There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram-negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient's thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients.

Therapy-related acute leukaemia (TRAL) is a significant concern, when considering treatment with mitoxantrone for multiple sclerosis (MS). We re-evaluated the literature, identifying all case reports and series of > 50 patients reporting TRAL cases in MS. TRAL was diagnosed in 0.73% of the 12,896 patients identified. Median onset was 22 months following treatment. We calculated a number needed to harm of 137.5 exposed patients, significantly higher than our 2008 analysis. We found that 82.8% of patients were exposed to > 60 mg/m(2) with a relative risk of 1.85 (p = 0.018) compared to < 60 mg/m(2), strongly suggesting a relationship to dose. MS treatment regimens which limit the mitoxantrone dose to < 60 mg/m(2) reduce the risk of TRAL.

Non-steroidal antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues.

The role of cetuximab in treatment-related hematologic toxicity is not clear. We performed a meta-analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta-analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05-1.27, p=0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53-4.65, p=0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08-1.22, p<0.01). Additionally, K-ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11-1.54, p=0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.

Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer.

Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs).

A systematic review and meta-analysis of fatigue and hepatic adverse events associated with lapatinib use in solid tumor patients were performed.

We performed a systematic review and meta-analysis of thyroid function abnormalities associated with seven vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitors (sorafenib, sunitinib, axitinib, cediranib, pazopanib, regorafenib and vandetanib). Eligible studies included randomized Phase II and III trials of patients with solid tumors on sorafenib OR sunitinib OR axitinib OR cediranib OR pazopanib OR regorafenib OR vandetanib; describing events of hypothyroidism or hyperthyroidism. Our search strategy yielded 195 potentially relevant citations on the seven agents from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 12 clinical trials were considered eligible for the meta-analysis, including six sunitinib studies, four cediranib studies and two axitinib studies. Patients treated with these agents had a significantly increased risk of all-grade hypothyroidism and the relative risk (RR) of all-grade hypothyroidism was 3.59 (95% CI = 2.40-5.38, p ≤ 0.0001). Exploratory subgroup analysis showed no effect of tumor types or agent used on the RR of hypothyroidism. Our meta-analysis has demonstrated that these three agents are associated with a significantly increased risk of all-grade hypothyroidism; with no difference - on subgroup analysis - between sunitinib and cediranib. Clinicians should be aware of these risks and perform regular thyroid function monitoring.

Several studies have demonstrated that a serum-based proteomic test (VeriStrat * ) is able to predict the clinical outcome of non-small-cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, these studies have limited power to draw a precise conclusion because of their small sample sizes and inconsistent results. Therefore, a meta-analysis was carried out in an attempt to provide more persuasive evidence.

Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system.

Hematopoietic stem cell transplant (HSCT) recipients are at high risk of contracting Clostridium difficile infection (CDI). We systematically searched the PubMed and EMBASE databases through March 2014 and performed a random-effects meta-analysis to estimate the prevalence and trends of CDI over time. Among 48 eligible articles that included 12,025 patients at risk, we estimated that 7.9% (95% confidence interval [CI], 6.5% to 9.5%) of HSCT patients are diagnosed with CDI during the peri-transplantation and late post-transplantation periods, an estimation that is relatively consistent across studies (τ(2) = .032). Prevalence of CDI is significantly higher among the 5120 allogeneic patients (9.3% [95% CI, 7.0% to 11.9%]), compared with the 4665 autologous patients (5.2% [95% CI, 3.8% to 6.9%]) (P = .02), and as many as 1 of 10 allogeneic transplant recipients are expected to be diagnosed with CDI compared with 1 of 20 autologous transplantation patients. However, this difference did not reach statistical significance when stratified data from the same centers were examined (P = .11). Importantly, we found an increasing trend of CDI diagnosis both worldwide (P = .02) and across studies conducted in North America (P = .03) over the last 34 years. Notably, studies with a follow-up period that extended through the late post-transplantation period (after day +100) had a similar prevalence of CDI as those that followed patients only during the peri-transplantation period (up to day +100) (P = .94). In summary, CDI is common in the hematopoietic transplantation setting and the majority of infections occur in the peri-transplantation period. The prevalence is almost 9-times higher than that reported among all hospital stays, with an increasing trend over time.

