Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER-2 cohort study.

OBJECTIVE: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. DESIGN: Prospective multicentre observational study. SETTING: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. SAMPLE: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late-stage ovarian cancer. MAIN OUTCOME MEASURES: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30). Secondary: EORTC ovarian cancer module (OV28), progression-free survival. RESULTS: Patients' preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre-surgical baseline in the EORTC QLQ-C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high-SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated-measures model, there were no clinically or statistically meaningful differences in EORTC QLQ-C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high-SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post-surgery, which resolved by 6-12 months. CONCLUSIONS: The global QoL of patients undergoing low-, intermediate- and high-SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery. TWEETABLE ABSTRACT: Compared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer.

Hickman catheter and implantable port devices for the delivery of chemotherapy: a phase II randomised controlled trial and economic evaluation.

BACKGROUND: In the United Kingdom, totally implantable venous access systems (TIVAS) are not routinely used. Compared with Hickman catheters, these devices are more expensive and complex to insert. However, it is unclear whether the higher costs may be offset by perceived greater health benefits. This pilot trial aimed to generate relevant data to inform the design of a larger definitive randomised controlled trial. METHODS: This was a phase II prospective, randomised, open trial from two UK oncology centres. The primary end point was overall complication rate. Secondary end points included individual complication rates, time to first complication and quality of life. Analysis was by intention to treat. An economic evaluation was also carried out. RESULTS: A total of 100 patients were randomised in a 3 : 1 ratio to receive a Hickman or a TIVAS. Overall, 54% of patients in the Hickman arm suffered one or more complications compared with 38% in the TIVAS arm (one-sided P=0.068). In the Hickman arm, 28% of the devices were removed prematurely due to a complication compared with 4% in the TIVAS arm. Quality of life based on the device-specific questionnaire was greater in the TIVAS arm for 13 of the 16 questions. The economic evaluation showed that Hickman arm was associated with greater mean cost per patient £1803 (95% CI 462, 3215), but similar quality-adjusted life years -0.01 (95% CI -0.15, 0.15) than the TIVAS arm. However, there is much uncertainty associated with the results. CONCLUSIONS: Compared with Hickman catheters, TIVAS may be the cost-effective option. A larger multicentre trial is needed to confirm these preliminary findings.

Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis.

BACKGROUND: Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls. METHODS: We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls. FINDINGS: Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7-16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0-12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96-1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8-23·6) in 48 964 cancer survivors and 13·9% (9·8-18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08-1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86-1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44-1·14; p=0·16) differed significantly between cancer patients and their spouses. INTERPRETATION: Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses. FUNDING: None.

Raf kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in Dukes' B colorectal cancer patients.

AIMS: There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. METHODS AND RESULTS: We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. CONCLUSIONS: Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients.This demonstrates the potential utility of RKIP in identifying 'high-risk' Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.

OBJECTIVE: ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC). METHODS: The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. RESULT: Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. CONCLUSION: Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

Survey on the management of early cervical cancer among members of the GCIG.

OBJECTIVE: To establish the different imaging and treatment options offered to patients with early cervical cancer by members of the Gynecologic Cancer Intergroup. METHODS: A questionnaire was developed and disseminated electronically to members of the Gynecologic Cancer Intergroup and was completed online. RESULTS: One hundred sixty-two members viewed the questionnaire; 88 members started it; however, only 64 members fully completed it. Most (89.9%) of respondents used the International Federation of Gynecology and Obstetrics classification system when staging cervical cancer, using adjuncts to clinical staging: 33 respondents (37.5%) advocated computed tomography, 61 respondents (69.3%) advocated magnetic resonance imaging, 26 respondents (29.6%) positron emission tomography-computed tomography, and 36 respondents (40.9%) advocated staging lymphadenectomy, with 69.4% (50) performing lymphadenectomies laparoscopically. The external iliac nodal group was the nodal group that was consistently part of the lymphadenectomy with other nodal groups variably removed depending on the stage. All centers offered fertility-conserving surgery in stage IA1 cervical cancer and most up to and including stage IB1 with no lymphovascular space invasion. The fertility-conserving procedures performed varied among respondents: 20.3% (15 respondents) abdominal radical trachelectomy, 47.35 (35 respondents) radical vaginal trachelectomy, 58.1% (43 respondents) trachelectomy, 97.3% (72 respondents) cone biopsy, and 67.6% (50 respondents) large loop excision of the transformation zone. When fertility conservation was not desired, there was variation in the surgical techniques offered. Chemotherapy was used to downstage tumors preoperatively in 16.4% (11) before fertility-conserving surgery and 50.8% (34) before radical surgery. CONCLUSIONS: There are wide variations in the use of preoperative imaging, when pelvic and para-aortic lymph nodes are removed, and as to which surgical procedure should be offered in the management of cervical cancer both when fertility conservation is and is not an issue.

Current academic clinical trials in ovarian cancer: Gynecologic Cancer Intergroup and US National Cancer Institute Clinical Trials Planning Meeting, May 2009.

OBJECTIVE: To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration. METHODS: In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting. RESULTS: The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues. The clinical trials discussed spanned the spectrum of ovarian cancer from initial diagnosis, staging, and cytoreductive surgery to consolidation chemotherapy, and treatment of recurrent disease. CONCLUSIONS: Ongoing and effective collaboration with industry, government, and patients aims to ensure that the most important scientific questions can be answered rapidly. We encourage women with ovarian cancer and their oncologists to consider participation in the academic clinical trials conducted by the member groups of the Gynecologic Cancer Intergroup.

ABCB1 (MDR 1) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy.

PURPOSE: The human ABCB1 gene encodes P-glycoprotein, which transports a broad range of anticancer drugs, including paclitaxel. Although the functional consequences of ABCB1 polymorphisms have been the subject of numerous studies, few have assessed the association with clinical outcome. EXPERIMENTAL DESIGN: We assessed the association between the 2677G>T/A, 3435C>T, and 1236C>T ABCB1 polymorphisms and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin and subsequently tested significant observations in an independent validation set. RESULTS: Women who carried the minor T/A alleles at the 2677G>T/A polymorphism were significantly less likely to relapse following treatment compared with homozygote GG carriers (P(Log-rank)=0.001) in the Australian Ovarian Cancer Study cohort. Subgroup analyses showed that this effect was limited to cases with residual disease 1 cm (P(Log-rank)=0.3). This effect was not confirmed in an independent validation set of carboplatin/paclitaxel-treated patients (n=278) using a higher residual disease cut point (T/A polymorphism on progression-free survival in ovarian cancer patients who are treated with a taxane/carboplatin, which is dependent on the extent of residual disease, with a better prognosis for patients with the 2677T/A allele and minimal residual disease.

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands.

BACKGROUND: Hypermethylation of promoter CpG islands is strongly correlated to transcriptional gene silencing and epigenetic maintenance of the silenced state. As well as its role in tumor development, CpG island methylation contributes to the acquisition of resistance to chemotherapy. Differential Methylation Hybridisation (DMH) is one technique used for genome-wide DNA methylation analysis. The study of such microarray data sets should ideally account for the specific biological features of DNA methylation and the non-symmetrical distribution of the ratios of unmethylated and methylated sequences hybridised on the array. We have therefore developed a novel algorithm tailored to this type of data, Methylation Linear Discriminant Analysis (MLDA). RESULTS: MLDA was programmed in R (version 2.7.0) and the package is available at CRAN 1. This approach utilizes linear regression models of non-normalised hybridisation data to define methylation status. Log-transformed signal intensities of unmethylated controls on the microarray are used as a reference. The signal intensities of DNA samples digested with methylation sensitive restriction enzymes and mock digested are then transformed to the likelihood of a locus being methylated using this reference. We tested the ability of MLDA to identify loci differentially methylated as analysed by DMH between cisplatin sensitive and resistant ovarian cancer cell lines. MLDA identified 115 differentially methylated loci and 23 out of 26 of these loci have been independently validated by Methylation Specific PCR and/or bisulphite pyrosequencing. CONCLUSION: MLDA has advantages for analyzing methylation data from CpG island microarrays, since there is a clear rational for the definition of methylation status, it uses DMH data without between-group normalisation and is less influenced by cross-hybridisation of loci. The MLDA algorithm successfully identified differentially methylated loci between two classes of samples analysed by DMH using CpG island microarrays.

Protocol for a systematic review and thematic synthesis of patient experiences of central venous access devices in anti-cancer treatment.

BACKGROUND: Three types of central venous access devices (CVADs)-peripherally inserted central catheters (PICCs), skin-tunnelled central catheters (Hickman-type devices), and implantable chest wall Ports (Ports)-are routinely used in the intravenous administration of anti-cancer treatment. These devices avoid the need for peripheral cannulation and allow for home delivery of treatment. Assessments of these devices have tended to focus on medical and economic factors, but there is increased interest in the importance of patient experiences and perspectives in this area. The aim of this systematic review is to synthesise existing research regarding patient experiences of these CVADs to help clinicians guide, prepare, and support patients receiving CVADs for the administration of anti-cancer treatment. METHOD: A systematic search of MEDLINE, Embase, and CINAHL research databases will be carried out along with a supplementary reference list search. This review will include quantitative, qualitative, and mixed methods studies published in peer-review journals, reporting some aspect(s) of patient experiences or perspectives regarding the use of PICC, Hickman, or Port CVADs for the administration of anti-cancer drugs. The methodological quality and risk of bias of included papers will be assessed using the Mixed Methods Appraisal Tool (MMAT). Relevant outcome data will be extracted from included studies and analysed using a thematic synthesis approach. DISCUSSION: The results section of the review will comprise thematic synthesis of quantitative studies, thematic synthesis of qualitative studies, and the aggregation of the two. Results will aim to offer an account of current understandings of patient experiences and perspective regarding PICC, Hickman-type, and Port devices in the context of anti-cancer treatment. Confidence in cumulative evidence will be assessed using the Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach. SYSTEMATIC REVIEW REGISTRATION: This systematic review protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO). Registration number: CRD42017065851 . This protocol was prepared using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols checklist (PRISMA-P) (Shamseer et al., BMJ 349: 2015).

A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma.

BACKGROUND AND PURPOSE: To assess the effectiveness of radiotherapy in preventing tumour seeding after chest drain or pleural biopsy in patients with malignant mesothelioma and to determine, if tract metastases appear, whether they are tender or troublesome to patients. PATIENTS AND METHODS: Patients with a histological diagnosis of pleural mesothelioma and an invasive procedure within the preceding 21 days were stratified by age, performance status and treatment centre. Randomisation was performed between immediate drain site radiotherapy 21Gy in three fractions (XRT arm) or best supportive care (BSC) with follow-up to 12 months. Patients were asked to complete questionnaires on treatment toxicity and on symptoms from any tract metastases detected. RESULTS: Sixty-one patients were recruited from two centres between 1998 and 2004; 56 men, 5 women, median age 70. 31 were allocated to drain site radiotherapy. Seven patients developed tract metastases associated with the drain site (four XRT arm, three BSC) and four developed metastases associated with subsequent procedures at other sites (three XRT, one BSC). Two patients each developed two tract metastases. Of the 12 metastases, nine overlay the previous drain site but three were adjacent to the site. No statistically significant difference was found in the risk of tract metastasis associated with the drain site between the arms (p=0.748). CONCLUSIONS: Prophylactic drain site radiotherapy in malignant pleural mesothelioma does not reduce the incidence of tumour seeding by the margin indicated by previous studies.

An exploration into study design for biomarker identification: issues and recommendations.

Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.

Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial.

PURPOSE: Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice. PATIENTS AND METHODS: One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model. RESULTS: There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (< or = 2 cm residual disease) than UK patients [corrected] (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy. CONCLUSION: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.

Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. METHODS AND ANALYSIS: Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13-20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. ETHICS AND DISSEMINATION: The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN10079972, Pre-results.

The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients.

Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to chemotherapy of patients' tumors remains unsubstantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemotherapy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched prechemotherapy plasma samples. Furthermore, hMLH1 methylation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an independent measure of function of the MMR pathway. Acquisition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confidence interval, 1.20-3.30; P = 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovarian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation during therapy and identify those patient populations who would be suitable for novel epigenetic therapies.

Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer.

OBJECTIVE: To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). DESIGN: Cost-utility analysis using decision analytic modelling by a Markov model. SETTING AND METHODS: Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10,000 iteration Monte Carlo simulation. RESULTS: SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29,719 (€37,619) (95% CI -51,985 to -9243). For a ceiling ratio of £30,000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. CONCLUSIONS: The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs. TRIAL REGISTRATION NUMBER: This economic analysis was undertaken as part of the CROP RCT study ISRCTN: 72677390; it was a pre-trial economic model developed and analysed during the pre-results stage of the RCT.

Critical evaluation of p53 as a prognostic marker in ovarian cancer.

The tumour suppressor gene encoding p53 has been shown from experimental studies to have a crucial role in how cells respond to DNA damage. p53 has important functions in apoptosis, cell-cycle arrest and DNA repair, largely mediated by its activity on gene transcription. However, despite this wealth of in vitro data, its role in how tumours respond to DNA damage induced by chemotherapeutic drugs remains controversial. In this review, we highlight some of the problems surrounding design and analysis of studies of p53 as a prognostic marker of clinical outcome, using ovarian cancer as an example. We aim to build on the knowledge of the published literature in ovarian cancer to identify criteria for clinical studies that should give a more definitive estimate of the role of p53 in clinical drug resistance. A search of three public databases using keywords combined with Boolean operators identified 64 clinical publications investigating the relationship of p53 to clinical outcome following chemotherapy in ovarian cancer. Although 43% of 215 published analyses from the 64 papers reported a significant correlation between p53 status and a clinical endpoint relevant to chemoresistance, only six analyses fulfil minimum criteria and none of these finds a statistically significant correlation of p53 with chemotherapy-resistance endpoints. The results from published clinical studies suggest a more complex role of p53 mutation in the mechanism of resistance in ovarian cancer than is suggested by in vitro studies.

Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.

PURPOSE: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity. PATIENTS AND METHODS: A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1. RESULTS: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival. CONCLUSIONS: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.

Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.

PURPOSE: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS). EXPERIMENTAL DESIGN: Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model. RESULTS: DNA methylation is associated with PFS at 20 of 302 loci (P < 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P ≤ 0.05, FDR ≤ 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P < 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39-3.15); permutation test P < 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P < 0.05). CONCLUSION: The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS.