups. Conclusions: Our results show that patients receiving FEC-D along with GCSF had lower rates of neutropenia and hospitalisations. Rates of neutropenia and dose delay are higher in the other groups. FEC-D is the most commonly used regimen in our institution likely due to the availability of GCSF. [Table: see text]

Individual patient meta-analysis: Taxane plus anthracycline reduces mortality from early breast cancer

Source Citation Early Breast Cancer Trialists' Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet. 2012;379:432-44. 22152853