IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Targeting nuclear factor-kappa B to overcome resistance to chemotherapy

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Can ginger ameliorate chemotherapy-induced nausea? Protocol of a randomized double blind, placebo-controlled trial

Background Preliminary research shows ginger may be an effective adjuvant treatment for chemotherapy-induced nausea and vomiting but significant limitations need to be addressed before recommendations for clinical practice can be made. Methods/Design In a double–blinded randomised-controlled trial, chemotherapy-naïve patients will be randomly allocated to receive either 1.2 g of a standardised ginger extract or placebo per day. The study medication will be administrated as an adjuvant treatment to standard anti-emetic therapy and will be divided into four capsules per day, to be consumed approximately every 4 hours (300 mg per capsule administered q.i.d) for five days during the first three cycles of chemotherapy. Acute, delayed, and anticipatory symptoms of nausea and vomiting will be assessed over this time frame using a valid and reliable questionnaire, with nausea symptoms being the primary outcome. Quality of life, nutritional status, adverse effects, patient adherence, cancer-related fatigue, and CINV-specific prognostic factors will also be assessed. Discussion Previous trials in this area have noted limitations. These include the inconsistent use of standardized ginger formulations and valid questionnaires, lack of control for anticipatory nausea and prognostic factors that may influence individual CINV response, and the use of suboptimal dosing regimens. This trial is the first to address these issues by incorporating multiple unique additions to the study design including controlling for CINV-specific prognostic factors by recruiting only chemotherapy-naïve patients, implementing a dosing schedule consistent with the pharmacokinetics of oral ginger supplements, and independently analysing ginger supplements before and after recruitment to ensure potency. Our trial will also be the first to assess the effect of ginger supplementation on cancer-related fatigue and nutritional status. Chemotherapy-induced nausea and vomiting are distressing symptoms experienced by oncology patients; this trial will address the significant limitations within the current literature and in doing so, will investigate the effect of ginger supplementation as an adjuvant treatment in modulating nausea and vomiting symptoms. Trial registration

Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment.

The nurse's role in managing chemotherapy-induced nausea and vomiting

Background Nurses play a substantial role in the prevention and management of chemotherapy-induced nausea and vomiting (CINV). Objectives This study set out to describe nurses’ roles in the prevention and management of CINV and to identify any gaps that exist across countries. Methods A self-reported survey was completed by 458 registered nurses who administered chemotherapy to cancer patients in Australia, China, Hong Kong, and 9 Latin American countries. Results More than one-third of participants regarded their own knowledge of CINV as fair to poor. Most participants (>65%) agreed that chemotherapy-induced nausea and chemotherapy-induced vomiting should be considered separately (79%), but only 35% were confident in their ability to manage chemotherapy-induced nausea (53%) or chemotherapy-induced vomiting (59%). Only one-fifth reported frequent use of a standardized CINV assessment tool and only a quarter used international clinical guidelines to manage CINV. Conclusions Participants perceived their own knowledge of CINV management to be insufficient. They recognized the need to develop and use a standardized CINV assessment tool and the importance of adopting international guidelines to inform the management of CINV. Implications for Practice: Findings indicate that international guidelines should be made available to nurses in clinically relevant and easily accessible formats, that a review of chemotherapy assessment tools should be undertaken to identify reliable and valid measures amenable to use in a clinical settings, and that a CINV risk screening tool should be developed as a prompt for nurses to enable timely identification of and intervention for patients at high risk of CINV.

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery

Background The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. Methods Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. Results Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34 %, (16/47). Disease recurrence occurred in 19 patients (19/47, 40 %). Median overall survival was 22 months, with 4-year survival of 47 %. Chemotoxicities were consistent with those previously reported for this regimen. Conclusion This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.

Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Systematic review of pharmacologic and non-pharmacologic interventions to manage cognitive alterations after chemotherapy for breast cancer

Purpose Cognitive alterations are reported in breast cancer patients receiving chemotherapy. This has adverse effects on patients’ quality of life and function. This systematic review investigates the effectiveness of pharmacologic and non-pharmacologic interventions to manage cognitive alterations associated with breast cancer treatment. Methods Medline via EBSCOhost, CINAHL and Cochrane CENTRAL were searched for the period January 1999 to May 2014 for prospective randomized controlled trials related to the management of chemotherapy-associated cognitive alterations. Included studies investigated the management of chemotherapy-associated cognitive alterations and used subjective or objective measures in patients with breast cancer during or after chemotherapy. Two authors independently extracted data and assessed the risk of bias. Results Thirteen studies involving 1138 participants were included. Overall, the risk of bias for the 13 studies were either high (n=11) or unclear (n=2). Pharmacologic interventions included psychostimulants (n=4), epoetin alfa (n=1), and Ginkgo biloba (n=1). Non-pharmacologic interventions were cognitive training (n=5) and physical activity (n=2). Pharmacologic agents were ineffective except for self-reported cognitive function in an epoetin alfa study. Cognitive training interventions demonstrated benefits in self-reported cognitive function, memory, verbal function and language and orientation/attention. Physical activity interventions were effective in improving executive function and self-reported concentration. Conclusion Current evidence does not favor the pharmacologic management of cognitive alterations associated with breast cancer treatment. Cognitive training and physical activity interventions appear promising, but additional studies are required to establish their efficacy. Further research is needed to overcome methodological shortfalls such as heterogeneity in participant characteristics and non-standardized neuropsychological outcome measures.

Nutritional risk of cancer patients receiving chemotherapy in the ambulatory care setting : a prospective study

Background Cancer itself can alter the metabolic and physiologic of the body's nutritional needs. As a result, some patients experience some degree of weight loss before the start of the treatment. Aim The aim of the study was to determine at which chemotherapy treatment cycle patients with cancer begin to exhibit signs and symptoms of malnutrition. Methods A prospective descriptive correlational design was used to assess the nutritional risk of 111 patients with cancer receiving chemotherapy in the ambulatory setting. The data were collected by using a nutritional screening tool. Findings The prevalence of malnutrition risk was 45% in patients undergoing the first cycle of chemotherapy. Patients who received the first three cycles of chemotherapy were 2.62 times more likely to develop malnutrition than those who received seven or more cycles. The risk of developing malnutrition varies depending on the type of cancer, the types of chemotherapy regime, the number of chemotherapy cycles, body mass index and the stage of cancer. Conclusion The study found about half of the patients had developed signs and symptoms of nutritional risk at cycle one. Hence, nutritional support may be required even before the start of chemotherapy.

The effectiveness of psychosocial interventions for cognitive dysfunction in cancer patients who have received chemotherapy : a systematic review

Background: Chemotherapy-related cognitive dysfunction (CRCD) refers to problems with memory,attention span, or concentration, experienced by patients with cancer who have had chemotherapy. CRCD can have a significant negative effect on a patient’s quality of life. The exact cause of CRCD is unknown but is presumed to be multifactorial. Objective: To conduct a systematic review of the effectiveness of psychosocial interventions designed to treat CRCD. Methods: Participants of interest to the review were over 18 years of age, diagnosed with cancer, and receiving chemotherapy or had received chemotherapy in the past. Interventions of interest were methods to improve cognitive function. Included study designs were randomized controlled trials, quasi-experimental trials, and quantitative observational studies. The primary outcome of interest was level of cognitive function. A three-step search strategy was utilized to identify studies published from 1985 to 2011 from a wide range of databases. Joanna Briggs Institute systematic review methods were used but findings were analyzed using the Cochrane Collaboration Review Manager 5.1 program.Weightedmean differences with 95% confidence intervals were calculated from the continuous data. Results: Searching identified 3,109 potentially relevant articles and 120 full-text articles were retrieved. Two further papers were sourced from reference lists of retrieved articles. From 122 papers, six were suitable for critical appraisal and six were included in the analysis. Meta-analysis was conducted on two cognitive behavioral therapy (CBT) trials for the outcome of inability to concentrate. Significant effect was seen for one CBT intervention at 20 weeks (p = .004). Significant effect from CBT on quality of life was seen at 6-month follow-up (p < .05). Conclusions: Despite some evidence of an effect, there is insufficient evidence at this stage to strongly recommend any of the interventions to assist in decreasing the effects of CRCD, except in terms of improving quality of life.

Exercise during chemotherapy for ovarian cancer (Echo) : study design features and outcomes of a Cancer Australia and Cancer Council Australia funded randomised, controlled trial

Ovarian cancer is the most common cause of gynaecological cancer death, with an overall 5-year relative survival of 43%. Impaired physical wellbeing and overall quality of life (QoL) represent major concerns for women during and following ovarian cancer treatment, predict survival and are amenable to change through interventions. Exercise, now considered an important part of overall management of a number of cancers, improves short-term outcomes (e.g., function, fatigue, QoL) during chemotherapy...

An exercise intervention during chemotherapy for women with recurrent ovarian cancer: A feasibility study

Objective: The aim of this study was to determine the feasibility of a combined supervised and home-based exercise intervention during chemotherapy for women with recurrent ovarian cancer. Secondary aims were to determine the impact of physical activity on physical and psychological outcomes and on chemotherapy completion rates. Methods: Women with recurrent ovarian cancer were recruited from 3 oncology outpatient clinics in Sydney and Canberra, Australia. All participants received an individualized exercise program that consisted of 90 minutes or more of low to moderate aerobic, resistance, core stability, and balance exercise per week, for 12 weeks. Feasibility was determined by recruitment rate, retention rate, intervention adherence, and adverse events. Aerobic capacity, muscular strength, fatigue, sleep quality, quality of life, depression, and chemotherapy completion rates were assessed at weeks 0, 12, and 24. Results: Thirty participants were recruited (recruitment rate, 63%), with a retention rate of 70%. Participants averaged 196 ± 138 min · wk of low to moderate physical activity throughout the intervention, with adherence to the program at 81%. There were no adverse events resulting from the exercise intervention. Participants who completed the study displayed significant improvements in quality of life (P = 0.017), fatigue (P = 0.004), mental health (P = 0.007), muscular strength (P = 0.001), and balance (P = 0.003) after the intervention. Participants completing the intervention had a higher relative dose intensity than noncompleters (P = 0.03). Conclusions: A program consisting of low to moderate exercise of 90 min · wk was achieved by two-thirds of women with recurrent ovarian cancer in this study, with no adverse events reported. Randomized control studies are required to confirm the benefits of exercise reported in this study.

Combination chemotherapy for primary small intestinal lymphoma in the Middle East

Twelve patients with primary small intestinal lymphoma were followed prospectively for 3 years. Endoscopic abnormalities were diagnostic of lymphoma in all cases where the duodenum was involved (83%). In three cases (25%) the disease extended to the stomach. One patient (8%) had diffuse small cell cleaved and 11 (92%) diffuse large cell lymphoma stages I (8%), II (25%), III (58%) and IV (8%). Nine of them were unresectable and primarily treated with combination chemotherapy; 67% achieved complete remission, 22% partial response and 11% no response. Only one patient relapsed and achieved a second remission. All complete remission patients are currently alive and free of disease at a median follow-up of 36 months. Overall survival for all patients is 58%, and disease-free survival is 50%. No instance of chemotherapy-related bleeding or perforation was seen. Tetracycline was necessary for the treatment of IPSID-associated diarrhea and malabsorption in spite of cytotoxic chemotherapy.

Chemotherapy-induced nausea and vomiting: A narrative review to inform dietetics practice

Chemotherapy-induced nausea and vomiting (CINV) are common nutrition-impact symptoms experienced by cancer patients. They exert a detrimental effect on dietary intake, risk of malnutrition and quality of life. While CINV are primarily managed with medication, dietitians play an important role in the management of CINV-related complications such as reduced dietary intake. This review discusses the burden of nausea and vomiting which cancer patients can experience, including its effect on quality of life, nutrition status, and treatment outcomes. Implications for dietetic practice include the need to explore the nature of reported symptoms, identify predisposing risk factors, and to consider the use of a variety of interventions that are individualised to the patient’s symptoms. There are little clinical data regarding effective dietetic interventions for nausea and vomiting. In summary, this review discusses dietetic-related issues surrounding CINV including the pathophysiology, risk factors, prevalence, and both pharmacological and dietetic treatment options.