European Journal of Cancer - Articles in Press

Quality-of-life among head and neck cancer survivors at one year after treatment – A systematic review - Corrected Proof

2012-05-14

Abstract: Background: The importance of quality-of-life (QoL) research has been recognised over the past two decades in patients with head and neck (H&N) cancer. The aims of this systematic review are to evaluate the QoL status of H&N cancer survivors one year after treatment and to identify the determinants affecting their QoL.Methods: Pubmed, Medline, Scopus, Sciencedirect and CINAHL (2000–2011) were searched for relevant studies, and two of the present authors assessed their methodological quality. The characteristics and main findings of the studies were extracted and reported.Results: Thirty-seven studies met the inclusion criteria, and the methodological quality of the majority was moderate to high. While patients of the group in question recover their global QoL by 12months after treatment, a number of outstanding issues persist – deterioration in physical functioning, fatigue, xerostomia and sticky saliva. Age, cancer site, stage of disease, social support, smoking, feeding tube placement and alcohol consumption are the significant determinants of QoL at 12months, while gender has little or no influence.Conclusions: Regular assessments should be carried out to monitor physical functioning, degree of fatigue, xerostomia and sticky saliva. Further research is required to develop appropriate and effective interventions to deal with these issues, and thus to promote the patients’ QoL.

Clear cell sarcoma of the kidney: A review - Corrected Proof

2012-05-14

Abstract: Clear cell sarcoma of the kidney (CCSK) is a rare renal tumour that is observed most often in children under 3years of age. Only a few large series of CCSK have been reported and patients with CCSK are often included among patients with other types of childhood renal tumours. The purpose of this paper is to review the published series and case reports of CCSK and to create an up-to-date overview of clinical and histological features, genetics, treatment, and outcome.

The EORTC QLQ-OH17: A supplementary module to the EORTC QLQ-C30 for assessment of oral health and quality of life in cancer patients - Corrected Proof

2012-05-10

Abstract: Aims: Assessment of oral and dental problems is seldom routine in clinical oncology, despite the potential negative impact of these problems on nutritional status, social function and quality of life (QoL). The aim was to develop a supplementary module to the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) focusing on oral health and related QoL issues in all cancer diagnoses.Methods: The module development followed the EORTC guidelines. Phases 1&2 were conducted in France, Germany, Greece, Netherlands, Norway and United Kingdom, while seven countries representing seven languages were included in Phase 3.Results: Eighty-five QoL-items were identified from systematic literature searches. Semi-structured interviews with health-care professionals experienced in oncology and oral/dental care (n=18) and patients (n=133) resulted in a provisional module with 41 items. In phase 3 this was further tested in 178 European patients representing different phases of disease and treatment. Results from the interviews, clinical experiences and statistical analyses resulted in the EORTC QLQ-OH17. The module consists of 17 items conceptualised into four multi-item scales (pain/discomfort, xerostomia, eating, information) and three single items related to use of dentures and future worries.Conclusion: This study provides a useful tool intended for use in conjunction with the EORTC QLQ-C30 for assessment of oral and dental problems. The increased awareness may lead to proper interventions, thereby preventing more serious problems and negative impact on QoL. The reliability and validity, the cross-cultural applicability and the psychometric properties of the module will be tested in a larger international study.

Comparison between a guaiac and three immunochemical faecal occult blood tests in screening for colorectal cancer - Corrected Proof

2012-05-09

Abstract: Background: The aim of this study was to compare the performance of the guaiac-based faecal occult blood test (G-FOBT), with that of three immunochemical faecal occult blood tests (I-FOBT) which allow automatic interpretation.Patients and methods: Under the French organised screening programme, 85,149 average-risk individuals aged 50–74 participating in the third screening round, performed both the G-FOBT (Hemoccult-II test) and one of the I-FOBTs: FOB-Gold, Magstream and OC-Sensor.Results: Given the chosen threshold, the positivity ratio between the different I-FOBTs and the G-FOBT was 2.4 for FOB-Gold, 2.0 for Magstream and 2.2 for OC-Sensor (P=0.17). The three I-FOBTs were superior to the G-FOBT for colorectal cancer (CRC) detection. The ratios for detection rates were 1.6 (FOB-Gold), 1.7 (Magstream) and 2.1 (OC-Sensor) (P=0.74). For non-invasive CRC they were, respectively, 2.5, 3.0 and 4.0 (P=0.83) and for advanced adenomas 3.6, 3.1 and 4.0 (P=0.39).Conclusions: This study provides further evidence that I-FOBT is superior to G-FOBT. None of the three I-FOBTs studied appeared to be significantly better than the others.

Infusion of calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in colorectal cancer: A systematic review and meta-analysis - Corrected Proof

Zhenjie Wu, Jun Ouyang, Zhenhua He, Sen Zhang — 2012-04-30

Abstract: Background: It is hypothesised that infusion of calcium and magnesium (Ca/Mg) can reduce the occurrence of oxaliplatin-related sensory neurotoxicity. However, more recent data have drawn a controversial picture concerning this topic.Methods: A comprehensive literature search was performed using Medline, Embase, Cochrane Library and Google Scholar database up to 1st August 2011. Keywords for the search were: calcium, magnesium and oxaliplatin. The odd ratio (OR) for neurotoxicity and relative risk (RR) for tumour response rate were calculated.Results: Seven studies (four randomised controlled trials (RCTs) and three cohorts) including a total of 1238 participants met our criteria. Meta-analysis of three RCT studies that reported in National Cancer Institute-Common Toxicity Criteria (NCE-CTC) showed that OR for neurotoxicity of Grade ⩾2 was not significant (OR 0.47; 95%confidence interval (CI) 0.22–1.00, P homogeneity=.729). The OR was also not significant in All Grades (OR 3.15, 0.32–31.35, P homogeneity=.952) and Grade 3 subgroup (OR 1.64, 0.30–9.00, P homogeneity=.656). No statistically significant difference was observed in RR for tumour response rate. (RR=0.91, 0.78–1.06, P homogeneity=.33)Conclusions: This meta-analysis does not support the hypothesis that infusion of Ca/Mg reduces the occurrence of neurotoxicity in oxaliplatin-treated patients with colorectal cancer measuring with NCE-CTC criteria. On the other hand, our results support the hypothesis that administrations of Ca/Mg do not impair the efficacy of oxaliplatin-based chemotherapy. However, large-scale randomised, controlled clinical trials will be required to confirm these hypotheses.

Stem cells in breast tumours: Are they ready for the clinic? - Corrected Proof

Matthew P. Ablett, Jagdeep K. Singh, Robert B. Clarke — 2012-04-30

Abstract: The concept of stem-like cells in cancer has been gaining currency over the last decade or so since evidence for stem cell activity in human leukaemia and solid tumours, including breast cancer, was first published. The evidence established that sub-populations of cells identified by antibodies to cell surface markers behaved like developmental stem cells in their capacity to re-grow the human tumour for several generations in experimental immune-deficient hosts. The experiments established that cells with tumourigenic capacity expressed ‘cancer stem cell’ (CSC) markers and that activity could also be measured by self-renewal of tumour sphere colonies in culture. In breast and other cancers, there is good evidence that CSCs are relatively resistant to radio- and chemotherapy indicating that novel CSC-targeted therapies are needed. Several pathways are promising targets in breast CSCs. There are several ways of combating CSC activity including inducing their apoptosis, inhibiting stem cell self-renewal to either stop their division or to promote their differentiation, or targeting the CSC niche that supports them. The first challenge for developing novel CSC therapies is to ascertain which of these CSC properties is being targeted. The second challenge is to determine suitable CSC biomarkers to measure the efficacy of the novel CSC therapies. We propose using biomarkers as a means to identify and assess CSC activity in clinical trials. This is likely to be demanding but feasible in the near future. Thus, we asked if CSCs are ready for the clinic, however, the emerging question becomes: is the clinic ready for cancer stem cells?

Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis - Corrected Proof

2012-04-30

Abstract: Aim: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107–14).Methods: Women, stratified by performance status (0–1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus ⩾6months), were randomly assigned to receive PLD 30mg/m2 IV followed by a 3-h infusion of trabectedin 1.1mg/m2 every 3weeks or PLD 50mg/m2 every 4weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred.Results: After a median follow-up of 47.4months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72–1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3months, trabectedin+PLD=10.6months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69–0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6–12months had the largest difference in OS (HR=0.64; 95%CI: 0.47–0.86; p=0.0027).Conclusions: The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.

