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Aim: The aim of this study was to compare the long-term outcome of women with primary or locally advanced breast cancer randomised to receive either doxorubicin and cyclophosphamide (AC) or doxorubicin and docetaxel (AD) as primary chemotherapy. Patients and methods: Eligible patients with histology-proven breast cancer with primary tumours ≥ 3 cm, inflammatory or locally advanced disease, and no evidence of distant metastases, were randomised to receive a maximum of 6 cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) i/v or doxorubicin (50 mg/m(2)) plus docetaxel (75 mg/m(2)) i/v every 3 weeks, followed by surgery on completion of chemotherapy. Results: Clinical and pathologic responses have previously been reported 1. Time to relapse, site of relapse, and all-cause mortality were recorded. This updated analysis compares long-term disease-free (DFS) and overall survival (OS) using stratified log rank methods. A total of 363 patients were randomised to AC (n = 181) or AD (n = 182). At a median follow-up of 119 months, there is no significant difference between the two groups for DFS (P = 0.274) and OS (P = 0.327). The 10-year DFS for AC is 54% (95% CI 47-62%) and for AD 60% (95% CI 52-67). The 10-year OS is 49% (95% CI 42-57%) for AC and 51% (95% CI 43-58%) for AD. Metastatic breast cancer accounted for 89% of deaths in those treated with AC and 86% in those treated with AD. Estrogen receptor (ER) and nodal status were independent prognostic factors for DFS and OS (p Conclusions: This was one of the first studies to evaluate taxanes versus anthracyclines in the neoadjuvant setting. Our mature data do not support an added clinical benefit for the simultaneous administration of AD compared to AC. This supports current practice with respect to sequential treatment with taxanes followed by anthracyclines leading to an increase in pathological complete response rate and better survival outcomes. 1. Evans TR, Yellowlees A, Foster E et al. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an Anglo-Celtic cooperative Oncology group study. J Clin Oncol 2005, 23: 2988–2995. Citation Format: Chara Stavraka, T. R. Jeffry Evans, Joanna Dunlop, Helena Earl, David A. Cameron, Robert E Coleman, Timothy Perren, Robert CF Leonard, Janine L Mansi. 10-year outcome for women randomized in a phase III trial comparing doxorubicin and cyclophosphamide with doxorubicin and docetaxel as primary medical therapy in early breast cancer: An anglo-celtic cooperative oncology group study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-15.

The OPTION trial examined whether or not premenopausal women with early breast cancer receiving chemotherapy benefited from ovarian function protection with goserelin. This trial showed some preservation of ovarian function and fertility in women aged 40 years or less*. Additionally the OPTION trial examined the immediate and late impact of treatments on patients’ Quality of Life (QoL) over a 5 year period. Patients and Methods: In the OPTION trial 227 pre-menopausal patients with early stage breast cancer were randomly assigned to chemotherapy with or without goserelin. Patients were stratified by age into ≤40 years and > 40 years of age. QoL was assessed with the Functional Assessment of Cancer Therapy - Breast (FACT-B) and Endocrine Symptom checklist(ES) at baseline (pre- treatment), 3, 6, 12, 18 and 24 months, then annually to 5 years. Results:-Two hundred and thirteen patients were available for analysis of QoL results. There was a temporary increase in endocrine symptoms of menopause in the goserelin group that was statistically higher than in the controls (P = 0.02) and was associated with a decrease in the main outcome measure of global QoL, TOI. This contrasted with a longer term outcome favouring the intervention in terms of QoL and fewer adverse endocrine symptoms, though these later findings were not statistically significant. Conclusions: Cytotoxic chemotherapy with or without goserelin causes a short term decrement in QoL for up to 6 months in otherwise well women.* Ann Onc 2017 28 1811-1816. Citation Format: Robert CF Leonard, Janine Mansi, Ann Yellowlees, Lesley Fallowfield, Valerie Jenkins. Does goserelin have an effect on quality of life in women who have chemotherapy for early breast cancer? Results from the OPTION randomised trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-12-11.

Background Gemcitabine is used to treat a wide range of tumours but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. Methods Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. Results Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well-tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on Days 1, 8 and 15 of a 28-day cycle. Conclusion NUC-1031 was well-tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive. Trial registration: clinicaltrials.gov identifier: NCT01621854

Purpose Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN. Methods Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach. Results Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk

Background: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients “OPTION” trial\ud (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of\ud primary ovarian insufficiency (POI) at 12 months in women randomised to 6–8 cycles of (neo)adjuvant\ud chemotherapy (CT) þ/ goserelin (G). Here we report the results of a secondary endpoint analysis of the\ud effects of CTþ/-G on markers of bone turnover.\ud Methods: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were\ud collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers\ud were evaluated for the overall population, according to age stratification at randomisation (r40 vs 440\ud years) and with exploratory analysis according to POI rates at 12 months.\ud Results: In the overall population, there was a significant increase in NTX at 6 months compared to\ud baseline in patients treated with CTþG (40.81 vs 57.82 p¼0.0074) with normalisation of levels thereafter.\ud BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving\ud CTþG, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and\ud 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36\ud months (CTþG 5.845 vs CT 8.5 p¼0.0006). These changes were predominantly seen in women 440\ud years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a\ud longer duration than women who maintained menses.\ud Conclusion: Addition of G to CT increases bone turnover during treatment with normalisation after\ud cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to\ud negate longstanding altered bone turnover associated with POI.\ud

Guidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI.Adult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups.Most regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF.Secondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

Goals of work: The aims of this study were to assess chemotherapy treatment characteristics, neutropenic event (NE) occurrence and related risk factors in breast cancer patients in Western Europe. Material and methods: Six retrospective audits of breast cancer chemotherapy were combined into a dataset of 2,860 individuals. NEs were defined as neutropenia-related hospitalisation, dose reduction >= 15% or dose delay >= 7 days. Summation dose intensity (SDI) was calculated to compare different types of chemotherapy regimens on a single scale. Risk factors of NE occurrence and of low relative dose intensity (RDI) >= 85% were identified by multiple logistic regression. Main results: Patient populations were comparable between audits. Until 1998, cyclophosphamide, methotrexate and fluorouracil regimens were most frequently used, but thereafter, anthracycline-based regimens were most common. NEs occurred in 20% of the patients and low RDI in 16%. NE occurrence predicted low RDI and was associated with higher age, bigger body surface area, lower body mass index, regimen type, more chemotherapy cycles planned, normal to high SDI, concomitant radiotherapy and year of treatment. First cycle NE occurrence predicted NEs from cycle 2 onwards. A risk score using age, SDI, number of planned chemotherapy cycles and concomitant radiotherapy differentiated patients with increasing NE risk (9-37%). An alternative score version not using concomitant radiotherapy performed moderately less well. Conclusions: NEs occurred frequently in this combined dataset and they affected treatment delivery. Identifying patients at high NE risk enables targeted prophylaxis and may avoid dose limitations.

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient–level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Background Chemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women's health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI. Patients and methods This was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI. Results A total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Mullerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups. Conclusion This study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.

Background:\ud The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel.\ud \ud Methods:\ud tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0–1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546).\ud \ud Findings:\ud Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10–10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63–68] in the gemcitabine group vs 65% [62–67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86–1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]).\ud \ud Interpretation:\ud The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup.\ud \ud Funding:\ud Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

The choice of chemotherapy for patients with metastatic breast cancer (MBC) depends on disease- and patient-related factors, but there is little guidance on dosing modifications for patients unable to receive the licensed dose. Nab-paclitaxel is a solvent-free form of paclitaxel that uses albumin as a drug carrier and exploits endogenous albumin transport pathways to achieve enhanced drug targeting and tumour penetration with reduced toxicity. It is approved for use at a dose of 260 mg/m(2) every three weeks in adults who have failed first-line treatment for MBC and for whom standard anthracycline-based therapy is not indicated. Emerging data suggest that weekly dosing schedules of nab-paclitaxel may provide clinical benefit in some patients, but the utility of these alternative dosing schedules remains unclear. A panel of breast cancer experts convened to review available literature for nab-paclitaxel in MBC and, taking into account their clinical experience, recommended that alternative dosing schedules may be considered according to the aggressiveness of disease and patient condition as follows: 125 mg/m(2) QW 3/4 (aggressive disease and fit), 100mg/m(2) QW 3/4 (aggressive or indolent disease and unfit). All dosing schedules were considered acceptable for fit patients with indolent disease. These recommendations are based on current evidence, and emerging data from ongoing trials may reinforce or modify the recommendations provided.

Purpose Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets. Methods We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status. Results Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients. Conclusion Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.

Introduction As clinicians we are commonly asked by patients ‘what is my chance of surviving breast cancer?’ A number of methods have been in use in anattempt to provide an answer including the TNM classification and the Nottingham Prognostic index (NPI). With the introduction of new machine learning methods and the vast amount of data available to us the call for new models that can predict survival more accurately. As clinicians we must question the usefulness of methods that only tell us whether a patient will survive ten years or die within that time. You may prefer to make a prognosis and be able to predict the likelihood of survival or death within a chosen time span. Objectives To develop a new predictive model based on a machine learning method known as the Naïve-Bayes Decision Tree (NBTree) classifier. Methods Data set: The Surveillance, Epidemiology, and End Results (SEER) data was used to build a data set of women diagnosed with breast cancer between 1990 and 1997. Inclusion criteria included: all women with a diagnosis of invasive ductal carcinoma, under the age of 70 and with a minimum follow up of ten years. Fields included in the data were tumour size, grade, number of positive lymph nodes, survival time and alive status. Model: NBTree is a classifier that combines a decision tree with a Naïve base classifier to build a model that provides the probabilities of outcome. The model was generated using the freely available statistical package R. The model was built based on tumour size, grade and number of positive lymph nodes. It was then validated using K-fold cross validation and tested on a subset of data. Results A total of 50,895 women were included in the analysis. The model was generated a total of 10 times and validated using 10-fold cross validation. The model was able to correctly classify patients 69.26% of the time. When tested on a sub-group of the data set (2000 cases) the model was able to correctly classify patients in 68% of the instances. Conclusion The NBTree probablistic - machine learning method provides a robust method of putting a value or probability to ten year survival following the diagnosis of breast cancer. Our future aim is to evaluate the method on European datasets to determine its accuracy for patient management relative to existing validated systems. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-19.

Non-randomised data suggest a protective benefit on ovarian function for using GnRH analogues to suppress menses during chemotherapy. However there have been no published randomised clinical trials to date that confirm this protection indicated by recovery of menstrual function. Observational data suggest that patient age and cumulative dose of alkylating agent or selection and intensity of dose other agents such as anthracyclines or taxanes are also important variables that determine the risk of chemotherapy-induced premature ovarian failure (POF). This trial in premenopausal women has tested the effect of goserelin (G) given randomly before and during adjuvant chemotherapy in premenopausal women with breast cancer. Any standard regimen was allowed but women were randomised in 2 strata, under 40 yrs and over 40 yrs at diagnosis. 227 patients were recruited by end December 2009, and 173 met the criteria for 1 year follow-up for this analysis; 140 patients of these 173 patients had provided adequate data on menstrual bleeding; 87 patients were aged under 40 and 53 patients were aged over 40 at the time of chemotherapy. Cessation of menstruation during chemotherapy was defined as at least two consecutive cycles with no menstrual bleeding since the previous cycle. Additionally, prior to the final cycle of chemotherapy, there had to be no return of menstrual bleeding. Of those patients who had ceased periods during chemotherapy, those with no further menstrual bleeding at 12 months follow up were deemed to have reached menopause. Patients were randomised to receive G or no G at start of chemotherapy. Primary endpoint was recovery of menses at 12 months from start of chemotherapy. Secondary endpoints included quality of life, oestrogen/LH/FSH levels at start and completion and at 12 months along with anti-mullerian hormone (AMH, as an indicator of impending ovarian failure). Endocrine data over time showed a close correlation with menses in that both measures indicated no protective effect in the treatment group. There was no significant difference with respect to POF when all patients were considered. However there was a trend to poorer recovery of menstrual function at 12 months in the under-40 yrs group who had G with 34.7% having POF in the G treated group and 15.8% in the chemotherapy only treated group (P ≥0.05). This is mirrored by the oestrogen data which show an incomplete recovery at 12 months of oestrogen in the G group compared with controls although a complete recovery at 24 months. LH and FSH levels showed appropriate suppression by G and thereafter similar levels to controls. Early follow up data on the hormone levels shows no difference between the treatment groups. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-07.

Purpose, patients and methods This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin. Results Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04–8.02, p value [ p ] = 0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37–12.4, p = 0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59–3.18, p = 0.45). Conclusions Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Purpose The Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC). Patients and Methods BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia–free survival, Hb response, safety, and quality of life (QoL). Results After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia–free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value. Conclusion In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

The management of breast cancer depends on the tumor and patient's characteristics. Anthracycline-based regimens have been proven to decrease the risk of relapse and prolong survival time in breast cancer. Taxanes have been incorporated not only into metastatic breast cancer but also into adjuvant regimens. Capecitabine, an oral fluoropyrimidine carbamate, has good single-agent activity and, together with docetaxel, demonstrated preclinical synergy and a survival benefit in metastatic breast cancer. Recent analyses show that capecitabine/docetaxel dosing flexibility for managing side effects does not compromise efficacy, and define this combination regimen as an important treatment option for its efficacy, tolerability and cost-effectiveness.

Screening and adjuvant postoperative therapies have increased survival among women with breast cancer. These tools are seldom applied in elderly patients, although the usually reported incidence of breast cancer is close to 50% in women 65 years or older, reaching 47% after 70 years in the updated Surveillance, Epidemiology, and End Results (SEER) database. Elderly breast cancer patients, even if in good medical health, were frequently excluded from adjuvant clinical trials. Women age 70 years who are fit actually have a median life expectancy of 15.5 years, ie, half of them will live much longer and will remain exposed for enough time to the potentially preventable risks of a relapse and specific death. In the last few years, a new concern about this issue has developed. Treatment now faces two major end points, as in younger women: to improve disease-free survival in the early stages, and to palliate symptoms in advanced disease. However, in both settings, the absolute benefit of treatment is critical because protecting quality of life and all its related aspects (especially functional status and independence), is crucial in older persons who have more limited life expectancy. Furthermore, the new hormonal compounds (aromatase inhibitors) and chemotherapeutic drugs (capecitabine, liposomal doxorubicin), are potentially less toxic than and equally as effective as older more established therapies. These new treatments bring new challenges including higher cost, and defining their benefit in elderly breast cancer must include an analysis of the cost/benefit ratio. These issues emphasize the urgent need to develop and support clinical trials for this older population of breast cancer patients both in the adjuvant and metastatic settings, a move that will take us from a prejudiced, age-based medicine to an evidence-based medicine.

