Lucinda Billingham

Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers

Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA–peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 × 103/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy.

Identification of serum biomarkers for colon cancer by proteomic analysis

Colorectal cancer (CRC) is often diagnosed at a late stage with concomitant poor prognosis. Early detection greatly improves prognosis; however, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their applicability. No serum-based test is currently of sufficient sensitivity or specificity for widespread use. In the best currently available blood test, carcinoembryonic antigen exhibits low sensitivity and specificity particularly in the setting of early disease. Hence, there is great need for new biomarkers for early detection of CRC. We have used surface-enhanced laser desorbtion/ionisation (SELDI) to investigate the serum proteome of 62 CRC patients and 31 noncancer subjects. We have identified proteins (complement C3a des-arg, α1-antitrypsin and transferrin) with diagnostic potential. Artificial neural networks trained using only the intensities of the SELDI peaks corresponding to identified proteins were able to classify the patients used in this study with 95% sensitivity and 91% specificity.

Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan–Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P=0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival (P=0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting.

Narrow‐band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder

To investigate whether narrow‐band imaging (NBI) flexible cystoscopy improves the detection rate of urothelial carcinomas (UCs) of the bladder. NBI is an optical image enhancement technology in which the narrow bandwidth of light is strongly absorbed by haemoglobin and penetrates only the surface of tissue, increasing the visibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two.

Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial

AIMS Whilst the CArdiac REsynchronization in Heart Failure (CARE-HF) trial has shown that cardiac resynchronization therapy (CRT) leads to reduced morbidity and mortality, the cost-effectiveness of this therapy remains uncertain. The aim of this study was to evaluate the incremental cost per quality adjusted life year (QALY) gained and incremental cost per life year gained of CRT plus medical therapy compared to medical therapy alone. METHODS AND RESULTS This prospective analysis based on intention to treat data from all patients enrolled in the CARE-HF trial at 82 clinical centres in 12 European countries. A total of 813 patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony were randomized to CRT plus medical therapy (n = 409) vs. medical therapy alone (n = 404). During a mean follow-up of 29.4 months CRT was associated with increased costs (4316, 95% CI: 1327-7485), survival (0.10 years, 95% CI: -0.01-0.21), and QALYs (0.22, 95% CI: 0.13-0.32). The incremental cost-effectiveness ratio was 19 319 per QALY gained (95% CI: 5482-45 402) and 43 596 per life-year gained (95% CI: -146 236-223 849). These results were sensitive to the costs of the device, procedure, and hospitalization. CONCLUSION Treatment with CRT appears cost-effective at the notional willingness to pay threshold of 29 400 (20,000 pounds sterlings) per QALY gained.

Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial.

BACKGROUND The role and dose of anticoagulants in thromboprophylaxis for patients with cancer receiving chemotherapy through central venous catheters (CVCs) is controversial. We therefore assessed whether warfarin reduces catheter-related thrombosis compared with no warfarin and whether the dose of warfarin determines the thromboprophylactic effect. METHODS In 68 clinical centres in the UK, we randomly assigned 1590 patients aged at least 16 years with cancer who were receiving chemotherapy through CVCs to no warfarin, fixed-dose warfarin 1 mg per day, or dose-adjusted warfarin per day to maintain an international normalised ratio between 1.5 and 2.0. Clinicians who were certain of the benefit of warfarin randomly assigned patients to fixed-dose or dose-adjusted warfarin groups. The primary outcome was the rate of radiologically proven, symptomatic catheter-related thrombosis. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN 50312145. FINDINGS Compared with no warfarin (n=404), warfarin (n=408; 324 [79%] on fixed-dose and 84 [21%] on dose-adjusted) did not reduce the rate of catheter-related thromboses (24 [6%] vs 24 [6%]; relative risk 0.99, 95% CI 0.57-1.72, p=0.98). However, compared with fixed-dose warfarin (n=471), dose-adjusted warfarin (n=473) was superior in the prevention of catheter-related thromboses (13 [3%] vs 34 [7%]; 0.38, 0.20-0.71, p=0.002). Major bleeding events were rare; an excess was noted with warfarin compared with no warfarin (7 vs 1, p=0.07) and with dose-adjusted warfarin compared with fixed-dose warfarin (16 vs 7, p=0.09). A combined endpoint of thromboses and major bleeding showed no difference between comparisons. We did not note a survival benefit in either comparison. INTERPRETATION The findings show that prophylactic warfarin compared with no warfarin is not associated with a reduction in symptomatic catheter-related or other thromboses in patients with cancer and therefore we should consider newer treatments. FUNDING Medical Research Council and Cancer Research UK.

Estrogen Receptor and Progesterone Receptor As Predictive Biomarkers of Response to Endocrine Therapy: A Prospectively Powered Pathology Study in the Tamoxifen and Exemestane Adjuvant Multinational Trial

PURPOSE The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. PATIENTS AND METHODS Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. RESULTS Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred < 4) and 77% were PgR- rich (Allred ≥ 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P = .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. CONCLUSION Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment.

Cost-effectiveness in clinical trials: using multiple imputation to deal with incomplete cost data.

Background Cost-effectiveness has become an important outcome in many clinical trials and has resulted in the collection of resource use data and the calculation of costs for individual patients. A specific example is a Cancer Research UK phase III trial comparing chemotherapy (CT) against standard palliative care in patients with advanced non-small cell lung cancer. Resource usage from trial entry until death were collected and costs obtained on a subset of 115 trial patients. For some patients, however, the unavailability of medical notes resulted in some cost components, and hence total cost, being missing. The 82 patients with complete data were not representative of all trial patients in terms of effectiveness and thus it was necessary to address the missing data problem. Methods Multiple imputation (MI) was used to impute values for the unobserved individual cost components, allowing total cost to be calculated and cost-effectiveness carried out for all patients in the cost sub-study. The results are compared with those from a complete case analysis. Results After MI, the results indicated that CT had a high probability of being cost-effective for a societal willingness to pay over £20 000 per life-year gained. This was in stark contrast with the complete case analysis, which suggested that CT was not a cost-effective use of resources at any reasonable level of willingness to pay for a life-year. Limitations Our findings are based on a relatively small retrospective study with all events observed. Conclusion In conclusion, cost-effectiveness analysis of the complete cases only may give biased results, and therefore, in situations where there are missing costs, MI is recommended. Clinical Trials 2007; 4: 154—161. http://ctj.sagepub.com

Excision Repair Cross-Complementation Group 1 (ERCC1) Status and Lung Cancer Outcomes: A Meta-Analysis of Published Studies and Recommendations

Purpose Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis. Methods Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately. Results 23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I2 always >30%), partly due to variability in thresholds defining ‘low’ and ‘high’ ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23–2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51–1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Eggers p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64–0.99). SCLC data were inadequate to draw firm conclusions. Conclusions Current evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials.

Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers.

SUMMARY There is a growing appreciation of the potential value of combining novel molecularly-targeted drugs with radiotherapy or chemoradiotherapy. Such approaches have the potential to improve locoregional disease control and cure rates across a diverse range of tumour types. In this report, we outline a rational framework for developing novel drug–radiation combinations. In doing so, we make recommendations regarding the core preclinical data sets that are required to serve as justification for studies in humans and describe potential clinical trial designs that may be adopted by investigators. Radiotherapy (RT) has a pivotal role in the management of many tumours, such that B50% of cancer patients will receive RT during the course of their illnesses and 40% of those cured of cancer will have received RT as part of their treatment (http://info.cancerresearchuk. org/). Indications for prescribing RT include (i) definitive, curative (radical) treatment; (ii) adjuvant therapy following surgery in an attempt to eradicate microscopic (or rarely macroscopic) residual disease; and (iii) as palliative treatment to ameliorate cancerrelated symptoms. In the majority of situations, RT is a highly localised treatment that targets defined volumes of tissue that are known (or suspected) to contain cancer cells. Wide-field hemibody (Bashir et al, 2008) or total body (Adkins and DiPersio, 2008) irradiation techniques are used rarely in very specific indications, such as metastatic bone disease or ‘conditioning’ before transplantation in haematological malignancies, respectively. In addition, the latest developments in stereotactic body RT (SBRT) techniques have also resulted in protocols that aim to treat oligometastatic disease spread through an organ (or more than