Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1) : a phase 3, randomised, double-blind, multicentre trial

BACKGROUND : mTOR inhibition has been shown to reverse trastuzumab resistance from hyperactivated the PIK/AKT/mTOR pathway due to PTEN loss, by sensitizing PTEN-deficient tumors towards trastuzumab. The BOLERO-1 study evaluated the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line therapy for HER2+ advanced breast cancer (ABC). METHODS : In this phase III, randomized, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were ≥18 years of age, with locally assessed HER2+ advanced breast cancer (ABC), with Eastern Cooperative Oncology Group performance status of 0-1, who had not received prior trastuzumab or chemotherapy for ABC, had measurable disease as per Response Evaluation Criteria in Solid Tumors or bone lesions in the absence of measurable disease, without prior systemic therapy for advanced disease except endocrine therapy. The patients were randomized 2:1 (with an interactive voice and web response system) to receive either daily everolimus (10 mg/day) orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on Day-1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4- week cycle. Randomization was stratified according to prior use of trastuzumab and visceral metastasis. Patients and investigators were blinded to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival (PFS) in the full study population and in the subset of patients with hormone receptor-negative (HR) breast cancer at baseline; the latter was added during the course of the study, prior to unblinding based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final PFS analyses are presented here. Clinicaltrials.gov identifier: NCT00876395. FINDINGS : Between 10-Sep-2009 and 16-Dec-2012, 719 patients were randomized to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41.3 months (IQR: 35.4 – 46.6 months). INTERPRETATION : The primary objective in the full population was not met; median PFS was 15.0 months with everolimus vs 14.5 months with placebo (hazard ratio, 0.89; 95% CI, 0.73-1.08; p=0.1166). In the HR subpopulation (n=311), median PFS with everolimus was 20.3 months vs 13.1 months with placebo (hazard ratio, 0.66; 95% CI, 0.48-0.91; p=0.0049), however, the protocol-specified statistical significance threshold (p=0.0044) was not crossed. The most common adverse events (AEs) with everolimus vs placebo were stomatitis (314 [66.5%] vs 77 [32.4%] patients), diarrhea (267 [56.6%] vs 111 [46.6%] patients), and alopecia (221 [46.8%] vs 125 [52.5%]). The most frequently reported grade 3/4 AEs in the EVE arm vs PBO arm were neutropenia (117 [24.8%] of 472 patients vs 35 [14.7%] of 238 patients), stomatitis (59 [12.5%] of 472 patients vs 3 [1.3%] of 238 patients), anemia (46 [9.7%] of 472 patients vs 6 [2.5%] of 238 patients) and diarrhea (43 [9.1%] of 472 patients vs 10 [4.2%] of 238 patients) On-treatment AE-related deaths were reported in 17 [3.6%] vs 0% of patients respectively.Interpretation: The primary objective of PFS was not met. However, consistent with the preliminary observations from BOLERO-3, everolimus prolonged median PFS by 7.2 months in patients with HR, HER2+ ABC, which warrants further investigation. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of AEs in patients treated with everolimus and chemotherapy is critical..Novartis Pharmaceuticals Corporation.http://www.journals.elsevier.com/the-lancet-oncology2016-07-31hb201

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Colon cancer: update on adjuvant therapy.

Colon cancer is a public health problem worldwide. Although potentially curable at early stages, a substantial number of patients will inevitably present with or eventually develop metastatic disease, which is often incurable. Despite the progress achieved with the introduction of new cytotoxic agents, recurrence rates for patients with resected stage II/III disease remain > 20%. Therefore, a great deal of effort and resources have been put into improving early diagnosis and prevention tools as well as the efficacy of adjuvant treatment. Oxaliplatin-based chemotherapy is now considered the standard of care in node-positive colon cancer, but there remains controversy with regard to the indication and type of adjuvant treatment in patients with nodenegative disease. Oral fluoropyrimidines play a growing role in the management of colorectal cancer and can be currently considered an alternative to 5-fluorouracil. Numerous reports have suggested that elderly patients benefit equally from chemotherapy, but the growing numbers of octogenarian and nonagenarian patients in our clinics, many of whom occasionally struggle through treatment, are a reminder of the challenges ahead. Finally, as we might have reached a plateau in terms of cytotoxic chemotherapy, numerous clinical trials are now focusing on the role of biologic agents in the adjuvant setting

Multinational clinical trials in oncology and post-trial benefits for host countries: where do we stand?

