Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer.

BACKGROUND: Mean survival in cancer trials can be estimated with statistical techniques to extrapolate study survival curves. This methodology was applied to data from the VELOUR trial, where use of the novel biologic aflibercept (ziv-aflibercept in the United States) in combination with fluorouracil+leucovorin+irinotecan (FOLFIRI), had significantly increased median overall survival (OS) by 1.44 months, vs placebo plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) resistant to, or that had progressed following, an oxaliplatin-containing regimen. METHODS: Parametric survival analyses were used to identify distributions with the best fit to the empirical VELOUR data. Mean OS for the two treatment groups (and pre-defined subgroups) was calculated from the fitted curves over a 15-year survival period. RESULTS: Overall, the log-logistic distribution was the best-fitting for both treatment arms and, with it, the estimated difference in mean OS over 15 years between aflibercept+FOLFIRI and placebo+FOLFIRI was 4.7 months. In addition, the survival advantage with aflibercept was at least 3 months for the ITT population, whichever distribution was used to extrapolate survival. CONCLUSION: Extrapolation of survival curves suggests the mean OS difference for aflibercept in the VELOUR trial is at least 3 months in the ITT population and selected subgroups.

Validation of personal protective equipment ensembles, incorporating powered air-purifying respirators protected from contamination, for the care of patients with high-consequence infectious diseases.

BACKGROUND: The UK High-Consequence Infectious Diseases (HCID) Network of high-level isolation units provides care for patients with contact- or airborne-transmissible highly infectious and highly dangerous diseases. In most HCID units, the healthcare workers (HCWs) wear personal protective equipment (PPE) ensembles incorporating a powered air-purifying respirator (PAPR) for head and respiratory protection. Some PAPRs have components worn outside/over other PPE, necessitating decontamination of re-usable elements. Two alternative PAPRs, with all re-usable elements worn under PPE, were trialled in this study. AIM: To undertake scenario-based testing of PAPRs and PPE to determine usability, comfort and ability to remove contaminated PPE without personal cross-contamination. METHODS: Trained healthcare volunteers (N=20) wearing PAPR/PPE ensembles were sprayed with ultraviolet fluorescent markers. They undertook exercises to mimic patient care, and subsequently, after doffing the contaminated PPE following an established protocol, any personal cross-contamination was visualized under ultraviolet light. Participants also completed a questionnaire to gauge how comfortable they found the PPE. FINDINGS AND CONCLUSIONS: The ensembles were tested under extreme 'worst case scenario' conditions, augmented by physical and manual dexterity tests. Participating volunteers considered the exercise to be beneficial in terms of training and PPE evaluation. Data obtained, including feedback from questionnaires and doffing buddy observations, supported evidence-based decisions on the PAPR/PPE ensemble to be adopted by the HCID Network. One cross-contamination event was recorded in the ensemble chosen; this could be attributed to doffing error, and could therefore be eliminated with further practice.

Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness.

BACKGROUND: Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-alpha (IFN-alpha)) in the treatment of advanced metastatic RCC. METHODS: Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-alpha) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator. RESULTS: Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63-1.0; P=0.0272). CONCLUSION: There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.

Rev-dependent expression of human immunodeficiency virus type 1 gp160 in Drosophila melanogaster cells.

Expression of the human immunodeficiency virus (HIV) structural proteins in mammalian cells is regulated posttranscriptionally by the viral Rev protein. Rev has been shown to trans-activate expression by relieving the nuclear sequestration of RNAs containing viral gag or env coding regions. We have studied the effects of Rev on expression of the HIV type 1 env gene in Drosophila melanogaster cells. We demonstrated that synthesis of the gp160 envelope protein was fully Rev dependent; that is, gp160 was produced only when Rev function was coexpressed in the cell. Analysis of total cellular RNA indicated that Rev did not significantly affect the overall levels of gp160 RNA production. Instead, mRNA encoding gp160 was found in the cytoplasm only in cells expressing Rev, whereas in cells lacking Rev, this RNA was present only in the nucleus. Furthermore, comparison of these results with the previously demonstrated Rev-independent expression of gp120 envelope protein with this system indicated that information contained in the gp41 coding region appears to be critical to the selective nuclear retention of gp160 transcripts in the absence of Rev. Our results clearly demonstrate that the mechanism of Rev action is conserved in the insect cell system, and, thus, Rev must function via cellular machinery common to most, if not all, higher cell systems.

Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F.

E2F is a mammalian transcription factor that appears to play an important role in cell cycle regulation. While at least two proteins (E2F-1 and DP-1) with E2F-like activity have been cloned, studies from several laboratories suggest that additional homologs may exist. A novel protein with E2F-like properties, designated E2F-2, was cloned by screening a HeLa cDNA library with a DNA probe derived from the DNA binding domain of E2F-1 (K. Helin, J. A. Lees, M. Vidal, N. Dyson, E. Harlow, and A. Fattaey, Cell 70:337-350, 1992). E2F-2 exhibits overall 46% amino acid identity to E2F-1. Both the sequence and the function of the DNA and retinoblastoma gene product binding domains of E2F-1 are conserved in E2F-2. The DNA binding activity of E2F-2 is dramatically enhanced by complementation with particular sodium dodecyl sulfate-polyacrylamide gel electrophoresis-purified components of HeLa cell E2F, and anti-E2F-2 antibodies cross-react with components of purified HeLa cell E2F. These observations are consistent with a model in which E2F binds DNA as a heterodimer of two distinct proteins, and E2F-2 is functionally and immunologically related to one of these proteins.

Mutational analysis of an inherently defective translation initiation site.

In a reverse of many studies of translational initiation sites, we have explored the basis for the inactivity of an apparently defective initiation site. Gene VII of the filamentous phage f1 has a translational start site with highly unusual functional properties and a sequence dissimilar to a prokaryotic ribosome binding site. The VII site shows no activity in assays of independent initiation, even in a deletion series designed to remove potentially interfering RNA secondary structure. Activity from the VII site is only observed if the site is coupled to a source of translation immediately upstream, but its efficiency is low at a one-nucleotide spacing from the stop codon of the upstream cistron and extremely sensitive to the distance between the stop codon and the gene VII AUG. These and other atypical characteristics of coupling distinguish the VII site from most coupled initiation sites. To identify the pattern of nucleotide substitutions that give the VII site the capacity for independent initiation, a series of designed and random point mutations were introduced in the sequence. Improving the Shine-Dalgarno complementarity from GG to GGAG or GGAGG made activity detectable, but at only low levels. Random substitutions, each increasing activity above background by a small increment, were found at 16 positions throughout the region of ribosome contact. These substitutions lengthened the Shine-Dalgarno complementarity or changed the G and C residues present in the wild-type site to A or T. Significant activity was not observed unless a strong Shine-Dalgarno sequence and a number of the up-mutations were present together. The nature and distribution of the substitutions and their agreement with the known preferences for nucleotides in initiation sites provide evidence that the VII site's major defect is its primary sequence overall. It appears to lack the specialized sequence required to bind free 30 S ribosomes, and thus depends on the translational coupling process to give it limited activity.

Translation of phage f1 gene VII occurs from an inherently defective initiation site made functional by coupling.

Expression of the filamentous phage f1 gene VII is shown to be translationally coupled to that of the upstream gene V. Fusions of the gene VII initiation site to the lacZ coding region were used to determine that initiation at the VII site is completely dependent on the process of translation having proceeded up to a stop codon immediately upstream from the VII site. Coupled expression from the VII site was found to be inefficient, proportional to the level of upstream translation, and very sensitive to the distance from the functional upstream stop codon. Independent expression from the VII site was not observed, even in a deletion series designed to remove potentially masking RNA structure. On the basis of the VII site's dissimilarity to ribosome binding site sequences and its properties overall, we suggest that it inherently lacks the features required for independent recognition by ribosomes, and acquires the ability to initiate synthesis of gene VII protein by virtue of the coupling process.

Isolation of circadian clock mutants of Neurospora crassa.

Three mutants of Neurospora crassa have been isolated which have altered period lengths of their circadian rhythm of conidiation. The strains, designated "frequency" (frq), were obtained after mutagenesis of the band (bd) strain with N-methyl-N'-nitro-N-nitrosoguanidine. In continuous darkness at 25 degrees bd has a period length of 21.6 +/- 0.5 hours; under the same conditions the period length of frq-1 is 16.5 +/- 0.5 hours; frq-2, 19.3 +/- 0.4 hours; and frq-3, 24.0 +/- 0.4 hours. Each of the mutants segregates as a single nuclear gene. All three mutants appear very tightly linked to each other, but it has not yet been determined whether the mutants are allelic. No major changes in the responses to light and temperature have been observed in any of the mutants. It is suggested that these mutants represent alterations in the basic timing mechanism of the circadian clock of Neurospora.

Complementation analysis of linked circadian clock mutants of Neurospora crassa.

A fourth mutant of Neurospora crassa, designated frq-4, has been isolated in which the period length of the circadian conidiation rhythm is shortened to 19. +/- 0.3 hours. This mutant is tightly linked to the three previously isolated frq mutants, and all four map to the right arm of linkage group VII about 10 map units from the centromere. Complementation tests suggest, but do not prove, that all four mutations are allelic, since each of the four mutants is co-dominant with the frq+ allel--i.e., heterokaryons have period lengths intermediate between the mutant and wild-type--and since heterokaryons between pairs of mutants also have period lengths intermediate between those of the two mutants.

Recombinant gene expression in cultured Drosophila melanogaster cells.

Cultured Drosophila Schneider line 2 cells provide a versatile and efficient system for the expression of recombinant gene products that retain authentic properties. An efficient method now exists for the expression of large amounts of recombinant protein from continuous cell lines. In addition, Schneider line 2 cells have proven reliable as a background for in vivo studies of gene regulation and protein function.

Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance.

Systemic and coronary hemodynamic effects of prenalterol, a beta-1 receptor agonist, were determined in patients with chronic congestive heart failure, initially after intravenous administration (10 patients) and then after oral administration (eight patients). Cardiac index increased by 33 percent and 30 percent after intravenous and oral prenalterol, respectively. The increase in stroke volume index and stroke work index and decrease in pulmonary capillary wedge pressure and systemic vascular resistance were not significant. Myocardial oxygen consumption and coronary sinus blood flow increased in the majority of patients, although these changes were not statistically significant. There were no significant changes in transmyocardial norepinephrine or epinephrine balance. The systemic and coronary hemodynamic effects of both intravenous and oral prenalterol were similar. Major side effects included sudden death (two patients) and hypotension and bradycardia (three patients) during oral prenalterol treatment. It is concluded that improved left ventricular function following both intravenous and oral prenalterol may be associated with increased myocardial oxygen consumption, and serious adverse effects may occur during prenalterol therapy.

Collagenase production by early and late passage cultures of human fibroblasts.

Comparison of the proteins secreted by early and late passage cell cultures of human fibroblasts revealed a high level of immunoreactive collagenase (Mr = 55,000 Da and 58,000 Da) in the late passage cell culture conditioned medium. Both molecular weight species reacted with a monoclonal anticollagenase antibody and were apparently glycosylation varaents of the same protein. The question of whether the apparent age-dependent differences in collagenase synthesis reflected changes in protein synthesis or secretion was addressed by assaying immunoreactive collagenase and collagenase mRNA. Immunofluorescence microscopy of cellular collagenase revealed that the percentage of collagenase positive cells ranged from 1 to 6% (early passage) to 35 to 46% (late passage) indicating that the late passage cells had higher basal levels of collagenase synthesis. Later passage cultures also secreted higher levels of immunoprecipitable collagenase into the culture medium and Northern analysis established that the basal level of collagenase mRNA was also 10 times greater in late passage cells. High basal levels of collagenase were also observed in fibroblasts cultured from an in vivo aged donor and from donors with Werner's syndrome. Collagenase production was induced in both early and late passage cell cultures by exposure to fibroblast extracellular matrix, fibroblast conditioned media, polypeptide growth factors, or phorbol esters. The induced levels were always greater in the late passage cell cultures than in the early passage cell cultures.

Cytokine response profiles predict species-specific infection patterns in human GI nematodes.

This study investigated associations between pre-treatment cytokine expression and infection patterns, before and after de-worming, in humans exposed to two gastrointestinal nematode species. Quantitative measures of Ascaris lumbricoides and Trichuris trichiura infection (based on faecal egg counts) were estimated immediately before and 8-9 months after treatment in a Cameroonian population. Whole blood cytokine responses to parasite-derived antigens were assayed immediately pre-treatment. An overall measure of the tendency towards species-specific infection (increasing with A. lumbricoides faecal egg counts and decreasing with T. trichiura faecal egg counts) was significantly positively related to IL-10 levels in older (14-57 year) hosts. There was a significant negative influence of IL-5 on reinfection probability in T. trichiura but not A. lumbricoides. This effect coincided with reduced reinfection success in T. trichiura compared to A. lumbricoides. T(H)2 cytokine expression by younger hosts (4-13 year) was negatively associated with contemporary A. lumbricoides faecal egg counts before treatment. Following treatment, the pre-treatment T(H)2 cytokine expression data for younger hosts (now reflecting responsiveness 8-9 months in the past) were negatively associated with T. trichiura faecal egg counts. Taken together, these observations suggest a successional interaction between T(H)2-driven immune responses and species infection over time. However, any differential effects of the measured immune responses on species-specific recruitment, maturation and mortality were superimposed upon (and outweighed by) the effects of other factors favouring coinfection.

Radiological evaluation of asymmetrical limitation of hip abduction during the first year of life.

Asymmetrical limitation of abduction of the hip may be found on screening of children in the first year of life. The clinical features identified may occur in congenital dislocation of the hip but most infants do not have or develop hip dislocation. Radiological changes are present on the side of limitation of abduction and include a higher acetabular angle, retardation of femoral head epiphyseal development, pelvic obliquity and a rotational deformation of the pelvis in the transaxial plane. The appearances are postural deformities due to persistent infant positioning and are self-correcting. If aggressive treatment methods are to be avoided, the radiologist should not confuse these changes with those of congenital hip dislocation or subluxation.

Chemical sterilization of bacterially contaminated bone without destruction of osteogenic potential.

A method to sterilize bone that has been contaminated or to assure sterility of allografts would be quite useful in the practice of orthopedics. The literature documents the osteogenic potential of demineralized bone matrix, prepared by treatment with hydrochloric acid and ethanol. We became interested in whether these potent antibacterial agents could render contaminated bone sterile and thus usable. Thus, we tested immersion in 70% ethanol or 0.6 N hydrochloric acid as sterilization methods for contaminated bone specimens. Bone fragments were (heavily) surface contaminated for 30-60 s by immersion in a suspension of either Escherichia coli, Staphylococcus aureus, or Bacillus subtilis and then placed in either the ethanol or hydrochloric acid solutions for 15 min, 30 min, 1 h, 2 h, 4 h, or 8 h. Subsequently, they were incubated in broth culture for 14 days. Using 70% ethanol, 80-90% of contaminated bone specimens were sterile in 4 h and all were sterile in 8 h. Using 0.6 N hydrochloric acid, only 10% of bone specimens contaminated with Staphylococcus aureus, 60% with Escherichia coli, and 90% with Bacillus subtilis were sterile in 8 h. Consequently, 70% ethanol could possibly by used as an antiseptic or sterilizing agent for contaminated bone, although we feel that such bone should also be demineralized. Ethanol should not be used for routine treatment of mineralized cortical bone as it has been shown to diminish the already poor osteogenic potential of cortical bone.

The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy. DATA SOURCES: The assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 7745 titles and abstracts. Two clinical trials (reported in 12 papers) were included. No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients. Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups. Third-line treatment with cetuximab plus best supportive care or panitumumab plus best supportive care appears to have statistically significant advantages over treatment with best supportive care alone in patients with KRAS WT status. For the economic evaluation, five studies met the inclusion criteria. The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with best supportive care is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with best supportive care is £150,000 per QALY and for cetuximab plus irinotecan compared with best supportive care is £88,000 per QALY. All ICERs are sensitive to treatment duration. LIMITATIONS: In the specific populations of interest, there is a lack of evidence on bevacizumab, cetuximab and cetuximab plus irinotecan used second line and on bevacizumab and cetuximab plus irinotecan used third line. For cetuximab plus irinotecan treatment for KRAS WT people, there is no direct evidence on progression-free survival, overall survival and duration of treatment. CONCLUSIONS: Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT for patients with KRAS WT status receiving cetuximab plus irinotecan. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation.

BACKGROUND: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.

BACKGROUND: Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). OBJECTIVE: This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. DATA SOURCES: Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. RESULTS: Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. LIMITATIONS: Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. CONCLUSIONS: From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. FUNDING: The Health Technology Assessment Programme of the National Institute for Health Research.