The angiogenesis inhibitor pazopanib has been approved for the treatment of advanced renal cell cancer (RCC) and soft tissue sarcoma. Severe and fatal hepatotoxicity has been observed in its clinical studies. This analysis was conducted to determine the risk of liver toxicity by a systematic review and meta-analysis of clinical trials.

Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low.

In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions.

The incidence of renal cell cancer (RCC) has been steadily increasing over the past decade. Advances in understanding the pathophysiology and carcinogenesis RCC have led to the development of novel therapies that target molecular pathways. Everolimus is a synthetic, orally available analogue of rapamycin that inhibits the activation of mTOR. Everolimus extended progression-free survival in RCC patients from 1.9 months (for patients receiving a placebo) to 4.9 months. Grades 3 and 4 adverse events include stomatitis, fatigue, pneumonitis, infections, asthenia, diarrhea, mucosal inflammation, dyspnea, rash, anorexia and dry skin. Grades 3 and 4 laboratory abnormalities include lymphopenia, anemia, thrombocytopenia, hyperglycemia, hypophosphatemia, hypercholesterolemia, hypertriglycemia, elevated creatinine, elevated alkaline phosphatase, elevated aspartate aminotransferase and elevated alanine aminotransferase. Studies have been conducted to evaluate any synergistic effect of combination therapies and continue to need to be further evaluated.

The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of cytotoxic treatment. It continues to affect a significant proportion of patients despite the widespread use of antiemetic medication. In traditional medicine, ginger (Zingiber officinale) has been used to prevent and treat nausea in many cultures for thousands of years. However, its use has not been confirmed in the chemotherapy context. To determine the potential use of ginger as a prophylactic or treatment for CINV, a systematic literature review was conducted. Reviewed studies comprised randomized controlled trials or crossover trials that investigated the anti-CINV effect of ginger as the sole independent variable in chemotherapy patients. Seven studies met the inclusion criteria. All studies were assessed on methodological quality and their limitations were identified. Studies were mixed in their support of ginger as an anti-CINV treatment in patients receiving chemotherapy, with three demonstrating a positive effect, two in favor but with caveats, and two showing no effect on measures of CINV. Future studies are required to address the limitations identified before clinical use can be recommended.

Chemotherapy offers cancer patients the potential benefits of improved mortality and morbidity but may cause detrimental outcomes due to adverse drug events (ADEs), some of which requiring time-consuming, resource-intensive and costly clinical management. To appropriately assess chemotherapy agents in an economic evaluation, ADE-related parameters such as the incidence, (dis)utility and cost of ADEs should be reflected within the model parameters. To date, there has been no systematic summary of the existing literature that quantifies the utilities of ADEs due to healthcare interventions in general and chemotherapy treatments in particular.

There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy.

Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (C min) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile "reference" range: 520-1390 ng/mL). Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, α1 acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above. Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered.

Pseudomyxoma peritonei (PMP) is an uncommon but lethal variant of adenocarcinoma. Many recent case series have reported improved survival with the combination of cytoreductive surgery and intraperitoneal chemotherapy (IPEC) in treating PMP. The aim of this study was to analyze the published studies for improved survival with this treatment strategy.

Many published studies reflect the growing application of complementary and alternative medicine, particularly Chinese herbal medicine (CHM) use in combination with conventional cancer therapy for advanced non-small cell lung cancer (NSCLC), but its efficacy remains largely unexplored. The purpose of this study is to evaluate the efficacy of CHM combined with conventional chemotherapy (CT) in the treatment of advanced NSCLC. Publications in 11 electronic databases were extensively searched, and 24 trials were included for analysis. A sum of 2,109 patients was enrolled in these studies, at which 1,064 patients participated in CT combined CHM and 1,039 in CT (six patients dropped out and were not reported the group enrolled). Compared to using CT alone, CHM combined with CT significantly increase one-year survival rate (RR = 1.36, 95% CI = 1.15-1.60, p = 0.0003). Besides, the combined therapy significantly increased immediate tumor response (RR = 1.36, 95% CI = 1.19-1.56, p<1.0E-5) and improved Karnofsky performance score (KPS) (RR = 2.90, 95% CI = 1.62-5.18, p = 0.0003). Combined therapy remarkably reduced the nausea and vomiting at toxicity grade of III-IV (RR = 0.24, 95% CI = 0.12-0.50, p = 0.0001) and prevented the decline of hemoglobin and platelet in patients under CT at toxicity grade of I-IV (RR = 0.64, 95% CI = 0.51-0.80, p<0.0001). Moreover, the herbs that are frequently used in NSCLC patients were identified. This systematic review suggests that CHM as an adjuvant therapy can reduce CT toxicity, prolong survival rate, enhance immediate tumor response, and improve KPS in advanced NSCLC patients. However, due to the lack of large-scale randomized clinical trials in the included studies, further larger scale trials are needed.

Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95% confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine ± adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95% CI 0.55-0.93) and 0.77 (95% CI 0.60-0.99), respectively. However, when compared with the vincristine + adriamycin-based regimen, the OS was similar (HR = 0.87, 95% CI 0.57-1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy.

Second-generation azoles may be more effective than first-generation azoles in the prevention of fungal infections in hematology patients. We performed a systematic review with meta-analysis of randomized controlled trials comparing second- with first-generation azoles in hematology patients with respect to proven or probable invasive fungal infections, invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from the studies due to the development of adverse effects. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials electronic databases as well as conference proceedings from 2002 to 2012 for randomized controlled trials comparing second-generation azoles (voriconazole, posaconazole) versus first-generation azoles (fluconazole, itraconazole). Treatment effect measures for all outcomes were expressed as odds ratio with 95 % confidence interval. Meta-analysis was performed using Review Manager, version 5.1. Data from four randomized clinical trials representing a large population of patients demonstrated that antifungal prophylaxis with second-generation azoles reduces proven or probable invasive fungal infections, invasive aspergillosis, and receipt of empirical antifungal therapy in high-risk hematology patients, while there were no differences between second- and first-generation azoles with regard to overall mortality and patients or withdrawal from the studies due to the development of adverse effects. In conclusion, antifungal prophylaxis with second-generation azoles can significantly reduce the incidence of invasive fungal infections and invasive aspergillosis but with no risk of an increase in adverse events.

The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities.

To evaluate the effect of ginger as an antiemetic modality for the control of chemotherapy-induced nausea and vomiting (CINV).

Branch retinal vein occlusion (BRVO) is one of the most common occurring retinal vascular abnormalities. The pathogenesis of BRVO is thought to involve both retinal vein compression and damage to the vessel wall, possibly leading to thrombus formation at sites where retinal arterioles cross retinal veins. The most common cause of visual loss in patients with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss and improve visual acuity (VA) in up to two thirds of individuals with MO secondary to BRVO, however, limitations to this treatment exist and newer modalities have suggested equal or improved efficacy. Recently, antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has been used successfully to treat MO resulting from a variety of causes. As elevated intraocular levels of VEGF have been demonstrated in patients with retinal vein occlusions there is a strong basis for the hypothesis that anti-VEGF agents may be beneficial in the treatment of vascular leakage and MO.

Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy improves overall survival in metastatic and early HER2-overexpressing breast cancer. In this paper we systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key unanswered clinical questions. All trials of HER2-targeted neoadjuvant therapy were identified through non-date-limited searches of PubMED® and Biosis® and congress abstract book searches from 2000-2011. Eligible trials were prospective, had at least 10 patients and a clear definition of pathological complete response (pCR) rate. A total of 50 trials fulfilled the eligibility criteria; 41 single-arm phase II studies were identified, 37 with trastuzumab and 4 with lapatinib, with significant variability in baseline tumour characteristics and pCR rates (range 12-66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense of increased non-cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab. Significant advances have been made in HER2 targeting, resulting in a marked increase in the number of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade?

Nausea and vomiting are well recognized in different clinical situations, suggesting that no single mechanism is likely to be responsible for their production. Chemotherapy-induced nausea and vomiting (CINV) can have a negative impact on quality of life and this may lead to a refusal of curative therapy or to a decline in palliative benefits offered by cytotoxic treatment. Palonosetron is a new agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), and differs from the other agents by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy (MEC).

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

To compare the efficacy and safety of short-term versus long-term hormonotherapy (HT) plus radiotherapy (RT) or prostatectomy (RP) for prostate cancer.