Current treatments for metastatic breast cancer are not associated with significant survival benefits despite response rates of over 50%. High-dose therapy with autologous bone marrow transplantation (ABMT) has been investigated, particularly in North America, and prolonged survival in up to 25% of women has been reported, but with a significant treatment-related mortality. However, in patients with haematological malignancies undergoing autologous transplantation, haematopoietic reconstruction is significantly quicker and mortality lower than with ABMT, when peripheral blood progenitor cells (PBPCs) are used. In 32 women with metastatic breast cancer, we investigated the feasibility of PBPC mobilisation with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) after 12 weeks' infusional induction chemotherapy and the subsequent efficacy of the haematopoietic reconstitution after conditioning with melphalan and either etoposide or thiotepa. PBPC mobilisation was successful in 28/32 (88%) patients, and there was a rapid post-transplantation haematopoietic recovery: median time to neutrophils > 0.5 x 10(9) l-1 was 14 days and to platelets > 20 x 10(9) l-1 was 10 days. There was no procedure-related mortality, and the major morbidity was mucositis (WHO grade 3-4) in 18/32 patients (56%). In a patient group of which the majority had very poor prognostic features, the median survival from start of induction chemotherapy was 15 months. Thus, PBPC mobilisation and support of high-dose chemotherapy is feasible after infusional induction chemotherapy for patients with metastatic breast cancer, although the optimum drug combination has not yet been determined.

Three hundred and ninety women participated in the quality of life (QL) study of ACCOG1, a high-dose vs conventional adjuvant chemotherapy breast cancer trial, for patients with a high risk of relapse. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30, questions on menopausal symptoms and the Sexual Activity Questionnaire. Pretreatment, 6,12, 24, 36, 48 and 60-month assessments were conducted. For the high dose group the median decrease in global QL at 6 months was significantly greater than in the conventional group. At 12 months, however, the median change had returned to 0 for both groups. Social functioning was also significantly lower in the high-dose group at 6 months, again returning to prebaseline levels for both groups after 12 months. The most persistent changes appear to be in the effect of treatment in both arms on sexual outcomes, reflected in problems with discomfort and pleasure. Both high-dose and conventional chemotherapy showed persisting negative effects on sexual health. This has not been previously reported as a long-term complication of high-dose chemotherapy. However, it did not have long-term affects on sexual habit, which appeared to return to pretreatment frequency and similar to that of conventional chemotherapy by about 12 months from treatment.

Background: In a phase III trial, 3-weekly capecitabine (1250 mg/m 2 twice daily days 1–14) plus docetaxel (75 mg/m 2 day 1) demonstrated significantly superior overall survival to 3-weekly docetaxel (100 mg/m 2 day 1). We report a retrospective analysis of the impact of capecitabine/docetaxel dose reduction on safety and efficacy. Patients and methods: Safety and efficacy data were analyzed retrospectively according to the actual doses of capecitabine and docetaxel administered. Results: More patients receiving capecitabine/docetaxel (65%) had dose reductions for adverse events than docetaxel alone (35%). In most patients requiring dose reduction with the combination (80%), capecitabine and docetaxel were simultaneously reduced to 950 mg/m 2 and 55 mg/m 2 , respectively. Subsequently, there were fewer cycles (17%) with grade 3/4 adverse events than with the full doses (34%). Time to progression and overall survival appeared to be similar in patients starting the second cycle with reduced doses of capecitabine/docetaxel and those who continued to receive full doses of capecitabine/docetaxel for at least the first four cycles. Conclusions: Capecitabine/docetaxel dosing flexibility allows management of side-effects without compromising efficacy. This retrospective analysis, as well as multiple phase II studies of taxanes with reduced-dose capecitabine, shows that reducing the starting dose of capecitabine with docetaxel is a reasonable strategy for the treatment of patients with metastatic breast cancer. In addition, reducing the dose of both agents may be appropriate.

Summary Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SD⩾24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB P 0.0001 ). Efficacy persisted in those patients who had received ⩾3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease.

The incidence of breast cancer increases with age, reaching over 300 per 100 000 in women aged 70–75 years in the UK, increasing to almost 400 per 100 000 in women aged over 85 years. As a healthy 70-year old woman can now expect to live for an average of 15 years, control of breast cancer is likely to significantly affect survival. Variations exist in surgical care, radiotherapy and chemotherapy, depending on age; however, virtually all elderly women with hormone-responsive disease are given adjuvant endocrine therapy, usually tamoxifen. For older women who do not have hormone-responsive cancer, and who have high-risk disease characteristics, questions remain over their best management. Overview data of adjuvant chemotherapy in clinical trials show a significant benefit of chemotherapy for women up to the age of 69 years but, for older women, there are too few data to draw any firm conclusions. When considering treatment options for older women, assessment is critical; functional status and comorbidity are some of the factors linked to shorter survival.

Many patients with breast cancer suffer from anaemia, as a consequence of the disease itself or its treatment. Anaemia has a negative impact on treatment outcome and overall survival, and affects the quality of life (QoL) of patients with cancer. Previously, cancer-related anaemia was treated with blood transfusion, but this is inconvenient, offers only temporary improvement in haemoglobin (Hb) level and is associated with several risks. Consequently, blood transfusion is usually reserved for patients with severe anaemia (Hb levels

Background Patients with Glanzmann thrombasthenia (GT) have normal platelet counts but abnormal platelet aggregation and carry the risk of life-threatening bleeding. We report three patients who received bone marrow transplantation (BMT) for type I GT and discuss the risk and management of anti-platelet antibodies. Patients and Results Diagnosis of GT was made through abnormal platelet aggregation studies or the absence of GPIIb/IIIa by flow cytometry. All patients had severe bleeding requiring multiple red blood cell transfusions. One patient received an unrelated donor transplant and two received matched sibling donor transplants following conditioning therapy with busulfan, cyclophosphamide, and fludarabine. Two patients developed an anti-platelet antibody, treated in one with intravenous immune globulin (IVIG). Engraftment of white blood cells and platelets was achieved on day +13 to +14 and +17 to +25, respectively. Complete donor chimerism and GPIIb/IIIa+ platelets are sustained at +22 to +30 months post transplant. Conclusions In summary, patients with GT and history of severe hemorrhage can be cured with BMT, but the presence of anti-platelet antibodies should be sought and platelet transfusions minimized prior to transplant. IVIG may be helpful in cases of refractory immune thrombocytopenia related to anti-platelet antibodies. Improvement in transplant-related complications with current transplant regimens allows consideration of BMT for life-threatening non-malignant disorders such as GT. Pediatr Blood Cancer © 2005 Wiley-Liss, Inc.

Background Long-term survival rates among children diagnosed with severe aplastic anemia (SAA) are excellent due to the success of human leukocyte antigen (HLA)-identical related hematopoietic stem cell transplantation (HSCT), concurrent advances in immunosuppressive treatment (IST), and improved supportive care. The challenge in making treatment recommendations for children with SAA, therefore, is to balance the apparent chronicity and morbidity following IST, with the potential up-front toxicity and complications of HSCT. Methods This review provides an update on the diagnosis and a risk-based treatment algorithm for children with acquired SAA. Recent experience using alternative donor HSCT and efforts to extend HSCT eligibility through advances in donor matching, de-escalation of conditioning regimens, and potential marrow graft engineering are highlighted. We discuss IST response rates, risks of relapse, and complications including clonal evolution. Conclusions While good treatment options exist for a majority of children diagnosed with SAA, novel non-transplantation treatments for unresponsive and relapsed patients without suitable transplant donors are needed. Further improvements in outcome will ultimately require a more complete understanding of the pathophysiology of aplastic anemia (AA). © 2005 Wiley-Liss, Inc.

Objectives: Maintenance hormone therapy after first-line chemotherapy is routinely used by many clinicians in advanced breast cancer patients with potentially hormone-sensitive tumors, although there are insufficient evidences in the literature to support this practice. We investigated the effects of the third-generation aromatase inhibitor letrozole as a maintenance therapy in postmenopausal patients who had responded or had stable disease with first-line chemotherapy. Methods: Fifty-eight patients (median age 62 years, range 31–80) were recruited and received letrozole, 2.5 mg/day starting within 8 weeks since the last cycle of chemotherapy. Estrogen and/or progesterone receptor status was positive in 81% of the patients, unknown in 19%; 57% of the patients had visceral disease. First-line chemotherapy included anthracyclines and/or taxanes in 74% of cases. Results: The median time to progression (TTP) from starting letrozole was 18.5 months. A shorter TTP was found in patients with abnormal CA 15-3 levels at the start of maintenance letrozole (median TTP, 9.9 months: p = 0.01), or with levels increasing >25% from baseline during the first 6 months of letrozole therapy (median TTP, 8.2 months: p < 0.0001). Response status improved during letrozole in 15.5% of patients who had obtained less than a complete response to chemotherapy. Maintenance treatment was well tolerated and had no significant impact on quality of life scores. Conclusions: This study provides evidence in support of the common clinical practice of maintenance hormone therapy after chemotherapy in suitably selected patients with advanced breast cancer.

