Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311.

PURPOSE: The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. METHODS: This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. RESULTS: In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. CONCLUSION: For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II.

Background: Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS)-II prevention and ductal carcinoma in situ (DCIS) trials, and its association with early symptoms. Patients and methods: In the prevention trial, 3864 postmenopausal women were randomized to placebo versus anastrozole. A total of 2980 postmenopausal women with DCIS were randomized to tamoxifen versus anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided. Results: In the prevention trial, adherence was 65.8% [anastrozole (65.7%) versus placebo (65.9%); HR = 0.97 (0.87-1.09), P = 0.6]. Adherence was lower for those reporting arthralgia in the placebo group (P = 0.02) or gynecological symptoms in the anastrozole group (P = 0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% [anastrozole (67.5%) versus tamoxifen (65.8%); HR = 1.06 (0.94-1.20), P = 0.4]. Hot flashes were associated with greater adherence in the anastrozole arm (P = 0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials. Conclusions: In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

BACKGROUND: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. PATIENTS AND METHODS: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. RESULTS: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. CONCLUSION: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.

Improving decision making about clinical trial participation - a randomised controlled trial of a decision aid for women considering participation in the IBIS-II breast cancer prevention trial.

BACKGROUND: Decision aids may improve informed consent in clinical trial recruitment, but have not been evaluated in this context. This study investigated whether decision aids (DAs) can reduce decisional difficulties among women considering participation in the International Breast Cancer Intervention Study-II (IBIS-II) trial. METHODS: The IBIS-II trial investigated breast cancer prevention with anastrazole in two cohorts: women with increased risk (Prevention), and women treated for ductal carcinoma in situ (DCIS). Australia, New Zealand and United Kingdom participants were randomised to receive a DA (DA group) or standard trial consent materials (control group). Questionnaires were completed after deciding about participation in IBIS-II (post decision) and 3 months later (follow-up). RESULTS: Data from 112 Prevention and 34 DCIS participants were analysed post decision (73 DA; 73 control); 95 Prevention and 24 DCIS participants were analysed at follow-up (58 DA; 61 control). There was no effect on the primary outcome of decisional conflict. The DCIS-DA group had higher knowledge post decision, and the Prevention-DA group had lower decisional regret at follow-up. CONCLUSIONS: This was the first study to evaluate a DA in the clinical trial setting. The results suggest DAs can potentially increase knowledge and reduce decisional regret about clinical trial participation.

Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem).

BACKGROUND: Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. METHODS: Female patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. RESULTS: 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. CONCLUSION: Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended. Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number ACTRN12606000191594.

Symptoms of endocrine treatment and outcome in the BIG 1-98 study.

There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Data on patients randomized into the monotherapy arms of the BIG 1-98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n = 4,798) and at the 12-month landmark (n = 4,682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed for disease-free survival (DFS) and for breast cancer free interval (BCFI), using regression analysis to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Median follow-up was 7.0 years. Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses [e.g., 12-month landmark, HR (95 % CI) for DFS = 0.65 (0.49-0.87), and for BCFI = 0.70 (0.49-0.99)]. By contrast, reporting of vasomotor symptoms was less clearly associated with DFS [12-month DFS HR (95 % CI) = 0.82 (0.70-0.96)] and BCFI (12-month DFS HR (95 % CI) = 0.97 (0.80-1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.

Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report.

BACKGROUND: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. RESULTS: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. CONCLUSION: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.

Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial.

BACKGROUND: Several studies have reported discordant results regarding the impact of the CYP2D6 phenotype on both the effectiveness and the degree of endocrine symptoms associated with tamoxifen. Other studies have suggested that menopausal symptoms may be a predictive factor to tamoxifen response. METHODS: We investigated the relationship between the CYP2D6-predicted phenotype and tamoxifen response in a nested case-control study among women from the International Breast cancer Intervention Study (IBIS-I), which evaluated tamoxifen in the preventive setting. RESULTS: In this retrospective analysis of the tamoxifen-treated women in the IBIS-I study, 9 women (16.6%) who developed oestrogen receptor-positive invasive breast cancer had a 2D6 poor or intermediate metaboliser phenotype compared with 45 (20.6%) controls. Adjusted matched logistic regression revealed no significant difference between cases and controls for extensive vs intermediate metaboliser phenotype (OR=0.81 (0.30-2.23), P=0.7) or extensive vs poor metaboliser phenotype (OR=1.02 (0.31-3.32), P=0.9). Controls in the tamoxifen group with a poor metaboliser phenotype developed nonsignificantly fewer hot flushes compared with those with an extensive metaboliser phenotype (OR=0.40 (0.12-1.31)), but those with the intermediate phenotype developed nonsignificantly more hot flushes (OR=1.38 (0.58-3.29)) in an unadjusted analysis. CONCLUSION: Data from the preventive IBIS-I study did not support an association between the CYP2D6 phenotype and breast cancer outcome or the development of endocrine symptoms in tamoxifen-treated women.

The sequential use of endocrine treatment for advanced breast cancer: where are we?

BACKGROUND: Hormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined. METHODS: We reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points. RESULTS: In this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated. CONCLUSION: We present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways.

Cryoprotective agent toxicity interactions in human articular chondrocytes.

BACKGROUND: Vitrification is a method of cryopreservation by which cells and tissues can be preserved at low temperatures using cryoprotective agents (CPAs) at high concentrations (typically ≥6.0 M) to limit the harmful effects of ice crystals that can form during cooling processes. However, at these concentrations CPAs are significantly cytotoxic and an understanding of their toxicity characteristics and interactions is important. Therefore, single-CPA and multiple-CPA solutions were evaluated for their direct and indirect toxicities on chondrocytes. METHODS: Chondrocytes were isolated from human articular cartilage samples and exposed to various single-CPA and multiple-CPA solutions of five common CPAs (dimethyl sulfoxide (DMSO), ethylene glycol (EG), propylene glycol (PG), glycerol (Gy) and formamide (Fm)) at both 6.0 and 8.1 M concentrations at 0 °C for 30 min. Chondrocyte survival was determined using a fluorescent cell membrane integrity assay. The data obtained was statistically analyzed and regression coefficients were used to represent the indirect toxicity effect which a specific combination of CPAs exerted on the final solution's toxicity. RESULTS: Multiple-CPA solutions were significantly less toxic than single-CPA solutions (P<0.01). The indirect toxicity effects between CPAs were quantifiable using regression analysis. Cell survival rates of approximately 40% were obtained with the four-CPA combination solution DMSO-EG-Gy-Fm. In the multiple-CPA combinations, PG demonstrated the greatest degree of toxicity and its presence within a combination solution negated any benefits of using multiple lower concentration CPAs. CONCLUSIONS: Multiple-CPA solutions are less cytotoxic than single-CPA solutions of the same total concentration. PG was the most toxic CPA when used in combinations. The highest chondrocyte survival rates were obtained with the 6.0 M DMSO-EG-Gy-Fm combination solution.

Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial.

BACKGROUND: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important. PATIENTS AND METHODS: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy. RESULTS: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk. CONCLUSION: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial.

BACKGROUND: There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR/ANZ DCIS trial have been histologically reviewed to determine the features of prognostic importance. METHOD: A total of 72% of 1694 cases entered into the UKCCCR/ANZ DCIS trial had full pathological review. A large number of histological features were assessed, blinded to outcome and compared regarding ability to predict ipsilateral recurrence, as either DCIS or progression to invasive carcinoma. RESULTS: Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width. Receipt of post-operative radiotherapy was also a strong prognostic factor.We report a novel sub-division of the large group of high-grade lesions, which enables identification of a very poor prognosis sub-group; namely, DCIS that is of high cytonuclear grade, predominantly (>50%) solid architecture, bearing extensive comedo-type necrosis (>50% of ducts). In addition, we found little difference in ipsilateral recurrence rates between low- and intermediate-grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence. CONCLUSION: We present a novel pathological classification for DCIS with substantially better prognostic discrimination for ipsilateral recurrence than the classical categorisation based on cytonuclear grade alone.

Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.