Specific-site methylation of tumour suppressor ANKRD11 in breast cancer - Corrected Proof

2012-04-26

Abstract: ANKRD11 is a putative tumour suppressor gene in breast cancer, which has been shown in our laboratory to be a co-activator of p53. Our data suggest that down-regulation of ANKRD11 is associated with breast tumourigenesis. Breast cancer cell lines treated with DNA demethylating agents resulted in up-regulation of ANKRD11 expression suggesting that promoter DNA methylation may be responsible for its down-regulation. The transcriptional activity of a CpG-rich region 2kb upstream of the transcription initiation site of ANKRD11 was investigated using dual-luciferase reporter assays. The constructs carrying –661 to –571bp promoter sequence showed significant transcriptional activity. Using the SEQUENOM Epityper Platform, the region between –770 and +399bp was analysed in 25 breast tumours, four normal breast tissues and five normal blood samples. The region between –770 and –323bp was shown to be frequently methylated in breast tumours. The methylation patterns of all analysed CpGs in this region were identical in the normal and tumour samples, except for a 19bp region containing three CpG sites. These sites had significantly higher levels of methylation in tumours (40%) compared to normal samples (6%). Our findings support the role of ANKRD11 as a tumour suppressor gene and suggest that aberrant DNA methylation of three CpGs in a 19bp region within the ANKRD11 promoter may be responsible for its down-regulation in breast cancer.

Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma - Corrected Proof

2012-04-23

Abstract: Background: Activation of the mammalian target of rapamycin (mTOR) pathway has been demonstrated in sarcoma. Trials using mTOR inhibitor in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest cytostatic effects. The combination of sirolimus and cyclophosphamide demonstrated synergistic anti-sarcoma activity in preclinical models; therefore, we conducted a phase II trial of sirolimus and cyclophosphamide in patients with advanced sarcoma.Methods: Patients received 4mg sirolimus daily and 200mg cyclophosphamide d1-7 and 15-21 every 28days. The primary objective was to estimate the 24-week PFS rate with a target of ⩾25%. Patients were followed for World Health Organisation (WHO) criteria tumour response by imaging every 8weeks. Serum levels of sirolimus, lipids and vascular endothelial growth factor were measured. Tumour tissue was analysed for mTOR, S6 ribosomal protein and cytochrome P450 3A4/5 by quantitative immunofluorescence.Results: Forty-nine eligible patients were enrolled from September 2008 to December 2009. Patients received a median of four cycles of therapy. Starting doses of drugs were tolerated in 79%. One patient achieved partial tumour response, 10 were progression-free for ⩾24weeks and two completed 12 cycles of treatment. Median PFS and overall survival (OS) were 3.4 and 9.9months, respectively. Serious adverse events attributed to therapy occurred in 11% and included infection, pneumonitis and thrombosis. Hypertriglyceridaemia from treatment and lower tumour phosphorylated-mTOR are associated with longer survival.Conclusions: Sirolimus and cyclophosphamide were tolerated by the majority of patients. About 20% of patients had stable sarcoma for at least 6months but objective tumour response was infrequent.

Population-based evidence of increased survival in human papillomavirus-related head and neck cancer - Corrected Proof

Mari Nygård, Bjarte Aagnes, Freddie Bray, Bjørn Møller, Jon Mork — 2012-04-19

Abstract: Background: Evidence from clinical, population-based and molecular studies has shown that human papillomavirus (HPV) infection can be a causal risk factor for a subset of head and neck squamous cell carcinomas (HNSCC). It is proposed that HPV-associated oropharyngeal cancer is a new disease entity that requires treatment and prevention strategies distinct from present recommendations.Methods: In our population-based study we estimated incidence and survival trends in 8270 patients with HPV-related HNSCC (HPV+HNSCC) and HPV-unrelated HNSCC (HPV–HNSCC) in Norway over the past three decades.Results: In the period 1981–1995, patients with HPV+HNSCC had poorer survival than HPV–HNSCC (adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI): 1.14–1.44). By 1996–2007, survival had increased in both groups, but the increase was significantly greater among HPV+HNSCC patients (HR 0.57, 95% CI: 0.48–0.67). During the same period, incidence also increased, but only for HPV+HNSCCs. From 1981–1995 to 1996–2007, median age at diagnosis for HPV+HNSCC decreased from 63.2 to 59.8years, while for HPV–HNSCC median age at diagnosis of 66.6years remained unchanged.Conclusions: We demonstrate a population level improvement in survival among patients with oropharyngeal squamous cell cancers commonly related to infection with HPV. In contrast, patients with HNSCC not related to HPV only showed a modest improvement in survival in the period 1981–2007. A concomitant increase in incidence and survival was observed for HPV-related cancers only. This trend cannot be explained by changes in treatment, cancer registration nor screening, but is most likely due to an increased prevalence of HPV-positive tumours.

Risk adapted chemotherapy for localised Ewing’s sarcoma of bone: The French EW93 study - Corrected Proof

2012-04-19

Abstract: Aim of the study: To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing’s sarcoma.Methods: Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5–30% residual cells or large unresected tumours >100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue.Results: From 1993 to 1999, 214 patients were enrolled. 5y-EFS and OS were 60% (95% confidence interval (CI), 53–66) and 69% (95% CI, 63–75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30–60) and 20% (95% CI, 7–43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours.Conclusion: These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.

Mammographic changes resulting from benign breast surgery impair breast cancer detection at screening mammography - Corrected Proof

2012-04-18

Abstract: Purpose: To study possible explanations for lower screening performance after previous benign breast surgery.Patients and methods: We included a consecutive series of 351,009 screening examinations in 85,274 women, obtained between January 1, 1997 and January 1, 2009. The examinations of women with screen detected cancers (SDC) or interval cancers (IC), diagnosed after previous benign breast surgery, were reviewed by two screening radiologists. They determined the presence and degree of post surgical changes, classified breast density and determined whether mammographic interpretation was hampered by tissue characteristics. They also assessed whether the cancer had already been visible at a previous screen.Results: Screening sensitivity was lower in women with prior benign breast surgery than without (63.5% (115/181) versus 73.5% (1643/2236), p=0.004). A total of 115 SDCs and 66 ICs were diagnosed in breasts after previous benign breast surgery. Post surgical mammographic alterations in the breast segment where cancer was diagnosed were more distinct in ICs than in SDCs (p=0.001). Women with post surgical mammographic changes at the location of the breast cancer had an increased interval cancer risk (OR=2.12, 95% confidence interval (CI)=1.05–4.26). Limited mammographic interpretation due to tissue characteristics was mentioned, only in three SDCs and one IC. The proportions of SDCs and ICS that were already visible at a previous screen were comparable for women with and without prior surgery (SDC: 47.5% versus 43.8%, p=0.3, IC: 50.0% versus 48.4%, p=0.8).Conclusion: Previous benign breast surgery decreases screening sensitivity and this is likely due to postoperative mammographic changes.

Neoadjuvant therapy for breast cancer has no benefits on overall survival or on the mastectomy rate in routine clinical practice. A population-based study with a median follow-up of 11years using propensity score matching - Corrected Proof

2012-04-18

Abstract: Background: Even though neoadjuvant chemotherapy has shown no benefits on overall survival (OS), it is being widely used in the treatment of breast cancer. This is based on the assumption that it may diminish the mastectomy rate and therefore be clinically relevant for patients. Our objective was to assess the impact of neoadjuvant chemotherapy on OS and on the rate of mastectomy in patients with non-metastatic primary operable breast carcinoma in routine practice.Methods: The Cote d’Or district breast cancer registry was used to analyse the OS and mastectomy rate in patients with invasive primary operable unilateral breast cancer diagnosed between 1982 and 2006. We performed Cox proportional hazard ratio (HR) analyses for OS and multivariate logistic regression for the mastectomy rate for the overall population. Different matching methods based on the propensity score were used as sensitivity analyses to ensure that corrections for selection bias were adequate.Results: We analysed 1578 patients, among whom 174 had received neoadjuvant chemotherapy. Median follow-up was 11.1years. There was no difference between the two treatment groups for OS (HR=1.08 (95% confidence interval (CI): 0.77–1.51 for neoadjuvant chemotherapy)). The mastectomy rate was higher among patients treated with neoadjuvant chemotherapy (odds ratio 1.54 (95%CI: 1.03–2.31)). Sensitivity analyses confirmed these results: for OS, there was no difference between the two populations precisely matched using propensity scores (HR 1.08; 95%CI: 0.671–1.65).Conclusion: Despite long term follow-up, neoadjuvant chemotherapy provided no benefit for either OS or the mastectomy rate in our population.

Long term renal toxicity of ifosfamide in adult patients – 5year data - Corrected Proof

James K. Farry, Carlos D. Flombaum, Sheron Latcha — 2012-04-16

Abstract: Ifosfamide is indicated as first line treatment in a variety of solid tumours in adults. It is known to be nephrotoxic and is often used following therapy with, or as concomitant therapy with other potent nephrotoxins. To date, there are sparse case reports on the incidence of acute kidney injury (AKI) or chronic kidney disease (CKD) in adults exposed to ifosfamide. The available data on the long term renal complications for patients exposed to ifosfamide are thus based entirely on the paediatric population. The aim of this study was to assess the long term effects of ifosfamide exposure on renal function in an adult population and to determine if there are any treatment or patient specific factors that contribute to long term nephrotoxicity. The mean decline in estimated glomerular filtration rate (eGFR) following the first cycle of ifosfamide was 15ml/min/1.73m2. Thereafter, there was a slower but steady decline in eGFR. No patient progressed to end stage renal disease (ESRD). Patient age and concomitant exposure to carboplatin were the only two factors which significantly affected eGFR. This represents the only long term study on the nephrotoxicity of ifosfamide in adults.

Risk factors to predict the incidence of surgical adverse events following open or laparoscopic surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial - Corrected Proof

2012-04-16

Abstract: Aims: To identify risk factors for major adverse events (AEs) and to develop a nomogram to predict the probability of such AEs in patients who have surgery for apparent early stage endometrial cancer.Methods: We used data from 753 patients who were randomised to either total laparoscopic hysterectomy or total abdominal hysterectomy in the LACE trial. Serious adverse events that prolonged hospital stay or postoperative adverse events (using common terminology criteria 3+, CTCAE V3) were considered major AEs. We analysed pre-surgical characteristics that were associated with the risk of developing major AEs by multivariate logistic regression. We identified a parsimonious model by backward stepwise logistic regression. The six most significant or clinically important variables were included in the nomogram to predict the risk of major AEs within 6weeks of surgery and the nomogram was internally validated.Results: Overall, 132 (17.5%) patients had at least one major AE. An open surgical approach (laparotomy), higher Charlson’s medical co-morbidities score, moderately differentiated tumours on curettings, higher baseline Eastern Cooperative Oncology Group (ECOG) score, higher body mass index and low haemoglobin levels were associated with AE and were used in the nomogram. The bootstrap corrected concordance index of the nomogram was 0.63 and it showed good calibration.Conclusions: Six pre-surgical factors independently predicted the risk of major AEs. This research might form the basis to develop risk reduction strategies to minimise the risk of AEs among patients undergoing surgery for apparent early stage endometrial cancer.

Matched-case comparison of neoadjuvant chemotherapy in patients with FIGO stage IB1-IIB cervical cancer to establish selection criteria - Corrected Proof

2012-04-16

Abstract: Objective: Neoadjuvant chemotherapy (NACT) for cervical cancer still remains controversial. NACT was evaluated to establish selection criteria.Methods: A matched-case comparison was designed for the NACT group (n=707) and primary surgery treatment (PST; n=707) group to investigate short-term responses and high/intermediate risk factors (HRFs/IRFs). The 5-year disease-free survival (DFS) and overall survival (OS) rates were stratified by NACT response, HRFs/IRFs, International Federation of Gynecology and Obstetrics (FIGO) stage and tumour size, respectively.Results: The clinical and pathological response rates were 79.3% and 14.9% in the NACT group. In comparison to the PST group, IRFs but not HRFs were significantly decreased (P<0.05), and the 5-year DFS rate was significantly improved in the NACT group (88.4% versus 83.1%, P=0.021). Moreover, the 5-year DFS and OS rates were favourably increased in the clinical responders in comparison to the PST group and the clinical non-responders (P<0.05). Compared to those of clinical non-responders, the 5-year DFS and OS rates of clinical responders, with or without HRFs, were also significantly increased (P<0.01). In stage IB2, the 5-year DFS and OS rates were significantly increased, whereas operation duration declined in the NACT group (P<0.05). For patients with stage IB tumours of 2–5cm, the 5-year DFS and OS rates of clinical responders were significantly improved (P<0.05).Conclusions: NACT is a suitable option for patients with cervical cancer, especially for NACT responders and patients with stage IB, which provides a new concept of fertility preservation for young patients.

What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question? - Corrected Proof

2012-04-16

Abstract: Background: Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC.Patients and methods: Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R2) between treatment effects on candidate surrogate (pCR, LC, DP) and OS.Results: The median follow-up was 5.6years. Compared to RT (881pts), CRT (886pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR)=1.04 {0.88–1.21}). CRT significantly improved LC (HR=0.54, 95%confidence interval (CI): 0.41–0.72). PFS was validated as surrogate for OS with R2=0.88. Neoadjuvant treatment effects on LC (R2=0.17) or DP (R2=0.31) did not predict effects on OS.Conclusion: Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.

Prediction of prognosis after trimodal therapy in patients with locally advanced squamous cell carcinoma of the oesophagus - Corrected Proof

Michael Stahl, Nils Lehmann, Martin K. Walz, Martin Stuschke, Hansjochen Wilke — 2012-04-13

Abstract: Background: Due to the poor prognosis of locally advanced oesophageal cancer, predictive markers are warranted to better select patients who may benefit from multimodal therapy.Patients and methods: Patients with oesophageal cancer from two multicentric prospective trials were selected for having received radiochemotherapy followed by macroscopic complete tumour resection. Several pretreatment and treatment related factors were retrospectively analysed for their ability to serve as predictive markers.Results: Overall 107 patients with squamous cell carcinomas stage T3-4 N and M0 were included in the analysis. All of them had complete preoperative radiochemotherapy. Microscopic (n=96) or macroscopic (N=11) complete resection was achieved by transthoracic oesophagectomy. The median follow-up time exceeded 6years. Local progression free and overall survival were significantly hampered in patients with residual tumour in their resected specimen (n=76) compared with patients who showed a pathohistologic complete tumour remission (n=31) (overall survival rate at 3years 25.2% versus 65.6%; hazard ratio (HR)=3.50 (95%-confidence interval (CI) 1.91–6.44); p<0.0001). A multivariable analysis proved both resection status and pathohistologic results to be independent acting predictive factors for local progression free and overall survival after preoperative radiochemotherapy with surgery.Conclusions: From our study it appears that the pathohistologic results can be a valuable surrogate marker for predicting long term survival and local tumour control in patients with locally advanced squamous cell carcinoma (SCC) of the oesophagus after preoperative radiochemotherapy and surgery. Moreover, even after intensive preoperative therapy a complete tumour resection seems to be an important precondition for long term survival.

Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: Incidence, radiographic findings and correlation with clinical outcome - Corrected Proof

2012-04-09

Abstract: Background: Mammalian target of rapamycin (mTOR) inhibitors are approved for use in patients with metastatic renal cell carcinoma (mRCC) and are under investigation in several other malignancies. We assessed the incidence, clinical presentation and computed tomography (CT) findings of pneumonitis associated with mTOR inhibitors in mRCC. Correlation between radiological findings of pneumonitis and clinical outcome was also determined.Methods: We retrospectively reviewed the clinical data and serial CT scans from patients with mRCC treated with either temsirolimus or everolimus. Serial chest CT scans were reviewed in consensus, read by two independent radiologists for the presence of pneumonitis, and corresponding clinical data were reviewed for symptoms and clinical outcome. The baseline and follow up CTs were reviewed to assess outcome to therapy.Results: The study population consisted of 46pts, 21 treated with temsirolimus and 25 with everolimus (M:F 2.5:1; median 63years, range 31–79years). CT evidence of pneumonitis was seen in 14/46pts (30%), at a median of 56days on mTOR inhibitor treatment (range 31–214days). Respiratory symptoms at the time of radiographically detected pneumonitis, were observed in 7pts. Stable disease (SD) by Response Evaluation Criteria in Solid Tumours (RECIST) was achieved in 12/14pts (86%) who developed radiographic pneumonitis compared to 14/32 (44%) without pneumonitis (p=0.01) The mean change of tumour long axis size for target lesions by RECIST, normalised for 30days on therapy was –2.9% in the pneumonitis group and +4.3% in the non-pneumonitis group (p=.002).Conclusions: Preliminary data suggest that pneumonitis may be a marker of stable disease by RECIST and therefore, of therapeutic benefit. Careful patient assessment should be undertaken before the drug is discontinued.

Mastectomy trends for early-stage breast cancer: A report from the EUSOMA multi-institutional European database - Corrected Proof

2012-04-06

Abstract: Introduction: Recent single-institution reports have shown increased mastectomy rates during the last decade. Further studies aiming to determine if these reports could be reflecting a national trend in the United States of America (US) have shown conflicting results. We report these trends from a multi-institutional European database.Patients and methods: Our source of data was the eusomaDB, a central data warehouse of prospectively collected information of the European Society of Breast Cancer Specialists (EUSOMA). We identified patients with newly diagnosed unilateral early-stage breast cancer (stages 0, I or II) to examine rates and trends in surgical treatment.Results: A total of 15,369 early-stage breast cancer cases underwent surgery in 13 Breast Units from 2003 to 2010. Breast conservation was successful in 11,263 cases (73.3%).Adjusted trend by year showed a statistically significant decrease in mastectomy rates from 2005 to 2010 (p=0.003) with a progressive reduction of 4.24% per year. A multivariate model showed a statistically significant association of the following factors with mastectomy: age <40 or ⩾70years, pTis, pT1mi, positive axillary nodes, lobular histology, tumour grade II and III, negative progesterone receptors and multiple lesions.Conclusion: Our study demonstrates that a high proportion of patients with newly diagnosed unilateral early-stage breast cancer from the eusomaDB underwent breast-conserving surgery. It also shows a significant trend of decreasing mastectomy rates from 2005 to 2010. Moreover, our study suggests mastectomy rates in the population from the eusomaDB are lower than those reported in the US.

Sinonasal, genital and acrolentiginous melanomas show distinct characteristics of KIT expression and mutations - Corrected Proof

2012-04-05

Abstract: KIT aberrations predict the outcome of targeted therapies in acrolentiginous (ALM) and mucosal (MM) melanoma patients.KIT immunoreactivity and mutation status was assessed in 41 ALM and 25 MM patients. Of these, 19 ALM and 15 MM patients had matched primary and metastatic lesions. P-ERK was investigated in a subset of 9 ALM and 7 MM matched primary/metastatic pairs by immunohistochemistry.Heterogeneous KIT immunoreactivity was observed in both primary and metastatic lesions. Mutations were present in four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar mucosal samples carried KIT mutations in contrast to sinonasal lesions (p=0.0109). In KIT-mutated tumours, the mutations were present in KIT expressing as well as KIT negative cells, as shown by Laser Capture Microdissection (LCM). P-ERK expression was preferentially found in metastases.KIT mutations predict treatment outcome with KIT inhibitors. Therefore, especially vulvar melanoma patients should be screened for activating KIT mutations.

Economic impact of healthcare resource utilisation patterns among patients diagnosed with advanced melanoma in the United Kingdom, Italy, and France: Results from a retrospective, longitudinal survey (MELODY study) - Corrected Proof

2012-04-05

Abstract: Objective: To describe patterns of healthcare resource utilisation and associated costs for patients with advanced melanoma in the United Kingdom (UK), Italy, and France.Methods: For patients receiving systemic treatment, or supportive care, data describing hospitalisations, hospice care, and outpatient visits were retrieved retrospectively from advanced disease diagnosis as part of a multicountry observational study. Costs were estimated by multiplying utilisation level by unit cost. In an exploratory analysis, costs were compared between individuals who died within one year of initiating first-line treatment (short-term survivors) and those with ⩾1year follow-up (long-term survivors).Results: Hospitalisation costs were highest in France (€6262 per-person compared with €3225 in the UK and €2486 in Italy), reflecting higher rates of hospitalisation. In contrast, outpatient costs were highest in the UK (€782 per-person, compared with €115 in France and €72 in Italy), reflecting the highest rate and frequency of outpatient visits and the highest cost per visit. Hospitalisation rates were consistently higher during supportive care compared with systemic therapy. Roughly one-third of patients entered clinical trials and were not included in the analysis. In exploratory analysis, total costs were generally higher for long-term survivors, but monthly per-patient costs were generally lower for long-term survivors, consistent with a hypothesis that resource utilisation and costs do not necessarily increase proportionally with extended survival.Conclusion: Total costs associated with resource utilisation for advanced melanoma patients varied across countries. Overall cost differences were due to differences in frequency and intensity of utilisation patterns and variation in unit costs of health resources.

Early discontinuation of tamoxifen intake in younger women with breast cancer: Is it time to rethink the way it is prescribed? - Corrected Proof

2012-04-05

Abstract: Background: Tamoxifen is the main recommended adjuvant hormonal treatment for premenopausal women with hormone-responsive early breast cancer. Little data is available on compliance and persistence to tamoxifen intake in younger women.Methods: Using the French National Health Insurance System database, we constituted a cohort of 288 women who were diagnosed with breast cancer and received at least one supply of tamoxifen for breast cancer between September 2005 and July 2011. Medical records and mailed questionnaires provided complementary sources of data. Time to treatment discontinuation and associated predictors were studied using techniques for censored data.Results: Among women who received a prescription of tamoxifen, 6.1% (16) did not fill any prescription. After 2years of tamoxifen intake, 29.7% (95%confidence interval (CI) 24.1–36.4) had discontinued their treatment; after 3years this percentage increased to 39.5% (95%CI 32.9–47.0). The risk of treatment discontinuation rose sharply during the 1st year of treatment and remained approximately constant in the second year. After multivariate adjustment, tamoxifen discontinuation increased significantly with low social support (Hazard Ratio (HR)=2.1; 95%CI 1.2–3.4), and self-reporting of non-compliance behaviour (HR=2.2; 95%CI 1.3–3.7).Conclusion: The consequences of high treatment discontinuation rates in younger women with long potential life expectancy may be significant. There is an urgent need to acknowledge and tackle compliance issues in the field of oncology, unless we are willing to accept inefficient prescriptions of efficacious drugs.

Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: Evidence from a systematic review and meta-analysis - Corrected Proof

2012-03-30

Abstract: Background: The prognostic significance of p53 aberration in hepatocellular carcinoma (HCC) remains inconclusive. This systematic review and meta-analysis aimed to provide comprehensive evidence on the association of p53 alterations with recurrence-free survival (RFS) and overall survival (OS) in HCC patients.Methods: Systematic literature searches were conducted until July 2010. Meta-analysis was performed to estimate prognostic effects of p53 alterations on patient outcomes in HCC. Sensitivity and subgroup analyses were also conducted in the meta-analysis.Results: Thirty-seven studies (7 tumour p53 mutation, 23 tumour p53 expression and 7 serum anti-p53 antibodies) were included in the systematic review and meta-analysis. The average percentages of p53 mutation, p53 expression upregulation and anti-p53 antibody level elevation in HCC patients were 31.5%, 35.0% and 23.8%, respectively. Tumour p53 alterations were associated significantly with poor patient outcomes in HCC: the summary hazard ratio (HR) of mutant p53 versus wild type p53 phenotype was 2.58 [95% confidence interval (CI): 1.96–3.41] for OS and 3.19 [95% CI: 2.21–4.60] for RFS, respectively; and the summary HR of upregulated p53 expression versus low/undetectable p53 expression was 1.68 [95% CI: 1.49–1.90] for OS and 1.89 [95% CI: 1.34–2.66] for RFS, respectively. However, elevated serum anti-p53 antibody was only associated with poor OS in HCC group with a high proportion of (⩾50%) of hepatitis C virus (HCV) infection [HR: 1.92; 95% CI: 1.30–2.85]. Moreover, sensitivity analyses showed that the results of meta-analyses were not altered.Conclusion: HCC patients with p53 mutation and upregulated expression in tumour tissue have a shorter OS and RFS than patients with wild type p53 and low/undetectable p53 expression. However, the prognostic value of serum anti-p53 antibody is required to be further examined.

MC1R, SLC45A2 and TYR genetic variants involved in melanoma susceptibility in Southern European populations: Results from a Meta-analysis - Corrected Proof

2012-03-30

Abstract: Background and methods: Seven genetic biomarkers previously associated with melanoma were analysed in a meta-analysis conducted in three South European populations: five red hair colour (RHC) MC1R alleles, one SLC45A2 variant (p.Phe374Leu) and one thermosensitive TYR variant (p.Arg402Gln). The study included 1639 melanoma patients and 1342 control subjects.Results: The estimated odds ratio (OR) associated with carrying at least one MC1R RHC variant was 2.18 (95% confidence interval (CI): 1.86–2.55; p-value=1.02×10−21), with an additive effect for carrying two RHC variants (OR: 5.02, 95% CI: 2.88–8.94, p-value=3.91×10−8). The SLC45A2 variant, p.Phe374Leu, was significantly and strongly protective for melanoma in the three South European populations studied, with an overall OR value of 0.41 (95%CI: 0.33–0.50; p-value=3.50×10−17). The association with melanoma of the TYR variant p.Arg402Gln was also statistically significant (OR: 1.50; 95%CI: 1.11–2.04; p-value=0.0089). Adjustment for all clinical potential confounders showed that melanoma risks attributable to MC1R and SLC45A2 variants strongly persisted (OR: 2.01 95%CI: 1.49–2.72 and OR: 0.50, 95%CI: 0.31–0.80, respectively), while the association of TYR p.Arg402Gln was no longer significant. In addition, stratification of clinical melanoma risk factors showed that the risk of melanoma was strong in those individuals who did not have clinical risk factors.Conclusion: In conclusion, our results show without ambiguity that in South European populations, MC1R RHC and SCL45A2 p.Phe374Leu variants are strong melanoma risk predictors, notably in those individuals who would not be identified as high risk based on their phenotypes or exposures alone. The use of these biomarkers in clinical practice could be promising and warrants further discussion.

Lung cancer in never smokers – A review - Corrected Proof

2012-03-30

Abstract: An estimated 10–25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate.The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation.The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers.In the present paper we review current clinical and molecular aspects of LCINS.

Enhancing the anticancer effect of the histone deacetylase inhibitor by activating transglutaminase - Corrected Proof

2012-03-29

Abstract: Histone deacetylase (HDAC) inhibitors have shown promising anticancer effects in clinical trials. However, a proportion of patients do not respond to HDAC inhibitor therapy. We have previously demonstrated that tissue transglutaminase (TG2) is one of the genes commonly up-regulated by HDAC inhibitors in vitro and in vivo, and that two structurally distinct TG2 protein isoforms, the full-length (TG2-L) and the short form (TG2-S), exert opposing effects on cell differentiation due to difference in transamidation activity. Here we show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) transcriptionally activates the expression of both TG2-L and TG2-S, and that up-regulation of TG2-L renders neuroblastoma cells less sensitive to SAHA-induced cytotoxicity. Combination therapy with SAHA and the transamidation activator Naringenin, a natural product found in citrus fruits, synergistically enhanced transamidation activity and SAHA-induced cytotoxicity in neuroblastoma cells, but not in normal non-malignant cells. In tumour-bearing N-Myc transgenic mice, SAHA and Naringenin synergistically suppressed tumour progression. Taken together, our data demonstrate that SAHA-induced TG2-L over-expression renders cancer cells less sensitive to SAHA therapy, and suggest the addition of Naringenin to SAHA and probably also other HDAC inhibitors in future clinical trials in cancer patients.

Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer - Corrected Proof

2012-03-29

Abstract: Background: Endocrine therapy is the preferred treatment for hormone-receptor (HR) positive metastatic breast cancer. In premenopausal patients, ovarian function suppression with goserelin in combination with anastrozole yielded promising results in phase II studies. Fulvestrant, a pure antioestrogen, yields high rates of disease stabilisation in postmenopausal women. Therefore, we investigated the feasibility and safety of fulvestrant plus goserelin in premenopausal women with HR-positive metastatic breast cancer.Methods: Premenopausal patients with metastatic breast cancer eligible for endocrine treatment received fulvestrant 250mg and goserelin 3.6mg every four weeks as first- to fourth-line therapy. Clinical benefit rate (CBR; response rate plus disease stabilisation ⩾6months) was defined as the primary study end-point. Time to progression (TTP) and overall survival (OS) were estimated using the Kaplan–Meier product limit method.Findings: Twenty-six patients received treatment as scheduled. 81% were pre-treated with tamoxifen and 69% had received prior aromatase inhibitors in combination with goserelin. The majority of patients (69%) presented with visceral metastases.Complete response was observed in a single patient, partial response in three and disease stabilisation ⩾6months in eleven patients, resulting in a CBR of 58%. Median TTP was 6months (95%confidence interval (CI), 2.4–9.6) and OS 32months (95%CI, 14.28–49.72), respectively.Interpretation: Results suggest that the combination of fulvestrant and goserelin offers promising activity in premenopausal patients and further investigation is warranted.

TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells - Corrected Proof

2012-03-29

Abstract: Most gastric cancer cells are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Since TRAIL resistance is associated with lipid rafts, in which both death receptors and epidermal growth factor receptors (EGFR) are enriched, our aim is to identify how lipid raft-regulated receptor redistribution influences the sensitivity of TRAIL in gastric cancer cells. In TRAIL-resistant gastric cancer cells, TRAIL did not induce effective death-inducing signalling complex (DISC) formation in lipid rafts, accompanied with EGFR translocation into lipid rafts, and activation of EGFR pathway. Knockdown of casitas B-lineage lymphoma-b (Cbl-b) enhanced TRAIL-induced apoptosis by promoting DISC formation in lipid rafts. However, knockdown of Cbl-b also enhanced EGFR translocation into lipid rafts and EGFR pathway activation induced by TRAIL. Either using inhibitors of EGFR or depletion of EGFR with small interfering RNA (siRNA) prevented EGFR pathway activation, and thus increased TRAIL-induced apoptosis, especially in Cbl-b knockdown clones. Taken together, TRAIL-induced EGFR activation through Cbl-b-regulated EGFR redistribution in lipid rafts antagonised TRAIL-induced apoptosis. The contribution of DISC formation and the inhibition of EGFR signal triggered in lipid rafts are both essential for increasing the sensitivity of gastric cancer cells to TRAIL.

Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials - Corrected Proof

2012-03-27

Abstract: Background: The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.Methods: Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log–rank and Cochran–Mantel–Haenszel tests.Results: In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p<0.001) and ORR (odds ratio 2.16; p<0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.Conclusion: Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10years in early stage breast cancer - Corrected Proof

2012-03-26

Abstract: Introduction: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval.Method: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10years event-free survival.Results: In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p⩽0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001).Conclusion: This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease.

Excess body weight and the risk of primary liver cancer: An updated meta-analysis of prospective studies - Corrected Proof

Yi Chen, Xiaolin Wang, Jianhua Wang, Zhiping Yan, Jianjun Luo — 2012-03-26

Abstract: Aims: To provide a quantitative assessment of the association between excess body weight (EBW) and the risk of primary liver cancer (PLC), we performed an updated meta-analysis of prospective observational studies.Methods: We searched PUBMED and EMBASE for studies of body mass index and the risk of PLC published through 15 th September 2011. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. The meta-regression and stratified methods were used to examine heterogeneity across studies.Results: A total of 26 prospective studies, including 25,337 PLC cases, were included in this analysis. Overall, excess body weight (EBW: body mass index (BMI)⩾25kg/m2) and obesity (BMI⩾30kg/m2) were associated with an increased risk of PLC, with significant heterogeneity (EBW: SRRs 1.48, 95%CIs 1.31–1.67, Ph<0.001, I2=83.6%; Obesity: SRRs 1.83, 95%CIs 1.59–2.11, Ph<0.001, I2=75.0%). Subgroup analyses revealed that the positive associations were independent of geographic locations, alcohol consumption, history of diabetes or infections with hepatitis B (HBV) and/or hepatitis C virus (HCV). Obese males had a higher risk of PLC than obese females did (P=0.027). A stronger risk of PLC with EBW was observed for patients with HCV (but not HBV) infection or cirrhosis compared with the general population.Conclusions: Findings from this meta-analysis strongly support that EBW or obesity is associated with an increased risk of PLC in both males and females.

Increased risk of lung cancer in individuals with a family history of the disease: A pooled analysis from the International Lung Cancer Consortium - Corrected Proof

2012-03-21

Abstract: Background and methods: Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals.Results: Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR)=1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR=1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR=1.44, 95% CI: 1.07, 1.93), after adjustment.Conclusions: The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.

Predictive value of alpha-fetoprotein in the long-term risk of developing hepatocellular carcinoma in patients with hepatitis B virus infection – Results from a clinic-based longitudinal cohort - Corrected Proof

2012-03-21

Abstract: Background: Although serum level of alpha-fetoprotein (AFP) has long been used to complement imaging tests in the screening and diagnosis of hepatocellular carcinoma (HCC), whether it can be used as a predictive marker of long-term risk for developing HCC in patients with hepatitis B virus (HBV) has not been extensively evaluated and thus remains controversial.Methods: We retrospectively conducted a clinic-based longitudinal cohort study including 617 Korean American patients with HBV who had been followed for up to 22years (median follow-up time, 6.2years) to evaluate the association between baseline serum AFP level and the long-term risk of HCC.Results: The median baseline AFP value of these patients was 3.8 ng/ml. Compared to patients with lower-than-median AFP value, those with higher-than-median baseline serum AFP had a significantly increased risk of developing HCC with a hazard ratio (HR) of 2.73 (95% confidence interval [CI] 1.25–5.99), independent of other major HCC risk factors. In addition, we calculated the cumulative incidence of HCC during different years of follow-up time by baseline serum AFP, and found that the cumulative incidence of HCC was significantly higher in HBV patients with high baseline serum AFP compared to those with low baseline serum AFP in each of the five follow-up time periods examined.Conclusions: Our results indicated that AFP was a strong independent prospective predictor of long-term HCC risk in high-risk HBV patients. More targeted prevention and early detection of HCC may be considered for these patients.

Cancer screening and health system resilience: Keys to protecting and bolstering preventive services during a financial crisis - Corrected Proof

2012-03-19

Abstract: The aim of this paper is to elucidate the rationale for sustaining and expanding cost-effective, population-based screening services for breast, cervical and colorectal cancers in the context of the current financial crisis. Our objective is not only to promote optimal delivery of high-quality secondary cancer prevention services, but also to underline the importance of strengthening comprehensive cancer control, and with it, health system response to the complex care challenges posed by all chronic diseases. We focus primarily on issues surrounding planning, organisation, implementation and resources, arguing that given the growing cancer burden, policymakers have ample justification for establishing and expanding population-based programmes that are well-organised, well-resourced and well-executed. In a broader economic context of rescue packages, deficits and cutbacks to government entitlements, health professionals must intensify their advocacy for the protection of vital preventive health services by fighting for quality services with clear benefits for population health outcomes.

Anandamide inhibits the Wnt/β-catenin signalling pathway in human breast cancer MDA MB 231 cells - Corrected Proof

2012-03-16

Abstract: We previously showed that methyl-F-anandamide, a stable analogue of the anandamide, inhibited the growth and the progression of cultured human breast cancer cells. As accumulating evidences indicate that the constitutive activation of the canonical Wnt pathway in human breast cancer may highlight a key role for aberrant activation of the β-catenin–TCF cascade and tumour progression, we studied the anandamide effect on the key elements of Wnt pathway in breast cancer cells. In this study we described that the treatment of human breast cancer cells, MDA MB 231 cells, with methyl-F-anandamide reduced protein levels of β-catenin in the cytoplasmic and nuclear fractions inhibiting the transcriptional activation of T Cell Factor (TCF) responsive element (marker for β-catenin signalling). The anandamide treatment resulted in up-regulation of epithelial markers, like E-cadherin with a concomitant decrease in protein levels of mesenchymal markers, including vimentin and Snail1. We, furthermore, observed that the induction of experimental epithelial-mesenchymal transition by exposure to adriamycin in MCF7 human breast cancer cell line was inhibited by anandamide treatment. In the present study we reported a novel anticancer effect of anandamide involving the inhibition of epithelial-mesenchymal transition, a process triggered during progression of cancer to invasive state.

Effects of the combination of RAD001 and docetaxel on breast cancer stem cells - Corrected Proof

Xiaobei Zhang, Sheng Zhang, Yan Liu, Jingjing Liu, Yi Ma, Yuanxi Zhu, Jin Zhang — 2012-03-15

Abstract: Recent evidence has suggested that breast cancer contains a rare population of cells called cancer stem cells (CSCs), which have an extensive self-renewal ability and contribute to metastasis and therapeutic resistance. This study evaluated the in vitro and in vivo effects of RAD001 (Everolimus) alone or in combination with docetaxel on stem cells from primary breast cancer cells and two breast cancer cell lines (MCF-7 and MDA-MB-231). In In vitro studies, we sorted ESA+CD44+CD24−/low cells as stem cells using flow cytometry from primary breast cancer cells, MCF-7 and MDA-MB-231 cell lines. MTT assays were used to quantify the inhibitory effect of the drugs on total cells and stem cells. Apoptosis and the cell cycle distributions of stem cells were examined by flow cytometry. The tumourigenicity of stem cells after treatment was investigated by soft agar colony formation assays. In In vivo studies, the BALB/c mice were injected with MDA-MB-231 stem cells and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analysed by immunohistochemistry. In In vitro studies, all three populations of stem cells were resistant to the standard treatment doses of docetaxel compared with total cells treated with the same drug. Treatment with RAD001 resulted in growth inhibition of all stem cells in a dose-dependent manner. An additive growth inhibitory effect of the combination treatment on the three stem cells was observed in in vitro compared with treatment with RAD001 alone (P<0.001). In addition, an increase in G2/M cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either single-agent group (P<0.01). In vivo, the volumes of the xenograft tumours significantly decreased in RAD001 alone group compared to control group (P=0.008), and RAD001 plus docetaxel therapy was much more effective at reducing tumour volume in mice compared with either single-agent alone (P<0.05). Compared with RAD001 alone, the combination of RAD001 and docetaxel reduced the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308) (P<0.05). We conclude that the combination treatment of RAD001 and docetaxel can inhibit the growth of stem cells in vitro and in vivo by inhibiting cell proliferation, inducing apoptosis, cell cycle arrest and reducing the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308). These data indicate that combination treatment with RAD001 and docetaxel may represent an effective therapy for breast cancer. However, further studies are required to evaluate the drug interaction between RAD001 and docetaxel in the clinical setting.

Biopsy diagnosis of intraductal carcinoma is prognostic in intermediate and high risk prostate cancer patients treated by radiotherapy - Corrected Proof

2012-03-14

Abstract: Aim: We investigated the prognostic significance of intraductal carcinoma of the prostate (IDC-P) in biopsies and transurethral resections prior to external beam radiotherapy with or without androgen deprivation.Methods: Cohort 1 consisted of 118 intermediate risk prostate cancer patients treated by radiotherapy, with biochemical relapse as primary end-point (median follow-up 6.5years). Cohort 2 consisted of 132 high risk patients, enrolled in a phase III randomised trial (EORTC 22863) comparing radiotherapy alone to radiotherapy with long-term androgen deprivation (LTAD) with clinical progression free survival as primary end-point (median follow-up 9.1years). Presence of IDC-P was identified after central review. Multivariable regression modelling and Kaplan–Meier analysis were performed with IDC-P as dichotomous variable.Results: IDC-P was a strong prognosticator for early (<36months) biochemical relapse (HR 7.3; p=0.007) in cohort 1 and for clinical disease-free survival in both arms of cohort 2 (radiotherapy arm: HR 3.5; p<0.0001; radiotherapy plus LTAD arm: HR 2.8, p=0.018). IDC-P retained significance after stratification for reviewed Gleason score in the radiotherapy arm (HR 2.3; p=0.03). IDC-P was a strong prognosticator for metastatic failure rate (radiotherapy arm: HR 5.3; p<0.0001; radiotherapy plus LTAD arm: HR 3.6; p=0.05).Conclusions: IDC-P in diagnostic samples of patients with intermediate or high risk prostate cancer is an independent prognosticator of early biochemical relapse and metastatic failure rate after radiotherapy. We suggest that the presence of IDC-P in prostate biopsies should routinely be reported.

Population attributable risk of aflatoxin-related liver cancer: Systematic review and meta-analysis - Corrected Proof

Yan Liu, Chung-Chou H. Chang, Gary M. Marsh, Felicia Wu — 2012-03-14

Abstract: Background: Over 4 billion people worldwide are exposed to dietary aflatoxins, which cause liver cancer (hepatocellular carcinoma, HCC) in humans. However, the population attributable risk (PAR) of aflatoxin-related HCC remains unclear.Methods: In our systematic review and meta-analysis of epidemiological studies, summary odds ratios (ORs) of aflatoxin-related HCC with 95% confidence intervals were calculated in HBV+ and HBV− individuals, as well as the general population. We calculated the PAR of aflatoxin-related HCC for each study as well as the combined studies, accounting for HBV status.Results: Seventeen studies with 1680 HCC cases and 3052 controls were identified from 479 articles. All eligible studies were conducted in China, Taiwan, or sub-Saharan Africa. The PAR of aflatoxin-related HCC was estimated at 17% (14–19%) overall, and higher in HBV+ (21%) than HBV− (8.8%) populations. If the one study that contributed most to heterogeneity in the analysis is excluded, the summarised OR of HCC with 95% CI is 73.0 (36.0–148.3) from the combined effects of aflatoxin and HBV, 11.3 (6.75–18.9) from HBV only and 6.37 (3.74–10.86) from aflatoxin only. The PAR of aflatoxin-related HCC increases to 23% (21–24%). The PAR has decreased over time in certain Taiwanese and Chinese populations.Conclusions: In high exposure areas, aflatoxin multiplicatively interacts with HBV to induce HCC; reducing aflatoxin exposure to non-detectable levels could reduce HCC cases in high-risk areas by about 23%. The decreasing PAR of aflatoxin-related HCC reflects the benefits of public health interventions to reduce aflatoxin and HBV.

Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 - Corrected Proof

2012-03-14

Abstract: Aim: To use published literature and experts’ opinion to investigate the clinical meaning and magnitude of changes in the Quality of Life (QOL) of groups of patients measured with the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).Methods: An innovative method combining systematic review of published studies, expert opinions and meta-analysis was used to estimate large, medium, and small mean changes over time for QLQ-C30 scores.Results: Nine hundred and eleven papers were identified, leading to 118 relevant papers. One thousand two hundred and thirty two mean changes in QOL over time were combined in the meta-analysis, with timescales ranging from four days to five years. Guidelines were produced for trivial, small, and medium size classes, for each subscale and for improving and declining scores separately. Estimates for improvements were smaller than respective estimates for declines.Conclusions: These guidelines can be used to aid sample size calculations and interpretation of mean changes over time from groups of patients. Observed mean changes in the QLQ-C30 scores are generally small in most clinical situations, possibly due to response shift. Careful consideration is needed when planning studies where QOL changes over time are of primary interest; the timing of follow up, sample attrition, direction of QOL changes, and subscales of primary interest are key considerations.

Prospective validation of a risk calculator which calculates the probability of a positive prostate biopsy in a contemporary clinical cohort - Corrected Proof

2012-03-09

Abstract: Background: Prediction models need validation to assess their value outside the development setting.Objective: To assess the external validity of the European Randomised study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC) in a contemporary clinical cohort.Methods: The RC calculates the probability of a positive sextant prostate biopsy (P(posb)) using serum prostate-specific antigen (PSA), results of digital rectal examination, transrectal ultrasound (TRUS) and ultrasound assessed prostate volume. We prospectively validated the RC in 320 biopsied men (55–75years), with no previous prostate biopsy, included in five Dutch hospitals in 2008–2011. If the P(posb) was ⩾20% a biopsy was recommended.The performance of the RC was tested by comparing the observed outcomes to predicted probabilities, using the area under the curve (AUC) and decision curves analyses.Results: Compared to the screening cohort, men in the clinical cohort differed. They had higher PSA levels (median 6.8 versus 4.3ng/ml, p<0.01), less TRUS-lesions (27% versus 34%, p=0.01) and more prostate cancer (PCa) at biopsy (43% versus 25%, p<0.01). Mainly eight biopsy cores were taken. Despite the differences between these cohorts, the mean observed probability agreed with the mean predicted probability (43% versus 40%). The RC predicted P(posb) better than a model with PSA and digital rectal examination, AUC 0.77 (95% confidence interval (CI) 0.72–0.83) and 0.71 (95%CI 0.65–0.76, p<0.01), respectively. This was confirmed by the decision curves analysis. Under the 20% threshold, 17% (11/63) of the biopsied men were diagnosed with PCa. Two of 11 men had an important cancer (Gleason 3+4).Conclusions: The ERSPC RC performs well in a Dutch clinical cohort in men with previous PSA tests and contemporary biopsy schemes, and outperforms a PSA and DRE-based approach in the decision to perform a biopsy.

miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2 - Corrected Proof

2012-03-09

Abstract: MicroRNAs are strongly implicated in cancer but their specific roles and functions in the major cancers have yet to be fully elucidated. In this study, we defined the expression and function of miR-137, which we found to be downregulated in glioma samples and glioma cells by qRT-PCR. Ectopic expression of miR-137 in glioma cell lines inhibited proliferation and invasion. Using computational and expression analysis, Cox-2 was identified as a candidate target of miR-137. Reporter assay with 3′UTR of Cox-2 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-137, providing strong evidence that miR-137 was a direct regulator of Cox-2. Expression analysis further revealed that Cox-2 was elevated in glioma and associated with survival of patients. Furthermore, we observed that Cox-2 knockdown resulted in effects similar to those with miR-137 transfection in glioma cells. In conclusion, our study demonstrates that miR-137 deregulation is common in glioma, and restoration of its function inhibits cell proliferation and invasion, suggesting that miR-137 may act as a tumour suppressor.

Opposite effects of microchimerism on breast and colon cancer - Corrected Proof

2012-03-07

Abstract: Background: Detection of Y chromosome, thought to originate from previous pregnancies with a male fetus, is common in women. Lower concentrations have been reported in women with breast cancer than cancer-free women. Data in women with other types of cancer are sparse. The purpose of the study was to determine whether the lower concentrations predate cancer diagnosis, and whether a possible beneficial effect was specific to breast cancer.Methods: We conducted a prospective case–cohort study of 50–64-year-old Danish women enrolled in the Diet, Cancer and Health cohort. Blood samples and questionnaire data were obtained during 1993–1997 when all women were cancer-free. In 2006 all women were followed up for incident breast and colon cancer in national registers. In blinded analyses, we analysed buffy coat DNA for Y chromosome (DYS14) as a marker of male microchimerism.Results: We detected male microchimerism in 70% of 272 cancer-free women, 40% of 89 women who later developed breast cancer, and 90% of 67 women who later developed colon cancer. The corresponding odds ratios were 0.30 (95% confidence interval (CI) 0.17–0.52) for breast, and 3.9 (95%CI 1.6–9.5) for colon cancer.Conclusion: Detection of male microchimerism was strongly associated with reduced risk of developing breast cancer and also the increased risk of developing colon cancer. Confirmatory findings based on an improved study design, failure to identify important confounders and the strength of the associations lead us to believe that microchimerism may be highly relevant to later cancer development. However, the present study does not allow us to identify the underlying biological mechanisms.

Successful centralisation of patients with vulvar carcinoma: A population-based study in The Netherlands - Corrected Proof

2012-03-05

Abstract: Introduction: In general, centralisation of care for patients with rare malignancies is advised in order to improve outcome with respect to prognosis and treatment related morbidity. Therefore, centralisation of women with vulvar squamous cell carcinoma (SCC), which is an extremely rare tumour, has been advocated by the national guidelines of the Dutch Society of Obstetrics and Gynaecology in 2000. The objective of this study was to determine whether this advice has been adapted and has led to improved survival.Methods: All patients diagnosed with vulvar malignancies between 1989 and 2008 in the Eastern part of the Netherlands were retrieved from the population-based cancer registry held by the Comprehensive Cancer Centre, The Netherlands. Patient- and tumour characteristics and vital status until January 2011 were retrieved. Data of patients diagnosed in two periods (before and after release of the guideline; 1989–1999 and 2000–2008) were compared. Relative survival rates were calculated as a good approximation of cause-specific survival.Results: A total number of 382 patients with vulvar SCC with invasion >1mm, who had an indication for groin surgery, were included in the analysis. In the first decade 62% (123 of 198 patients) were treated in a specialised oncology centre, which increased to 93% (172 of 184 patients) in the more recent period. Overall, the 5year relative survival improved slightly from 69% (95% confidence interval (CI) 60–77%) to 75% (95% CI 65–83%). After adjustment for age and stage, being treated in a specialised oncology centre was an independent prognostic factor for survival.Conclusion: Centralisation of care for vulvar SCC patients has been well adopted in the Eastern part of the Netherlands. Being treated in a specialised oncology centre was associated with a better survival after adjustment for age and stage.

Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells - Corrected Proof

2012-03-05

Abstract: The multitargeted tyrosine-kinase inhibitor sunitinib is a highly effective anti-angiogenic and cytostatic agent in the therapy of various tumours. While malignant gliomas have been shown to be responsive to sunitinib, detailed studies analysing human meningiomas are missing. We therefore analysed the effects of sunitinib in two benign (BenMen-1, HBL52) and two malignant (IOMM-Lee, KT21MG) human meningioma cell lines and found that DNA synthesis was significantly (p⩽0.001) inhibited following 1, 2 or 5μM sunitinib, with IC50 values between 2 and 5μM in all cell lines. This effect was associated with a G2M-arrest at 10μM for BenMen-1, HBL52 and IOMM-Lee, and 20μM in KT21MG cells. Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10μM or higher. Corresponding, cell viability assays showed a significant (p⩽0.001) short term decrease of viable cells (24h) only for high sunitinib concentrations with IC50-values between 10 and 20μM. However, pre-irradiated meningioma cells (5Gy) showed a sensitivity shift towards IC50-values around 5μM sunitinib. We also found that 5μM strongly reduced meningioma cell migration in vitro. Western blot analyses showed abolished platelet derived growth factor receptor (PDGFR)-autophosphorylation after sunitinib. Interestingly, the drug also inhibited the autophosphorylation of the receptor tyrosine kinase fms-like tyrosine kinase 3 (Flt3) in a dose-dependent manner. Taken together, the present data show that micromolar sunitinib has strong cytostatic and anti-migratory effects on human meningioma cells.

Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies - Corrected Proof

2012-03-05

Abstract: Introduction: 3-Hydroxy-methylglutaryl coenzyme-A reductase inhibitors (statins) improve survival following pelvic irradiation for cancer. Large studies suggest that patients with hypertension may have reduced gastrointestinal (GI) toxicity. Animal data suggest that statins and ACE inhibitors (ACEi) may protect against normal tissue injury. Their efficacy in humans has not been reported.Aims/methods: To evaluate the impact of statins and ACEi on normal tissue toxicity during radical pelvic radiotherapy. GI symptomatology was recorded prospectively before radiotherapy, weekly during treatment and 1 year later using the Inflammatory Bowel Disease Questionnaire – Bowel (IBDQ-B) subset. Cumulative acute toxicity (IBDQ-B AUC) and worst score were determined. Dose, brand and duration of statin and/or ACEi usage were obtained from General Practitioners.Results: Of 308 patients recruited, 237 had evaluable acute drug and toxicity data and 164 had data at 1year. Acutely, 38 patients (16%) were taking statins, 39 patients (16.5%) were taking ACEi and 18 patients (7.6%) were taking statin+ACEi. Mean changes in acute scores were 7.3 points (non-statin users), 7.3 (non-ACEi users) and 7.0 (non-statin+ACEi users) compared to 4.8 points (statin users), 5.0 points (ACEi users) and 4.9 points (statin+ACEi users). Statin use (p=0.04) and combined statin+ACEi use (p=0.008) were associated with reduced acute IBDQ-B AUC after controlling for baseline scores (ANOVA). At 1 year, users maintained higher IBDQ-B scores than non-users in all user subgroups.Conclusion: Use of statin or statin+ACEi medication during radical pelvic radiotherapy significantly reduces acute gastrointestinal symptoms scores and also appears to provide longer-term sustained protection.

High galectin-1 expression correlates with poor prognosis and is involved in epithelial ovarian cancer proliferation and invasion - Corrected Proof

2012-03-05

Abstract: Purpose: Galectin-1 (Gal-1) is a 14-kDa laminin-binding galectin involved in several biological events including regulation of tumour proliferation and metastasis. In this study, we investigated the clinical significance of Gal-1 expression and its functional role in cell proliferation and invasion in epithelial ovarian cancer (EOC).Experimental design: We evaluated the expression of Gal-1 in 52 serous, 11 endometrioid, and 3 mucinous type EOC tumour samples from 66 patients by immunohistochemistry. In vitro experiments were performed to determine the function of Gal-1 in cell survival, proliferation, and invasion in EOC cells using siRNA and anginex, a Gal-1 inhibitor, as well as recombinant Gal-1 protein.Results: Patients with strong Gal-1 peritumoural staining had poorer progression-free survival (PFS) than patients with weak peritumoural staining (p=0.03). Inhibition of Gal-1 by siRNA or anginex resulted in the inhibition of cell growth and proliferation of HeyA8 and SKOV3ip1 cells. Moreover, the ability of cells to migrate was significantly reduced by treatment of cells with Gal-1 siRNA but was increased by treatment of cells with recombinant Gal-1. When we evaluated the interaction between fibroblasts (T HESCs) and cancer cells (A2780-CP20), we found that MMP-2 expression in cancer cells was affected by Gal-1 secreted by fibroblast cells, which suggests that Gal-1 in human fibroblasts might affect the invasive abilities of tumour cells.Conclusion: Our results suggest that Gal-1 expression is a potential prognostic factor for PFS and that Gal-1 could be a novel treatment target in EOC patients.

Incidence of fractures causing hospitalisation in prostate cancer patients: Results from the population-based PCBaSe Sweden - Corrected Proof

2012-03-02

Abstract: Background: Prostate cancer patients have an increased risk of fractures as a consequence of skeletal metastases and osteoporosis induced by endocrine treatment. Data on incidence of fractures and risks in subgroups of men with prostate cancer are sparse. Our aim with this study is to report the risk of fractures among men with prostate cancer in a nationwide population-based study.Patients and methods: We identified 76,600 Swedish men diagnosed with prostate cancer 1997–2006 in the Prostate Cancer Data Base (PCBaSe) Sweden and compared the occurrence of fractures requiring hospitalisation with the Swedish male population.Results: Only men treated with gonadotropin releasing-hormone (GnRH) agonists or orchiectomy had increased incidence and increased relative risk of fractures requiring hospitalisation. Men treated with GnRH agonists had 9.8 and 6.3/1000 person-years higher incidence of any fracture and hip fracture requiring hospitalisation than the general population. The corresponding increases in incidence for men treated with orchiectomy were 16 and 12/1000 person-years, respectively. Men treated with orchiectomy, GnRH agonists, and antiandrogen monotherapy, had SIR for hip fracture of 2.0 (95% Confidence Interval 1.8–2.2), 1.6 (95% CI 1.5–1.8) and 0.9 (95% CI 0.7–1.1), respectively. Men treated with a curative intent (radical prostatectomy or radiotherapy) or managed with surveillance had no increased risk of fractures. Older men had the highest incidence of fractures while younger men had the highest relative risk.Conclusion: Prostate cancer patients treated with GnRH agonists or orchiectomy have significantly increased risk of fractures requiring hospitalisation while patients treated with antiandrogen monotherapy had no increase in such fractures. In absolute terms the excess risk in men treated with GnRH agonists corresponded to almost 10 extra fractures leading to hospitalisation per 1000 patient-years. Effects on bone density should be considered for men on long-term endocrine treatment. Unwarranted use of orchiectomy and GnRH agonists should be avoided.

Neoadjuvant chemotherapy, interval debulking surgery or primary surgery in ovarian carcinoma FIGO stage IV? - Corrected Proof

2012-03-01

Abstract: Objectives: The aim of this study was to investigate the impact of surgical approach, the extent of surgery and chemotherapy on overall survival in patients with ovarian carcinoma (OC) stage IV.Methods: We retrospectively collected population-based data from the Norwegian Radium Hospital code registry on the diagnosis and surgery of 238 patients diagnosed with OC stage IV from 1996–2005. All patients received platinum-based chemotherapy. Surgical approach was registered as primary debulking surgery (PDS), interval debulking surgery (IDS) and delayed primary surgery (DPS). Surgery level was classified as radical surgery (RS), standard surgery (SS) or suboptimal surgery (SUBS). Univariate and multivariate analyses identified prognostic factors in PDS, IDS and DPS groups and subgroups.Results: There were no differences in overall survival between the PDS, IDS and DPS groups. Surgery level was significantly associated with overall survival in the whole cohort (p<0.001), the PDS and IDS groups, but not in the DPS group. More patients with RS achieved no residual tumour (RT), but overall survival was not superior compared to no RT in the SS group. In 66 patients with no RT there were no differences in overall survival between those who underwent PDS, IDS and DPS. Chemotherapy with platinum/paclitaxel tended to improve survival. RT, World Health Organisation (WHO) performance status and histology were prognostic factors for overall survival in the whole cohort.Conclusion: No RT remains the objective, whether PDS, IDS or DPS is performed, and no differences in overall survival were found in the three treatment groups.

Prognostic value of circulating VEGFR2+ bone marrow-derived progenitor cells in patients with advanced cancer - Corrected Proof

2012-02-27

Abstract: We hypothesised that host-related markers, possibly reflecting tumour aggressiveness, such as circulating endothelial cells (CEC) and circulating VEGFR2+ bone marrow-derived (BMD) progenitor cells, could have prognostic value in patients with advanced cancer enrolled in early anticancer drug development trials.Baseline CECs (CD45–CD31+CD146+7AAD– cells) and circulating VEGFR2+-BMD progenitor cells (defined as CD45dimCD34+VEGFR2+7AAD– cells) were measured by flow-cytometry in 71 and 58 patients included in phase 1 trials testing novel anti-vascular or anti-angiogenic agents. Correlations between levels of CECs, circulating VEGFR2+-BMD progenitor cells, clinical and biological prognostic factors (i.e. the Royal Marsden Hospital (RMH) score), and overall survival (OS) were studied.The median value of CECs was 12 CEC/ml (range 0–154/ml). The median level of VEGFR2+-BMD progenitor cells was 1.3% (range 0–32.5%) of circulating BMD-CD34+ progenitors. While OS was not correlated with CEC levels, it was significantly worse in patients with high VEGFR2+-BMD progenitor levels (>1%) (median OS 9.0 versus 17.0months), and with a RMH prognostic score >0 (median OS 9.0 versus 24.2months). The prognostic value of VEGFR2+-BMD progenitor levels remained significant (hazard ratio (HR)=2.3, 95% confidence interval (CI), 1.1–4.6, p=0.02) after multivariate analysis. A composite VEGFR2+-BMD progenitor level/RHM score ⩾2 was significantly associated with an increased risk of death compared to scores of 0 or 1 (median OS 9.0 versus 18.4months, HR=2.6 (95%CI, 1.2–5.8, p=0.02)).High circulating VEGFR2+-BMD progenitor levels are associated with poor prognostics and when combined to classical clinical and biological parameters could provide a new tool for patient selection in early anticancer drug trials.