Background: Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. Methods: Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m(2)) followed by eight cycles of CMF (cyclophosphamide [600 mg/m(2)], methotrexate [50 mg/m(2)], and 5-fluorouracil [600 mg/m(2)]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m(2)), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m(2)) sup- ported by filgrastim (300 mug/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m(2)) and thiotepa (800 mg/m(2)). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle. Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. Results: At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (highdose arm = 62 %, 95 % CI = 56 % to 68 %; conventional-dose arm = 64 %, 95 % CI = 57 % to 70 %) (P =.38). Conclusion: Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.

There is long-standing controversy over the management of small, node-negative breast cancers. Surgical excision, with or without local radiotherapy, plus adjuvant tamoxifen will result in long-term disease-free survival for some 80% of patients. On the other hand, around 20% will develop distant metastases and this figure can be reduced by adjuvant chemotherapy (Early Breast Trialists, 1998). The issue is whether it is justifiable to expose all patients with early disease to the side effects of cytotoxic therapy for the benefit of the minority. If those at greatest risk of relapse could be identified at the time of diagnosis, treatment decisions would be simplified. Many attempts have been made to categorise patients with operable node-negative tumours according to their individual prognoses (Merkl and Osborne, 1989; Leonard, 1999; Isaacs et al, 2001; Mirza et al, 2002; Niu et al, 2002) but no single marker or combination of markers has gained widespread acceptance and authoritative guidelines achieve only very broad selection of ‘higher risk’ patients for adjuvant cytotoxic chemotherapy (Eifel et al, 2001; Goldhirsch et al, 2001). Most recently, a prognostic ‘gene-expression signature’ has been described, based on microarray analysis of 70 genes (van't Veer et al, 2002; van de Vijver et al, 2002). However, it will be some time before such sophisticated technology can be applied in routine diagnostic practice (Schubert, 2003). Meanwhile, the range of possible predictive indicators, identifiable by long-established techniques, continues to grow and the potential benefits of a simple and reliable prognostic index justify further assessment.

Despite the extensive literature clearly demonstrating the survival benefit for adjuvant chemotherapy in women with operable breast cancer, there are few data confirming this in routine practice. Some studies have suggested that not all women gain to the same extent, with older women showing a smaller benefit and lower doses achieving poorer outcomes. We therefore reviewed the case notes of 750 women treated over a 15-year period at The Edinburgh Cancer Centre with the same intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) regimen, to identify patient- and treatment-related factors influencing outcome in routine practice. The actuarial 10-year survival for these women was 59.3%, with the anticipated poorer outcome for those with more involved ipsilateral axillary nodes, higher grade and ER-negative tumours. There was no evidence that a lower delivered dose intensity or older age at presentation resulted in a poorer survival. Of particular interest was the observation that 45% of patients who had grade 2/3 neutropenia had a 10% absolute survival advantage over those with no neutropenia (P0.001). This strongly suggests that some degree of neutropenia has more influence on outcome than age or delivered dose intensity.

Most patients with operable breast cancer now receive postoperative medical treatment in the form of adjuvant chemotherapy, hormone manipulation or both. These additional interventions have led to a significant improvement in disease-free survival and overall survival. Clinical trials suggest that total chemotherapy dose delivered and dose intensity both affect long-term clinical outcomes, yet clinical practice audits conducted in Europe and the USA show that dose reductions and delays are widely applied when haematological toxicities such as neutropenia occur. In order to reduce the risk of neutropenic complications and help deliver chemotherapy planned dose on time, targeted use of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in breast cancer patients is recommended. The availability of neutropenia risk prediction models and the first once-per-cycle, fixed-dose rHuG-CSF (pegfilgrastim), will allow more patients to benefit from receiving their planned chemotherapy dose on time, and enable the use of new dose-dense chemotherapy strategies in the adjuvant treatment of primary breast cancer. These hold the prospect of further improving chemotherapy treatment outcomes. (C) 2003 Elsevier Ltd. All rights reserved.

Summary The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20–30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy.

Following the encouraging results achieved with the oral fluoropyrimidine capecitabine in clinical trials, a named patient programme was initiated in the UK, through which patients with advanced breast cancer were prescribed capecitabine monotherapy. In this programme, patients were treated with the standard dose of oral capecitabine (1250 mg/m 2 twice daily on days 1–14 of a 21-day treatment cycle). Efficacy and safety data were collected and analysed from 102 patients receiving outpatient treatment with capecitabine. All patients had previously received chemotherapy and for the majority (75%) this was in the metastatic setting. In total, 482 treatment cycles were administered, with a median of 4.5 treatment cycles (range 1–22) per patient. Tumour responses were observed in 20 patients (20%), with an additional 47 patients (46%) achieving disease stabilisation. The median time to disease progression was 4.1 months and median overall survival was 7.7 months. The most common treatment-related adverse events were palmar-plantar erythrodysaesthesia (PPE) (36%) and gastrointestinal toxicities (diarrhoea (33%) and nausea (24%)). Dose reductions due to adverse events were required in 33% of patients, but capecitabine was administered without a dose reduction for 90% of cycles. The results achieved with capecitabine in this named-patient programme confirm that, under ‘real practice' conditions, capecitabine is active and well tolerated in patients with advanced breast cancer.

PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 plus docetaxel 75 mg/m2 on day 1 (n = 255) or to docetaxel 100 mg/m2 on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P = .0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P = .0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P = .006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m2, with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m2. Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

PURPOSE: To compare 6% miltefosine solution (Miltex; Asta Medica, Frankfurt, Germany), a new topical cytostatic drug, with placebo as palliative treatment for cutaneous metastases from breast cancer. PATIENTS AND METHODS: In a double-blind, placebo-controlled, multicenter phase III study, a total of 52 patients with inoperable progressive skin lesions from histologically or cytologically confirmed breast cancer, not manageable by radiotherapy or systemic treatment, with superficial or flat skin lesions (estimated depth of invasion ≤ 1 cm) were randomized to receive either 6% miltefosine solution or placebo. The solution was applied at the dose of 2 drops/10 cm2, once daily during the first week and twice daily thereafter until treatment failure. RESULTS: Treatment groups were well balanced for patient characteristics at study entry except for a small difference in age. Time to treatment failure (TTF), the primary parameter of this study, showed miltefosine solution to be significantly superior to placebo (P = .007); the median TTF in the miltefosine solution group was nearly three times longer than that in the placebo group (56 days v 21 days). The rate of response based on intention to treat patients was 33.3% for miltefosine solution compared with 3.7% for placebo (P = .006). Cutaneous reactions were seen mainly in the miltefosine group, with the type and frequency similar to those observed in previous studies. CONCLUSION: 6% Miltefosine solution is confirmed as an effective palliative treatment option for cutaneous metastases from breast cancer. Skin reactions, when present, are well tolerated and only occasionally require cessation of treatment.

Although drugs such as the taxoids and vinorelbine have increased the options available for anthracycline-resistant metastatic breast cancer, new therapeutic options are needed, particularly for taxoid-refractory tumours. Increasing emphasis is being placed on the development of oral agents, which many patients prefer provided efficacy is not compromised, particularly if the oral agents are less toxic than current intravenous agents. Capecitabine, a new, oral fluoropyrimidine, mimics continuous infusion 5-FU and is activated preferentially at the tumour site. Phase II studies of capecitabine have demonstrated encouraging response rates in patients with few further treatment options (20% response with an additional 43% achieving stable disease in paclitaxel-refractory patients; 36% response with a further 23% achieving stable disease in anthracycline-refractory patients). In addition, a randomized, phase II trial demonstrated a response rate of 30% (95% Cl: 19–43%) with capecitabine as first-line treatment for metastatic breast cancer, compared with 16% (95% Cl: 5–33%) in patients receiving low-dose CMF. These trials also showed that capecitabine has a favourable safety profile typical of infused fluoropyrimidines. Both alopecia and myelosuppression were rare. Capecitabine may therefore provide an effective, well-tolerated and convenient alternative to intravenous cytotoxic agents, not only in taxoid-resistant patients, but also in anthracycline-resistant metastatic breast cancer or as first-line therapy. Furthermore, the low incidence of myelosuppression makes capecitabine an attractive agent for incorporation into combination regimens with agents such as epirubicin/doxorubicin, the taxoids and vinorelbine. © 2001 Cancer ResearchCampaign http://www.bjcancer.com

The Association of Cancer Physicians Breast Cancer Forum: Implications of Calman–Hine for breast cancer services

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of 'ifosfamide at a dose of 9g/m2 over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M18F) with a median age of 28 years (range 13–45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and ...

Between October 1993 and September 1994, 33 women with metastatic breast cancer aged between 29 and 74 years with a median age of 58 were entered into a study of oral chemotherapy from three UK centres. Patients by definition had metastatic disease and were fit and well with performance status 0 or 1 in 23 cases, 2 in seven cases and 3 in two cases (one missing). Five patients had received prior adjuvant CMF chemotherapy, nine first line non-anthracycline containing chemotherapy for relapse, eight patients second line non-anthracycline containing chemotherapy and all patients had had hormone therapy either as adjuvant or for relapsed disease. Adjuvant radiotherapy had been given to 17 and palliative radiotherapy to 12 patients. In nine patients there was one site of disease at start of therapy, in 10 two sites, in 11 three sites and in three patients four or more sites. The regimen comprised oral idarubicin 15 mg/m 2 on day 1, 10 mg/m 2 on days 2 and 3 and oral cyclophosphamide 250 mg/m 2 (maximum 400 mg) on days 1, 2 and 3. Treatment was continued until disease progression or toxicity. Results : Overall 25% of 32 evaluable patients responded objectively including one complete response; 50% of patients had stable disease and 25% of patients progression. Among patients who had had no prior chemotherapy the objective response rate was 37.5%; 45% of patients had symptomatic improvement. The most common severe toxicity was granulocytopenia WHO grade 3 or more in 69.7% of patients. Thrombocytopenia grade 3 or 4 was seen in four patients. Six patients had documented infections and all but four patients had alopecia. All patients complained of mild or moderate fatigue. Nausea and vomiting occurred in 75% of patients but only four individuals had grade 3 toxicity. Two patients stopped therapy after myocardial infarction and one after impaired cardiac function was noted. The median time to progression was 2.7 months (1–11.5 months) and median survival time 8.8 months (1–13+ months). Conclusion : The combination chemotherapy is active in heavily treated patients with manageable toxicity but there are problems in heavily pre-treated patients. There was good compliance in taking medication and at the doses chosen the drugs appear to be suitable for younger fitter patients.

The expression of MIB-1, a marker of proliferation, has been measured in tumours from 61 patients with large (>4 cm) operable breast cancers (T2,3 N0,1M,) treated with primary systemic therapy; either with hormone therapy (27 patients), chemotherapy (17 patients) or hormone therapy followed by chemotherapy (17 patients), in order to determine its role in predicting response and survival. Staining was variable between tumours (1–89% of malignant cells staining). There was no correlation between MIB-1 expression and oestrogen receptor concentration when both parameters were measured as a continuous variable, but MIB-1 values were significantly lower in ER-rich tumours compared with tumours which were ER-poor. Response to hormone treatment was restricted to oestrogen receptor positive tumours. Tumours which responded to treatment also had significantly lower MIB-1 values than those which did not (P< 0.004). In terms of response to chemotherapy, neither ER status or MIB-1 predicted for response. However, MIB-1 values were significantly higher in tumours proceeding to a complete pathological response as compared to those with a lesser degree of response (P< 0.01). The overall survival of patients at 10 years was 50%. Neither ER status or MIB-1 predicted for survival following primary hormone therapy. However, MIB-1 predicted for survival following primary chemotherapy; the survival of patients with tumours which showed high MIB-1 expression was significantly better than the survival of those patients with tumours which showed low MIB-1 expression (P< 0.003). In contrast, in the group of patients treated with chemotherapy after failed hormone therapy, survival was significantly worse in those with high MIB-1 expression (P< 0.005).

Cancer is the second leading cause of death in the world. In the UK cancer has overtaken heart disease as the leading cause of death. Breast cancer is the most common female cancer. In the UK one in 12 women or 27 000 cases of breast cancer present annually. Twothirds of these women are under the age of 70. Most patients have no evidence of metastatic disease at the time of presentation, but many subsequently relapse and the current mortality rate is around 50% [1]. In early disease chemotherapy as adjuvant treatment to surgery gives a 19–30% improvement in relapse-free and a 10–26% improvement in overall survival at 10 years [2]. Although breast cancer is one of the hormone sensitive cancers, one third of women are oestrogen receptor negative at presentation. They tend to be younger and pre-menopausal. All women who have metastatic disease that is initially oestrogen sensitive ultimately develop hormone resistance. Chemotherapy will give response rates of 45–80% with complete response rates of 5–25%. However these responses are short-lived with a median duration of 5–13 months. Subsequent treatments have a poorer result with shorter and fewer complete responses being achieved [3].

Summary Background Given as first- or second-line chemotherapy, docetaxel appears to have great potential in advanced breast cancer. Patients and methods Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere®) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1–7), 342 patients (91%) had at least one prior anthracycline-based regimen. Results Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients, 46% among the 299 patients who were ‘anthracycline resistant– and 35% among the 82 patients who were ‘anthracycline refractory’ (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg/m2with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan—Meier survival analysis yielded a median survival of 194 days (95% CI: 178–218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis. Conclusions The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an ‘anthracycline refractory’ population.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Breast cancer is the most common female cancer--one woman in 12 will have breast cancer at some stage during her life. Early-stage breast cancer is often curable; however, the prognosis is much worse in patients with multiple lymph node involvement or metastatic disease. The overall survival at five years is approximately 60% in women with positive lymph nodes, decreasing to 27%-44% when more than 10 lymph nodes are involved. After metastatic relapse, the mainstay of treatment is palliative. However, recent advances in supportive care have facilitated investigation into the use of dose-intensive chemotherapy regimens. The advancement of high-dose chemotherapy in breast cancer and results from clinical trials in both metastatic disease and the adjuvant setting are reviewed here. The true benefit of high-dose chemotherapy in breast cancer continues to be investigated. It is hoped that the results of worldwide, randomised clinical trials, due within the next three to five years, will provide a clearer indication of the value of high-dose chemotherapy, its costs and the patients whom it will benefit most.