OBJECTIVE: To compare a 'bypass-surgery-first' with a 'balloon-angioplasty-first' revascularisation strategy in patients with severe limb ischaemia (SLI) due to infrainguinal disease requiring immediate/early revascularisation. DESIGN: A stratified randomised controlled trial. A Delphi consensus study of vascular surgeons' and interventional radiologists' views on SLI treatment was performed before the trial. SETTING: Twenty-seven UK hospitals. PARTICIPANTS: Patients presenting with SLI as the result of infrainguinal atherosclerosis and who, in the opinion of the responsible consultant vascular surgeon and interventional radiologist, required and were suitable for both surgery and angioplasty. INTERVENTIONS: Patients were randomised to either 'bypass-surgery-first' or 'balloon-angioplasty-first' revascularisation strategies. MAIN OUTCOME MEASURES: The primary end point was amputation-free survival (AFS); secondary end points were overall survival (OS), health-related quality of life (HRQoL) and cost-effective use of hospital resources. RESULTS: AFS at 1 and 3 years was not significantly different for surgery and angioplasty. Interim analysis showed that surgery was associated with significantly lower immediate failure, higher 30-day morbidity and lower 12-month reintervention rates than angioplasty; 30-day mortality was similar. Beyond 2 years from randomisation, hazard ratios (HRs) were significantly reduced for both AFS (adjusted HR 0.37; 95% CI 0.17 to 0.77; p = 0.008) and OS (HR 0.34; 95% CI 0.17 to 0.71; p = 0.004) for surgery relative to angioplasty. By 2008 all but four patients had been followed for 3 years, some for over 7 years: 250 (56%) were dead, 168 (38%) were alive without amputation and 30 (7%) were alive with amputation. Considering the follow-up period as a whole, AFS and OS did not differ between treatments but for patients surviving beyond 2 years from randomisation, bypass was associated with reduced HRs for AFS (HR 0.85; 95% CI 0.50 to 1.07; p = 0.108) and OS (HR 0.61; 95% CI 0.50 to 0.75; p = 0.009), equating to an increase in restricted mean OS of 7.3 months (p = 0.02) and AFS of 5.9 months (p = 0.06) during the subsequent follow-up period. Vein bypasses and angioplasties performed better than prosthetic bypasses. HRQoL was non-significantly better in the surgery group; amputation was associated with a significant reduction in HRQoL. Over the first year, hospital costs for bypass were significantly higher (difference 5420 pounds; 95% CI 1547 pounds to 9294 pounds) than for angioplasty. However, by 3 and at 7 years the differences in cost between the two strategies were no longer significant. Patients randomised to surgery lived, on average, 29 days longer at an additional average cost of 2310 pounds. A 36-month perspective showed not significantly different mean quality-adjusted life times for angioplasty and surgery. The Delphi study revealed substantial disagreement between and among surgeons and radiologists on the appropriateness of bypass surgery or balloon angioplasty. CONCLUSIONS: The findings of our study suggest that in patients with SLI due to infrainguinal disease the decision whether to perform bypass surgery or balloon angioplasty first appears to depend upon anticipated life expectancy. Patients expected to live less than 2 years should usually be offered balloon angioplasty first as it is associated with less morbidity and cost, and such patients are unlikely to enjoy the longer-term benefits of surgery. By contrast, those patients expected to live beyond 2 years should usually be offered bypass surgery first, especially where a vein is available as a conduit. Many patients who could not undergo a vein bypass would probably have been better served by a first attempt at balloon angioplasty than prosthetic bypass. The failure rate of angioplasty in SLI is high (c. 25%) and patients who underwent bypass after failed angioplasty fared significantly worse than those who underwent surgery as their first procedure. The interests of a significant proportion of BASIL patients may have been best served by primary amputation followed by high-quality rehabilitation. Further research is required to confirm or refute the BASIL findings and recommendations; validate the BASIL survival prediction model in a separate cohort of patients with SLI; examine the clinical and cost-effectiveness of new endovascular techniques and devices; and compare revascularisation with primary amputation and with best medical and nursing care in those SLI patients with the poorest survival prospects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45398889.

Gefitinib treatment in hormone-resistant and hormone receptor-negative advanced breast cancer.

BACKGROUND: Acquired and de novo endocrine resistance in breast cancer (BC) may be associated with overexpression of epidermal growth factor receptor (EGFR). Gefinitib is an orally active selective EGFR inhibitor which might benefit advanced breast cancer (ABC) patients either with acquired hormone resistance or with hormone receptor (HR)-negative tumors. PATIENTS AND METHODS: A two-arm multicenter phase II trial of oral gefitinib 500 mg/day was planned in two groups of 45 patients with ABC for whom chemotherapy was not currently indicated. Group 1 had hormone-resistant BC defined as HR-positive BC with progression after treatment with tamoxifen and an aromatase inhibitor. Group 2 had HR-negative BC. Tumor response was assessed every 8 weeks. The primary end point was the clinical benefit rate (CBR). RESULTS: Forty patients with hormone-resistant BC had a CBR of 0%. Two of 25 HR-negative BC patients showed stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) at 24 weeks resulting in a CBR of 7.7% (95% CI 0.9% to 25.1%). Enrollment ceased due to the low CBR. Toxicity resulted in treatment interruption (46%), dose reduction (20%) and withdrawal (11%) of patients. CONCLUSION: At a dose of 500 mg/day, gefitinib monotherapy resulted in a low CBR and no tumor response was identified.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Improving informed consent: pilot of a decision aid for women invited to participate in a breast cancer prevention trial (IBIS-II DCIS).