International collaboration has undoubtedly played a key role in the extraordinary progress we have witnessed in some areas of oncology in recent years. It has allowed us, for instance, to design trials large enough to depict very small benefits, as well as high-quality trials in less incident types of cancer. For different reasons, developing countries have also shown growing interest in this international effort and have been participating in many international trials. However, the ever-growing costs of novel anti-cancer treatments and technologies have created unprecedented difficulties for health economies in developing countries. Although the issue of individual benefit for patients must also be taken into account, the actual benefit for their society may be minimal. This paper discusses the ethics of including patients from non-developed countries in clinical trials evaluating the role of treatments that are unlikely to be made available to them after the trial because of prohibitive costs. Upfront arrangements ensuring post-trial access to interventions that have been proven successful might be the best alternative to exclusion from the research.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Adjuvant anthracycline-based chemotherapy for early breast cancer: do the dose and schedule matter?

The rationale to justify the use of anthracyclines as adjuvant therapy for breast cancer is their proven superiority over CMF. Indeed, this has been demonstrated by a number of randomised clinical trials and recently confirmed by the Oxford meta-analysis. Nevertheless, the absolute benefit is modest (on average 4%), and with the cost of increased toxicity. Interestingly, many individual trials were unable to confirm the role of anthracyclines in early breast cancer, though most of these were either underpowered to show such small differences, or had inappropriate experimental arms. On the other hand, several trials included in the meta-analysis also had inadequate control arms. So far, probably only three trials were able to individually confirm this benefit: the American INT 0102, the Canadian MA5 and more recently, the British NEAT/NCTBG. Numerous different anthracycline schedules have been used as adjuvant therapy, many of these having never been compared to CMF. Unfortunately, as research is moving towards other more important questions, many of these uncertainties may never be clarified. In this paper, we review the current evidence behind some of the most commonly used anthracycline schedules.Comparative StudyJournal ArticleReviewinfo:eu-repo/semantics/publishe

New anticancer agents and therapeutic strategies in development for solid cancers: a clinical perspective.

In addition to well-known chemotherapeutic agents used in the treatment of solid cancers, promising novel cytotoxic agents are being investigated. Among them are analogs of existing cytotoxic agents, aimed at improving the therapeutic index, and new families such as the epothilone compounds. Agents that target the tyrosine kinase-dependent pathways, farnesyl transferase modulators, Raf kinase inhibitors, antisense molecules to Bcl-2 and proteasome modulators, agents that bind to key proteins involved in critical phases of the cell cycle, as well as antiangiogenesis strategies, are all promising approaches in the treatment of solid cancers. The combination of cytotoxics, hormonal agents or radiotherapy with new molecular-targeted therapies represents one of the main strategies to improve survival in solid cancers. A clinical perspective of these agents as monotherapy or combination therapy will be presented in this paper.Journal ArticleReviewinfo:eu-repo/semantics/publishe

Novel cytotoxic drugs: old challenges, new solutions.

The discovery of cytotoxic agents was revolutionary for anticancer therapy in the last century, improving survival rates and the quality of life of patients with different types of tumours. However, the development of agents that combine efficacy, safety and convenience remains a great challenge, due to the narrow therapeutic index of some drugs, the fact that they may damage not only cancer cells, but also normal and healthy tissue and the occurrence of resistance, limiting anticancer efficacy. Novel cytotoxic agents have brought certain advantages over the conventional ones, such as shorter administration time, mechanisms to overcome drug resistance and lower incidence of adverse events. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience in the treatment of patients with cancer.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

The 17q12-q21 amplicon: Her2 and topoisomerase-IIalpha and their importance to the biology of solid tumours.

Her2 and topoisomerase-IIalpha (T2A) gene amplification are separate events, although the latter is more frequently seen in Her2 amplified (34-90%) than in Her2 non-amplified (5-10%) tumours. There is a better correlation between Her2 amplification and protein overexpression in breast cancer (BC) than in other tumour types. This marker is also considered a powerful prognostic factor in BC, with similar data emerging in other solid tumours such as bladder, ovarian, endometrial, gastro-oesophageal and non-small cell lung cancer. Her2 amplification and/or overexpression are highly predictive of response to HER2-targeted compounds such as trastuzumab and lapatinib but have been inconsistent predictors of response to cytotoxic chemotherapy. There is also evidence that these tumours are relatively resistant to anti-oestrogen therapy (tamoxifen) but not to oestrogen deprivation (e.g. with aromatase inhibitors). T2A aberrations are uncommon events in solid tumours, with an overall prevalence of approximately 10%. T2A amplification has shown inconsistent correlation with T2A protein expression in preclinical and clinical studies, mainly because non-genetic events such as proliferation rate can also affect protein expression. Expression of T2A protein has not been shown to reliably predict response to T2A inhibitors, despite the fact that this enzyme is the direct target for these compounds. In BC, T2A amplification appears to be a good predictor of response to anthracyclines, but these data are still in the process of validation. The significance of T2A deletions is currently under investigation, but contrary to what was previously thought, it may also predict benefit from treatment with T2A inhibitors. The prognostic significance of T2A aberrations is currently unknown.Journal ArticleReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe