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• Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function.

  Authors: Rafael Morales-Barrera, Joaquim Bellmunt, Cristina Suárez, Claudia Valverde, Marta Guix, Cesar Serrano, Manuel Gallén, Joan Carles

  European journal of cancer (Oxford, England : 1990).

  BACKGROUND: Cisplatin-based combination chemotherapy is the mainstay of treatment for locally advanced or metastatic urothelial carcinoma. However, standard dose schedule of cisplatin cannot be usedBACKGROUND: Cisplatin-based combination chemotherapy is the mainstay of treatment for locally advanced or metastatic urothelial carcinoma. However, standard dose schedule of cisplatin cannot be used in patients with impaired renal function. We evaluated the safety and efficacy of gemcitabine and a split dose administration of cisplatin in patients with renal dysfunction. PATIENTS AND METHODS: Patients with locally advanced or metastatic urothelial carcinoma with creatinine clearance between 35 and 59ml/min received gemcitabine 2500mg/m(2) and cisplatin 35mg/m(2) on day 1 and day 15 for an every 28day schedule. RESULTS: Between March 2004 and November 2009, 38 patients were treated. Median creatinine clearance was 49ml/min. Median number of cycles per patient was 3 (1-7). There were 15 partial responses (39%) and 12 patients had stable disease (31%). Median progression free survival and overall survival were 3.5 and 8.5months (mo), respectively. Grade 3-4 haematological toxicities were: neutropenia 9%, anaemia 6% and thrombocytopenia 16%. No patient developed renal toxicity. CONCLUSIONS: Biweekly gemcitabine and cisplatin is an active and feasible regimen in this subset of patients and could be an option for unfit patients. However, results seem not to be superior to those obtained with carboplatin based regimens in this population of patients.

• Clear cell sarcoma of the kidney: A review.

  Authors: S L M Gooskens, R Furtwängler, G M Vujanic, J S Dome, N Graf, M M van den Heuvel-Eibrink

  European journal of cancer (Oxford, England : 1990).

  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 CCSKClear 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.

• Quality-of-life among head and neck cancer survivors at one year after treatment - A systematic review.

  Authors: W K W So, R J Chan, D N S Chan, B G M Hughes, S Y Chair, K C Choi, C W H Chan

  European journal of cancer (Oxford, England : 1990).

  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 toBACKGROUND: 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.

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

  Authors: Marianne Jensen Hjermstad, Mia Bergenmar, Sheila E Fisher, Sébastien Montel, Ourania Nicolatou-Galitis, Judith Raber-Durlacher, Susanne Singer, Irma Verdonck-de Leeuw, Joachim Weis, Noam Yarom, Bente B Herlofson

  European journal of cancer (Oxford, England : 1990).

  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 lifeAIMS: 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.

  Authors: J Faivre, V Dancourt, B Denis, E Dorval, C Piette, Ph Perrin, J M Bidan, C Jard, S Jung, R Levillain, J Viguier, J F Bretagne

  European journal of cancer (Oxford, England : 1990).

  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) whichBACKGROUND: 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.

• Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial.

  Authors: Andreas Obermair, Monika Janda, Jannah Baker, Srinivas Kondalsamy-Chennakesavan, Alison Brand, Russell Hogg, Thomas W Jobling, Russell Land, Tom Manolitsas, Marcelo Nascimento [......] Karfai Tam, Karen Chan, David H Wrede, Selvan Pather, Bryony Simcock, Rhonda Farrell, Gregory Robertson, Graeme Walker, Anthony McCartney, Val Gebski

  European journal of cancer (Oxford, England : 1990). 48(8):1147-1153.

  AIM: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS: Between October 2005 and June 2010, 760 patients with apparentAIM: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS: Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. RESULTS: The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107min, and median length of hospital stay was 2 and 5days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). CONCLUSIONS: Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

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

  Authors: Zhenjie Wu, Jun Ouyang, Zhenhua He, Sen Zhang

  European journal of cancer (Oxford, England : 1990).

  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 aBACKGROUND: 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.

• Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis.

  Authors: Bradley J Monk, Thomas J Herzog, Stanley B Kaye, Carolyn N Krasner, Jan B Vermorken, Franco M Muggia, Eric Pujade-Lauraine, Youn C Park, Trilok V Parekh, Andres M Poveda

  European journal of cancer (Oxford, England : 1990).

  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).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/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3weeks or PLD 50mg/m(2) 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.

• Stem cells in breast tumours: Are they ready for the clinic?

  Authors: Matthew P Ablett, Jagdeep K Singh, Robert B Clarke

  European journal of cancer (Oxford, England : 1990).

  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, wasThe 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?

• Specific-site methylation of tumour suppressor ANKRD11 in breast cancer.

  Authors: Sue Ping Lim, Nick C Wong, Rachel J Suetani, Kristen Ho, Jane Lee Ng, Paul M Neilsen, Peter G Gill, Raman Kumar, David F Callen

  European journal of cancer (Oxford, England : 1990).

  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 withANKRD11 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.

  Authors: Scott M Schuetze, Lili Zhao, Rashmi Chugh, Dafydd G Thomas, David R Lucas, Gino Metko, Mark M Zalupski, Laurence H Baker

  European journal of cancer (Oxford, England : 1990).

  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 butBACKGROUND: 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.

• Risk adapted chemotherapy for localised Ewing's sarcoma of bone: The French EW93 study.

  Authors: Nathalie Gaspar, Annie Rey, Perrine Marec Bérard, Jean Michon, Jean Claude Gentet, Marie Dominique Tabone, Henri Roché, Anne Sophie Defachelles, Odile Lejars, Emmanuel Plouvier, Claudine Schmitt, Binh Bui, Patrick Boutard, Sophie Taque, Martine Munzer, Jean-Pierre Vannier, Dominique Plantaz, Natacha Enz-Werlé, Odile Oberlin

  European journal of cancer (Oxford, England : 1990).

  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 histologicalAIM 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.

• Population-based evidence of increased survival in human papillomavirus-related head and neck cancer.

  Authors: Mari Nygård, Bjarte Aagnes, Freddie Bray, Bjørn Møller, Jon Mork

  European journal of cancer (Oxford, England : 1990).

  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 cellBACKGROUND: 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.

• Mammographic changes resulting from benign breast surgery impair breast cancer detection at screening mammography.

  Authors: Vivian van Breest Smallenburg, Lucien E M Duijm, Adri C Voogd, Frits H Jansen, Marieke W J Louwman

  European journal of cancer (Oxford, England : 1990).

  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 examinationsPURPOSE: 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.

• Adrenal function in adult long-term survivors of nephroblastoma and neuroblastoma.

  Authors: Marjolein van Waas, Sebastian J C M M Neggers, Judith P van Eck, Max M van Noesel, Aart-Jan van der Lely, Frank H de Jong, Rob Pieters, Marry M van den Heuvel-Eibrink

  European journal of cancer (Oxford, England : 1990).

  BACKGROUND: Adrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy. OBJECTIVE:BACKGROUND: Adrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy. OBJECTIVE: To assess adrenal function and its metabolic effects in survivors after adrenalectomy. METHODS: In this cross-sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1μg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t=30) and 60min. Homoeostatic Model Assessment (HOMA) was calculated. RESULTS: Adrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503nmol/l) (N=46) than in survivors with both adrenals intact (mean 393nmol/l, P=0.002) (N=52), and than in controls (mean 399nmol/l, P=0.013) (N=49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P<0.001), LDL-C (P=0.004), apolipoprotein-B (P<0.001) and HOMA (P=0.008). CONCLUSIONS: No adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma.

• 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.

  Authors: I Le Ray, S Dabakuyo, G Crehange, M Bardou, L Arnould, J Fraisse, P Fumoleau, B Coudert, S Causeret, P Arveux, P Maingon, F Bonnetain

  European journal of cancer (Oxford, England : 1990).

  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 mayBACKGROUND: 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.

• 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?

  Authors: F Bonnetain, J F Bosset, J P Gerard, G Calais, T Conroy, L Mineur, O Bouché, P Maingon, O Chapet, L Radosevic-Jelic, N Methy, L Collette

  European journal of cancer (Oxford, England : 1990).

  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 localBACKGROUND: 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 R(2)) 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 R(2)=0.88. Neoadjuvant treatment effects on LC (R(2)=0.17) or DP (R(2)=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.

• 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.

  Authors: Srinivas Kondalsamy-Chennakesavan, Monika Janda, Val Gebski, Jannah Baker, Alison Brand, Russell Hogg, Thomas W Jobling, Russell Land, Tom Manolitsas, Marcelo Nascimento [......] Karfai Tam, Karen Chan, David H Wrede, Selvan Pather, Bryony Simcock, Rhonda Farrell, Gregory Robertson, Graeme Walker, Anthony McCartney, Andreas Obermair

  European journal of cancer (Oxford, England : 1990).

  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 endometrialAIMS: 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.

  Authors: Ting Hu, Shuang Li, Yile Chen, Jian Shen, Xiong Li, Kecheng Huang, Ru Yang, Li Wu, Zhilan Chen, Yao Jia [......] Jun Xu, Qinghua Zhang, Ling Xi, Dongrui Deng, Hui Wang, Shixuan Wang, Weiguo Lv, Changyu Wang, Xing Xie, Ding Ma

  European journal of cancer (Oxford, England : 1990).

  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 theOBJECTIVE: 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.

• Long term renal toxicity of ifosfamide in adult patients - 5year data.

  Authors: James K Farry, Carlos D Flombaum, Sheron Latcha

  European journal of cancer (Oxford, England : 1990).

  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 otherIfosfamide 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/1.73m(2). 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.

• Prediction of prognosis after trimodal therapy in patients with locally advanced squamous cell carcinoma of the oesophagus.

  Authors: Michael Stahl, Nils Lehmann, Martin K Walz, Martin Stuschke, Hansjochen Wilke

  European journal of cancer (Oxford, England : 1990).

  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: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.

  Authors: Donnette A Dabydeen, Jyothi P Jagannathan, Nikhil Ramaiya, Katherine Krajewski, Fabio A B Schutz, Daniel C Cho, Ivan Pedrosa, Toni K Choueiri

  European journal of cancer (Oxford, England : 1990).

  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. WeBACKGROUND: 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.

  Authors: Carlos A Garcia-Etienne, Mariano Tomatis, Joerg Heil, Kay Friedrichs, Rolf Kreienberg, Andreas Denk, Marion Kiechle, Fatemeh Lorenz-Salehi, Rainer Kimmig, Günter Emons, Mahmoud Danaei, Volker Heyl, Uwe Heindrichs, Christoph J Rageth, Wolfgang Janni, Lorenza Marotti, Marco Rosselli Del Turco, Antonio Ponti

  European journal of cancer (Oxford, England : 1990).

  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 trendINTRODUCTION: 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.

• 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).

  Authors: K Johnston, A R Levy, P Lorigan, M Maio, C Lebbe, M Middleton, A Testori, C Bédane, C Konto, A Dueymes, U Sbarigia, M van Baardewijk

  European journal of cancer (Oxford, England : 1990).

  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 patientsOBJECTIVE: 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?

  Authors: Laetitia Huiart, Anne-Déborah Bouhnik, Dominique Rey, Carole Tarpin, Camille Cluze, Marc Karim Bendiane, Patrice Viens, Roch Giorgi

  European journal of cancer (Oxford, England : 1990).

  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 persistenceBACKGROUND: 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.

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