BACKGROUND: Patients and clinicians report difficulties with the process of informed consent to clinical trials and audiotape audits show that critical information is often omitted or poorly presented. Decision aids (DAs) may assist in improving consent. AIMS: This study piloted a DA booklet for a high priority breast cancer prevention trial, IBIS-II DCIS, which compares the efficacy of an aromatase inhibitor (anastrozole) with tamoxifen in women who have had surgery for ductal carcinoma in situ (DCIS). METHOD: Thirty-one Australian women participating in the IBIS-I breast cancer prevention trial and who are currently in follow-up agreed to read the IBIS-II DCIS participant information sheet and the DCIS DA booklet, complete a set of standardized questionnaires, and provide feedback on the DA via a semi-structured phone interview. RESULTS: Women found the DA helpful in deciding about trial participation, reporting that it aided their understanding over and above the approved IBIS-II DCIS participant information sheet and was not anxiety provoking. Women's understanding of the rationale and methods of clinical trials and the IBIS-II DCIS trial was very good; with more than 80% of items answered correctly. The only areas that were not understood well were the concepts of randomization and blinding. CONCLUSIONS: This study suggests that the DA will be acceptable to and valued by potential participants in the IBIS-II DCIS study. The revised DA is currently being evaluated prospectively in a randomized controlled trial. If successful, such DAs could transform the consent process to large clinical trials and may also reduce dropout rates.

Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer.

Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, -2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.

Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial.

BACKGROUND: The aim was to determine whether early open surgical repair would benefit patients with small abdominal aortic aneurysm compared with surveillance on long-term follow-up. METHODS: The 1090 patients who were enrolled into the UK Small Aneurysm Trial between 1991 and 1995 were followed up for aneurysm repair and mortality until November 2005. RESULTS: By November 2005, 714 patients (65.5 per cent) had died, 929 (85.2 per cent) had undergone aneurysm repair, 150 (13.8 per cent) had died without aneurysm repair and 11 (1.0 per cent) remained alive without aneurysm repair. After 12 years, mortality in the surgery and surveillance groups was 63.9 and 67.3 per cent respectively, unadjusted hazard ratio 0.90 (P = 0.139). Three-quarters of the surveillance group eventually had aneurysm repair, with a 30-day elective mortality of 6.3 per cent (versus 5.0 per cent in the early surgery group, P = 0.366). Estimates suggested that the cost of treatment was 17 per cent higher in the early surgery group, with a mean difference of 1326 pounds. The death rate in these patients was about twice that in the population matched for age and sex. CONCLUSION: There was no long-term survival benefit of early elective open repair of small abdominal aortic aneurysms. Even after successful aneurysm repair, the mortality among these patients was higher than in the general population.

Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial.

BACKGROUND: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.

Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients.

BACKGROUND: Orthopaedic surgeons vary in their management of displaced intracapsular fractures of the hip in healthy older patients. The aim of this investigation was to determine the functional, clinical, and resource consequences of three different types of surgical treatment. METHODS: The study was a multicenter randomized controlled trial. Reduction and fixation was compared with bipolar hemiarthroplasty with cement and total hip replacement with cement. Participating surgeons elected to randomize their patients to be treated with either one of the three types of procedures or with either fixation or bipolar hemiarthroplasty. Functional outcomes were measured with a hip-rating questionnaire and the EuroQol health status measure. Clinical outcomes included mortality and complications. The direct health service costs were compared. Participants were followed up for two years. RESULTS: Two hundred and seven patients were randomized to be treated with one of the three operations, and ninety-one were randomized to be treated with either fixation or bipolar hemiarthroplasty. There were no differences in the mortality rates among the treatment groups. The rate of secondary surgery was highest in the fixation group (39% compared with 5% in the group treated with bipolar hemiarthroplasty and 9% in the group treated with total hip replacement). The fixation group had the worst hip-rating-questionnaire and EuroQol scores at four and twelve months. The total hip replacement group had significantly better functional outcome scores at twenty-four months than the other two groups. Although fixation was initially the least costly procedure, this short-term advantage was eroded by significantly higher costs for subsequent hip-related hospital admissions. CONCLUSIONS: Arthroplasty is more clinically effective and cost-effective than reduction and fixation in healthy older patients with a displaced intracapsular fracture of the hip. The long-term results of total hip replacement may be better than those of bipolar hemiarthroplasty.