Re-challenge chemotherapy with gemcitabine plus carboplatin in patients with non-small cell lung cancer.

Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer (NSCLC), the patients' overall survival remains poor. Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC. NSCLC relapse has been attributed to acquired drug resistance, but the repopulation of sensitive clones may also play a role, in which case re-challenge may be appropriate. Here, we report the results of re-challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first-line setting and had either partial response or a progression-free interval of longer than 6 months. In this retrospective study, the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed. All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study. These patients were offered second-line treatment on confirmation of clear radiological disease progression. The overall response rate was 15% and disease control rate was 75%. The median survival time was 10.4 months, with 46% of patients alive at 1 year. These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy.

New advances in the second-line treatment of small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in the U.K., with small cell histology accounting for 15%-20% of cases. Small cell lung cancer (SCLC) is initially a chemosensitive disease, but relapse is common, and in this group of patients it remains a rapidly lethal disease with a particularly poor prognosis. The choice of second-line chemotherapy for patients with relapsed SCLC has been an area of difficulty for oncologists, and until recently there was no randomized evidence for its use over best supportive care (BSC). Topotecan is currently the only drug licensed in Europe and the U.S. for this indication, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with BSC. In this article, we review the current evidence for the use of second-line cytotoxic therapy and also the emerging role of novel agents and targeted therapies in this setting. In particular, we explore the role of the Bcl-2 protein family, which are key regulators of mitochondrial apoptosis and are implicated in resistance to anticancer therapies. SCLC overexpresses antiapoptotic members of the Bcl-2 family in approximately 80% of cases. Several Bcl-2 inhibitors, including obatoclax, are currently entering clinical trials in SCLC and are an exciting area of drug development in the relapsed setting.

Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation.

The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.

Chasing the Golden Hour - Lessons learned from improving initial neutropenic sepsis management.

Neutropenic sepsis remains a time critical and potentially fatal complication of systemic anti-cancer therapy. A target 'door to needle' time of one hour for first dose empirical intravenous antibiotics continues to be promoted nationally. A baseline audit (June 2011) highlighted shortfalls in care in the Belfast Trust, with only 15% of patients receiving antibiotics within sixty minutes. A multi-professional group within the Trust was established to try and initiate the improvements in neutropenic sepsis recognition and initial management that were urgently required. A number of strategies have been developed over the last five years. Firstly an integrated care pathway was introduced, which is currently used by nursing and medical staff for patients presenting with suspected neutropenic sepsis, through acute cancer centre assessment areas and emergency departments, as well as inpatients developing neutropenic sepsis. An initial reaudit June 2012 demonstrated improvement (62% meeting 1hour target), but a subsequent audit, January 2013, was disappointing (only 50% meeting 1hour target). In response, a new compact, user-friendly care pathway was introduced. A range of other measures have also been subsequently introduced. Patients' care is continually monitored through simple ward based documentation, completed after initial treatment of each neutropenic sepsis episode. A patient group direction facilitates nurse led prescribing and administration of first dose antibiotics. Regular multidisciplinary education sessions and improved access to regional guidelines have also been prioritised. From November 2013, consistently greater than 80% of patients have met the one hour target. Recent data continues to be encouraging; in July 2016 100% of patients received first doses within sixty minutes, in October 95% of patients. Significant sustained improvements in meeting the sixty minute target have been demonstrated. The combination of measures ensures neutropenic sepsis is considered and basic clinical care delivered quickly and safely, through a co-ordinated standardised approach, to avoid complications.

Improving the safety of chemotherapy prescribing in oncology through the introduction of an assessment proforma.

Chemotherapy remains a high risk treatment with the potential to cause significant patient morbidity and mortality. In the UK the Manual for Cancer Services: Chemotherapy Measures provides national quality measures for essential elements that should be incorporated and documented in chemotherapy assessments. It was recognised that in the outpatient oncology chemotherapy unit in the Cancer Centre, Belfast City Hospital, Northern Ireland, that the written records of chemotherapy assessments were sub-optimal. At baseline (December 2015) median completion of chemotherapy assessment documentation was only 63%, based on a scoring system incorporating key assessment parameters from the Manual for Cancer Services and Belfast Trust standards for record keeping. A target of median chemotherapy assessment documentation being at least 95% complete was set. A paper chemotherapy assessment proforma was developed and introduced over an eight month period, using small tests of change and continuous data collection and feedback. The proportion of chemotherapy assessments documented using the proforma increased, as it was adjusted to be more user friendly and particularly after it started being pre-filed in medical notes. Increased use of the proforma correlated with improvement in completeness of chemotherapy assessment documentation. From week 29 to project completion (week 33), following proformas being routinely pre-filed and uptake increasing, assessments were on average 97% complete. Documentation of a patient's performance status, a critical aspect of the assessment, also improved to a median of 99% over the last seven weeks of the project from a baseline of 88%. The proforma has been positively viewed by staff with 94% agreeing it promotes safety. The introduction of a chemotherapy assessment proforma is a simple measure which can result in improved documentation of chemotherapy assessments, including performance status. It also serves as a prompt for safe decision making regarding chemotherapy prescriptions, enhancing the quality of outpatient chemotherapy care being delivered.

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma.

BACKGROUND: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. METHODS: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. RESULTS: Median OS, from landmark, of patients with partial response (PR) was 12·8months, stable disease (SD), 9·4months and progressive disease (PD), 3·4months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p<0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. CONCLUSION: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM.

Afatinib treatment in advanced non-small cell lung cancer.

Despite some recent advances in the management of advanced non-small cell lung cancer (NSCLC), prognosis for these patients remains poor. Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have however provided a new therapeutic option in this disease setting and EGFR mutation testing is now routine practice for newly diagnosed NSCLC patients. A proportion of patients will not respond to first-generation EGFR-TKIs however, and those who do will ultimately develop resistance and disease relapse. Next-generation EGFR-TKIs which inhibit multiple members of the EGFR family are being developed in order to increase sensitivity and overcome resistance to existing agents. Afatinib (BIBW 2992) is an oral, irreversible inhibitor of EGFR and HER2 tyrosine kinases and is the most advanced of these agents in clinical development. Pre-clinical and early-phase clinical trials have demonstrated a favorable safety profile as a single agent and in combination with other anti-cancer agents, and provide evidence of clinical activity in advanced NSCLC. The LUX-Lung trials suggest that for selected patients, afatinib offers symptomatic improvement and prolonged progression-free survival, although this has not yet translated into improved overall survival. This article aims to review the use of EGFR-TKIs in the management of advanced NSCLC and the mechanisms underlying resistance to these agents. We will discuss the current pre-clinical and clinical data regarding afatinib, its potential to overcome resistance to first-generation TKIs, and its emerging role in advanced NSCLC treatment.