European Journal of Cancer

Editorial board

2010-02-01

EJC NEWS, Issue 3, 2010

2010-02-01

New data tells us more about cancer incidence in North Africa

Roberto Zanetti, Mohammed Adnane Tazi, Stefano Rosso — 2009-12-23

Abstract: Over the last few years, Cancer Registries in North Africa (Morocco, Algeria, Tunisia, Libya and Egypt) increased in number from one to nine, and now covers 13% of the total regional population. Their data can be considered of good or acceptable quality, according to available indicators. The pattern of risk shown by these Registries is quite unique. The total cancer burden in the North African countries is between one third and one half of what is observed in Europe. The overall incidence rate in men (world age standardised, per 100,000) ranges from 86.3 in Sétif, Algeria, to 156.1 in Garbiah, Egypt. The range is similar in women: from 80.3 in Sétif to 164.0 in Algier, both in Algeria. The case mix and the level of rates are quite homogeneous in the countries considered. The most frequent cancers are the same as in Europe (Lung, Breast and Prostate). This pattern completely differs from that of Central and Southern African countries, where infection-related cancers are predominant. The well-known excess risk for nasopharyngeal carcinoma in this area is confirmed, with rates reaching the level of 5.4 in men and 1.9 in women, which is 10 times higher than that in Europe.

Serum 25-hydroxyvitamin D at pregnancy and risk of breast cancer in a prospective study

2009-12-18

Abstract: Background: Several laboratory and epidemiological studies have inversely linked endogenous vitamin D and the risk of breast cancer. The acquisition of vitamin D over time on the relative risk (RR) of the disease development is not known. In a longitudinal study, we evaluated the association between vitamin D levels at pregnancy over time with the risk of breast cancer, and pregnancy-associated breast cancer.Method: The risk for subsequent development of breast cancer associated with serum 25-hydroxyvitamin (25-OHD) levels was assessed for consecutive (1st and 2nd pregnancy) samples of 100 cases, with mean lag times (μt) of 7.4 and 4.6 years between sampling and the diagnosis, and matched (parity, age, year, season) controls. Pregnancy-associated breast cancer (PABC, 111 case–control pairs, μt=1year) risk was also studied. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the lowest quintile as the reference.Results: Serum 25-OHD level was not associated with an increased risk neither at the 1st nor at the 2nd pregnancy samples (OR=1.4, 95%CI 0.6–3.4; OR 1.4, 95%CI 0.7–2.8, respectively), but was associated with an increased risk of PABC (OR=2.7, 95%CI 1.04–6.7).Conclusion: Generally, vitamin D may not be related to breast cancer risk but the increased PABC risk fits the association of vitamin D with the most aggressive cancers, and warrants caution with vitamin D supplementation during pregnancy.

Therapeutic indications in oncology: Emerging features and regulatory dynamics

Giovanni Tafuri, Hubert G.M. Leufkens, Richard Laing, Francesco Trotta — 2009-12-28

Abstract: The regulatory route leading to the definition of therapeutic indications of new compounds as well as extensions of indication (EoI) of already approved ones is a challenging process. If new anticancer drugs reach the market with a lack of complete evidence, this usually leads regulators to request additional data, post approval commitments or restrictions in therapeutic indications.This study aims at quantifying the time needed for anticancer drugs approved by the EMEA to get an extension, the rates and characteristics of extensions approved, and at exploring the regulatory process leading to the definition of new indications.A total of 103 therapeutic oncological indications, related to a cohort of 43 anticancer drugs, were retrieved between 1995 and 2008. The median time occurring between different indications for the same compound (defined as Time to New Extension, TtNE) significantly decrease from about 81 months in 1996 to 6 months in 2006. Twenty-four out of 43 approved anticancer medicines (about 56%) have only a single therapeutic indication, 12 of which were approved before 2005.When considering two different cohorts of drugs in relation to the time of approval (1995–2004 versus 2005–2008), although not statistically significant, the older cohort tended to have a decreased probability of having EoI when compared to the new cohort (OR=0.27; 95% confidence interval (CI): 0.07–1.04). With regard to the type of EoI (n=60), our findings showed that in 48% of cases the initially approved indication was extended to treat a different tumour, in 37% of cases the extension consisted in a switch of line within the same therapeutic indication. The other two types of indication broadening refer to a different tumour stage (8%) and to the inclusion of a new patient population (7%).The analysis of indication restrictions showed that in 20 cases out of 50 (40%) therapeutic indications were restricted by the Committee for Medicinal Products for Human Use (CHMP) during the assessment, with 60% of the restrictions occurring in 2006–2007.This study adds three main pieces of information: (i) the majority of anticancer drugs still have a single indication regardless of the year of approval; (ii) the time needed to obtain an extension of indication has decreased significantly over the last decade and (iii) a highest rate of regulatory restrictions is matched to shorter clinical developments.

