• Antivascular agents for non-small-cell lung cancer: current status and future directions.

      Amir, Eitan; Mandoky, Laszlo; Blackhall, Fiona H; Thatcher, Nick; Klepetko, Walter; Ankersmit, Hendrik Jan; Reza Hoda, Mir Ali; Ostoros, Gyula; Dank, Magdolna; Dome, Balazs; et al. (2009-11)
      BACKGROUND: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. OBJECTIVE: To summarize the current knowledge on antivascular therapy in patients with NSCLC. METHOD: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. RESULTS/CONCLUSION: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.
    • Biomarkers of angiogenesis and their role in the development of VEGF inhibitors.

      Murukesh, N; Dive, Caroline; Jayson, Gordon C; Department of Medical Oncology, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Cancer Research UK and University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2010-01-05)
      Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs.
    • Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma.

      Barrington, S F; Mackewn, J E; Schleyer, P; Marsden, P K; Mikhaeel, N G; Qian, W; Mouncey, P; Patrick, P; Popova, B; Johnson, P; et al. (2011-03)
      Multicentre trials are required to determine how [fluorine-18]-2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging can guide cancer treatment. Consistency in quality control (QC), scan acquisition and reporting is mandatory for high-quality results, which are comparable across sites.
    • Extensive-stage small-cell lung cancer--moving beyond response rate?

      Ferraldeschi, Roberta; Lorigan, Paul C (2009-05)
    • Hormone replacement therapy and breast cancer.

      Howell, Anthony; Evans, D Gareth R; Genesis Prevention Centre, University Hospital of South Manchester, Manchester, UK. (2011)
      There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT.It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies. Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women.
    • No study left behind: a network meta-analysis in non-small-cell lung cancer demonstrating the importance of considering all relevant data.

      Hawkins, Neil; Scott, David A; Woods, Beth S; Thatcher, Nick; Oxford Outcomes Ltd., Oxford, UK. neil.hawkins@oxfordoutcomes.com (2009-09)
      OBJECTIVE: To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non-small-cell lung cancer (NSCLC). METHODS: A recent National Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence. We also examined the importance of allowing for the correlations between the estimated treatment effects that can arise when analysing such networks. RESULTS: The analysis of the restricted network including only trials of docetaxel and erlotinib linked via the common placebo comparator produced an estimated mean hazard ratio (HR) for erlotinib compared with docetaxel of 1.55 (95% confidence interval [CI] 0.72-2.97). In contrast, the network meta-analysis produced an estimated HR for erlotinib compared with docetaxel of 0.83 (95% CI 0.65-1.06). Analyzing the wider network improved the precision of estimated treatment effects, altered their rankings and also allowed further treatments to be compared. Some of the estimated treatment effects from the wider network were highly correlated. CONCLUSIONS: This empirical example shows the importance of considering all potentially relevant data when comparing treatments. Care should therefore be taken to consider all relevant information, including correlations induced by the network of trial data, when comparing treatments.
    • Predictive algorithms for adjuvant therapy: TransATAC.

      Dowsett, Mitch; Salter, Janine; Zabaglo, Lila; Mallon, Elizabeth A; Howell, Anthony; Buzdar, Aman; Forbes, John F; Pineda, S; Cuzick, Jack; Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, London SW36JJ, UK. (2011-07)
      Estrogen receptor (ER) positive primary breast cancers have a wide range of clinical outcomes. Prediction of the likely course of the disease aids treatment decision-making. In the translational arm of the ATAC (anastrozole or tamoxifen alone or combined) trial (TransATAC) we have assessed individual and multiparameter biomarkers for their prediction of overall and distant recurrence. None of the biomarkers identified differential benefit for anastrozole versus tamoxifen. Each of ER, PgR, HER2 and Ki67 was associated with risk of recurrence. A combination of these to create a single predictor IHC4 was as informative as the 21-gene recurrence score (RS). Integration of each of these molecular profiles with classical clinicopathologic variables provided the most accurate prediction of outcome.
    • Second-line treatment of advanced non-small cell lung cancer.

      Gridelli, Cesare; Ardizzoni, Andrea; Ciardiello, Fortunato; Hanna, Nasser; Heymach, John V; Perrone, Francesco; Rosell, Rafael; Shepherd, Frances A; Thatcher, Nick; Vansteenkiste, Johan; et al. (2008-04)
      After failure of first-line chemotherapy for advanced non-small cell lung cancer, many patients remain candidates to receive further antitumor treatment. To guide clinical management of these patients and to suggest priorities for clinical research, an International Panel of Experts met in Naples (Italy) in April 2007. Results and evidence-based conclusions are presented in this article. Single-agent chemotherapy with docetaxel or pemetrexed is the recommended option for unselected patients with performance status 0 to 2 who are candidates for second-line chemotherapy for advanced non-small cell lung cancer. Docetaxel has demonstrated superiority compared with best supportive care. Pemetrexed has been shown to be noninferior to docetaxel, with a more favorable toxicity profile. Erlotinib is effective in pretreated patients, and can be given second-line in patients not suitable or intolerant to chemotherapy, and in all patients as third-line treatment after failure of second-line chemotherapy. Gefitinib failed to show superiority to placebo as second- or third-line treatment, but it has been shown to be noninferior to docetaxel. In selected patients such as lifetime nonsmokers or those of East-Asian ethnicity, erlotinib, or gefitinib (where licensed) may be considered as second-line treatment even if they are fit for chemotherapy. Best supportive care in addition to active treatment remains important for all patients, but may be the exclusive option for patients unsuitable for more aggressive therapy. Further research is mandatory, to find better treatments, and to identify clinical and molecular predictive markers of efficacy, both for chemotherapy and for novel biologic agents.