Nearly 85 % of lung-cancer-specific epidermal growth factor receptor (EGFR) sensitive mutations comprise a substitution at position 858 (21L858R) and deletion mutants in exon 19 (19del). The aim of this study was to assess the role of EGFR mutation subtypes in predicting the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) and the prognosis of patients with advanced non-small cell lung cancer (NSCLC).

To determine if a low fixed dosing strategy of capecitabine would produce comparable clinical activity with less adverse toxicities compared to published data with higher doses in the setting of metastatic breast cancer (mBC). We retrospectively analyzed patients treated with a low fixed dose of capecitabine (CAPE-L) at 1,000 mg twice daily for 14 days every 21 days. Outcomes included clinical benefit rate (CBR), overall response rates (ORR), time to progression (TTP), and overall survival (OS). A historical comparison group of mBC patients treated on 12 prior trials at the package-insert dose of capecitabine (n = 1,949) was utilized. Eighty-six patients were analyzed in our cohort. Positive hormone receptor status (79.1 vs. 50.6 %), and capecitabine as first-line chemotherapy (44.2 vs. 16.5 %) were more frequent in our cohort relative to the historical comparison. The median starting dose in our cohort was 633.5 mg/m(2). The CBR was similar between the CAPE-L and the standard dose cohorts (55.8 vs. 49.5 %), as was ORR (24.3 vs. 24 %), and median TTP (7 mo, 95 % CI 5.5-8.5 vs. 5.1 mo, 95 % CI 4.5-5.7). Median OS was longer in our cohort (24 mo, 95 % CI 16.8-31.2) than the historic standard dose cohort (12.1 mo, 95 % CI 9.6-14.4), a difference that was likely explained by the higher proportion of patients in the CAPE-L cohort who received capecitabine as first-line chemotherapy and who had hormone receptor positive disease. As expected, adverse events were less frequent with CAPE-L. We found that CAPE-L, which translates into a dose of 600-650 mg/m(2), appeared to have good clinical efficacy and acceptable toxicity.

Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.

Clinical data supporting the use of targeted agents for the treatment of metastatic renal cell carcinoma (RCC) are based predominantly on patients with clear cell histology. Little is known about the efficacy of these drugs in non-clear cell variants.

The aim of this meta-analysis was to gather current data and evaluate not only the risk of gastrointestinal (GI) perforation with bevacizumab, but also the potential risk factors for this adverse event.

Epidemiological studies support a protective role of lycopene against stroke occurrence or mortality, but the results have been conflicting. We conducted a meta-analysis to assess the relationship between dietary or circulating lycopene and stroke risk (including stroke occurrence or mortality). Relevant papers were collected by screening the PubMed database through October 2013. Only prospective studies providing relative risk estimates with 95% confidence intervals for the association between lycopene and stroke were included. A random-effects model was used to calculate the pooled estimate. Subgroup analysis was conducted to investigate the effects of various factors on the final results. The pooled analysis of seven prospective studies, with 116,127 participants and 1,989 cases, demonstrated that lycopene decreased stroke risk by 19.3% (RR=0.807, 95% CI=0.680-0.957) after adjusting for confounding factors. No heterogeneity was observed (p=0.234, I2=25.5%). Circulating lycopene, not dietary lycopene, was associated with a statistically significant decrease in stroke risk (RR=0.693, 95% CI=0.503-0.954). Lycopene could protect European, or males against stroke risk. Duration of follow-up had no effect on the final results. There was no evidence of publication bias. Lycopene, especially circulating lycopene, is negatively associated with stroke risk.

Intraperitoneal chemotherapy preceded by cytoreductive surgery should be the standard of care in the treatment of advanced epithelial ovarian cancer. This combination has been extensively examined in both the clinical and preclinical settings with favourable oncologic outcomes. Unfortunately, despite the existence of these evidence-based data, this management strategy remains underutilised.

The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies.

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.