No more axillary dissection in patients with ductal intraepithelial neoplasia (DIN)

2010-01-25

Abstract: Although it has been shown that axillary dissection (AD) is unnecessary and without a rational basis in patients with pure ductal intraepithelial neoplasia (DIN), it is evident from the literature that AD (i.e., in the USA and in the UK) has been still recently performed. Furthermore sentinel lymph node biopsy (SLNB) is not usually required in all cases of DIN, but may be indicated in certain specific cases. Even if the SLNB is positive, AD should not be performed immediately but only in cases where an invasive component is found on definitive pathological examination of the DIN lesions.

Chemotherapy-Induced Peripheral Neurotoxicity assessment: A critical revision of the currently available tools

2010-01-04

Abstract: Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way.CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made.In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison.

The validation of a simulation model incorporating radiation risk for mammography breast cancer screening in women with a hereditary-increased breast cancer risk

2009-11-30

Abstract: Introduction: For women with a BRCA1 or BRCA2 mutation or a strong family history of breast cancer, there is no clear estimation of the risk of tumour induction versus the beneficial effects of mammography screening available. This study aims to validate the Simulation Model on Radiation Risk and breast cancer Screening (SiMRiSc) model in these women, which can provide information on the benefits and risks of screening for breast cancer for various screening scenarios.Methods: The simulation model for breast cancer screening was developed and the values for model parameters including cancer induction due to radiation were derived from the literature. The simulation model was validated by comparing the outcome data of the model with the data from three published screening studies of women with an increased hereditary breast cancer risk. A sensitivity analysis was used to estimate the error margins of the outcome data and to analyse the sensitivity of the simulation model to each parameter.Results: The model predicted 71±4% of the reported tumours. When excluding the excess number of incident tumours detected in the first screening round, the model predicted 85±6% of the tumours reported. The model was most sensitive to changes in the parameters related to lifetime breast cancer risk and sensitivity of mammography.Conclusions: We conclude that the simulation model is suitable for the provision of accurate benefits’ and risks’ estimations necessary for the refinement of the screening guidelines for women at an increased risk of breast cancer.

Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to α1-acid glycoprotein plasma levels

2009-12-16

Abstract: Aim of the study: To determine the pharmacokinetics of gimatecan, a camptothecin with a lipophilic substitution in position 7, given orally to patients participating in the phase I study.Methods: Pharmacokinetics was evaluated in 78 patients after oral daily dose for 5days a week for 1, 2 or 3 weeks by HPLC with a fluorescence detector.Results: Gimatecan was mainly present in plasma as lactone (>85%), the active form as DNA-topoisomerase I poison. The AUC0–24 on the first day of treatment normalised per daily dose (mg/m2), ranged from 194 to 2909ngh/mL/mg/m2. The half-life was 77.1±29.6h, consequently Cmax and AUC rose 3–6-fold after multiple dosing. Multivariate analysis indicated the daily dose (p<0.0001) and the α1-acid glycoprotein (AGP) plasma levels (p<0.0001) as main predictors of gimatecan AUC0–24. In the overall analysis, daily dose and AGP plasma levels explained 85% of the deviance. The hydroxy metabolite ST1698 was present in plasma at low levels with AUC values of 5–15% of gimatecan. In mice, orally treated with gimatecan, plasma and tissue levels were 2-fold higher after treatment with a pro-inflammatory agent causing AGP induction.Conclusions: Gimatecan is orally absorbed and its variable plasma levels seem to be related to AGP plasma concentrations. Data obtained in mice, together with the fact that AGP levels largely exceeded gimatecan plasma concentrations, suggest that the increased gimatecan levels in patients with high AGP levels are not related to the binding of the drug to AGP with consequent reduced tissue drug distribution, but possibly to other mechanism associated with inflammation being AGP simply a marker of the inflammation process.

The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival

2009-12-14

Abstract: Aims of the study: There are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a ⩾30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC.Methods: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n=656) and validated in M-treated men (n=333).Results: Four independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0–1 factors, intermediate: 2 factors and poor: 3–4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p<0.0001); 30% PSAD in 78%, 66% and 58% of men (p<0.001); and measurable disease response in 19%, 9% and 5% of men (p=0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively.Conclusions: Risk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed.

A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer

2009-12-14

Abstract: Aim: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer.Methods: Previously untreated patients with PC were randomly allocated to Z-360 120mg, 240mg or placebo. Z-360/placebo was given on day –3 and gemcitabine 1000mg/m2 commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded.Results: Thirty-three patients with a median age of 62years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120mg, 240mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain.Conclusions: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Efficacy of data capture for patient-reported toxicity following radiotherapy for prostate or cervical cancer

2009-12-21

Abstract: We investigated the efficacy of data capture of patient-reported toxicity following radiotherapy by comparing electronic and paper formats. Patient-reported toxicity questionnaires based on items from the NCI Common Terminology Criteria for Adverse Events (CTCAE) were created for patients receiving radiotherapy. Electronic and paper questionnaires had identical questions. Thirty seven gynaecological cancer and 40 prostate cancer patients completed questionnaires. Both questionnaire formats (electronic and paper) were completed by each patient at time points before and after radiotherapy. The average questionnaire and subsection scores for each format were compared directly and by using intra-class correlation (ICC) coefficients. The internal consistency/reliability was assessed by determining Cronbach’s α coefficient. Patient preference for questionnaire format including clarity and ease-of-use was recorded. 324 questionnaires were collected as part of this study. A similar pattern of average subsection scores was found for the electronic and paper questionnaires. ICC coefficients for the mean overall questionnaire scores and subsection scores were high (>0.8). Cronbach’s α was generally greater than 0.6, indicating that the reliability was high. Of the patients that responded, 27.3% preferred the electronic format, 25.7% preferred the paper format and 47% had no preference. The average time taken to complete a questionnaire was about 9 minutes for each format. The different questionnaire formats measured toxicity effects consistently and were reliable for both gynaecological cancer and prostate cancer patients. The survey indicated that patients found the questionnaires clear, easy to understand and straightforward to complete. Electronic data capture of patient-reported toxicity for CTCAE is feasible and acceptable.

Historical cross-trial comparisons for competing treatments in advanced breast cancer – An empirical analysis of bias

C.K. Lee, S.J. Lord, M.R. Stockler, A.S. Coates, V. Gebski, R.J. Simes — 2009-12-25

Abstract: Purpose: Randomised controlled trials (RCTs) provide optimal evidence to assess the benefits of new treatments. However, clinicians routinely rely on cross-trial comparisons to assess competing treatments when head-to-head randomised comparisons are unavailable. We investigate the validity of cross-trial comparisons using individual patient data (IPD) where patients received the same treatment protocol. We also examine the extent to which statistical adjustment for baseline characteristics can account for inter-trial differences in outcomes.Patients and methods: We used pooled IPD of 378 women with advanced breast cancer assigned to oral cyclophosphamide, intravenous methotrexate and 5-fluorouracil (CMF) in the control arms of three first-line treatment RCTs (ANZ8101, ANZ8614 and ANZ0001) conducted between 1982 and 2001. The Kaplan–Meier method was used to compare progression-free survival (PFS) and overall survival (OS) across trials. Proportional hazard models were constructed to estimate the hazard rates across trials after adjustment for baseline characteristics.Results: The distribution of baseline characteristics varied across trials. There was a statistically significant difference in survival among women treated with CMF in these trials (logrank p=0.009). The median OS were 17.7, 10.3 and 10.1months for 0001, 8101 and 8614, respectively. The hazard ratios for survival, adjusted for baseline characteristics differences, were 1.44 (8614) and 1.45 (8101) compared to 0001 (p=0.03). PFS did not differ across trials (logrank p=0.38).Conclusions: Caution should be exercised when interpreting results from historical cross-trial comparisons even if the adjustment of baseline prognostic characteristics can be performed. Cross-trial comparisons have some role in hypothesis-generating, identifying and prioritising promising treatments for further investigation; however RCTs are still essential to guide sound clinical practice.

Prognostic impact of thymidine phosphorylase expression in breast cancer – Comparison of microarray and immunohistochemical data

2009-12-21

Abstract: Contrary findings exist according to the prognostic and predictive impact of thymidine phosphorylase (TP) expression in breast cancer. Goal of our study was to investigate TP expression on the mRNA level by microarray analysis in a large cohort of 1781 breast cancers and to analyse its prognostic impact. Furthermore we compared mRNA expression and immunohistochemical data to explain discrepancies between different studies.The prognostic value of TP mRNA expression was analysed among n=622 untreated patients. Strong expression in the subgroup of n=213 ER-negative cancer correlates with improved survival (P=0.012). In contrast, no difference in survival was detected in the ER-positive group. We also failed to observe a prognostic value of TP mRNA among n=435 endocrine-treated patients as well as n=111 CMF-treated patients.In an unsupervised analysis, TP clustered together with genes expressed in immune cells. Moreover, among normal tissues the highest TP mRNA expression was found in tissues of the immune system. The profile of TP expression in breast cancers correlates to a metagene of interferon induction whereas the expression of TP among normal tissues correlates to a metagene for macrophages. When comparing microarray data with immunohistochemistry from the same n=51 samples, there was no correlation with stained carcinoma cells. In contrast, the correlation with stromal staining was highly significant (P<0.001). Thus TP mRNA from microarray mainly reflects expression in stromal and immune cells. This could account for discrepant results from mRNA and IHC studies.In conclusion, the tumour infiltrating immune cells seem to be a major source of TP expression and predict a favourable prognosis in ER-negative breast cancer. Our data point to a role of TP in host immune response.

Effect of oral clodronate on bone mass, bone turnover and subsequent metastases in women with primary breast cancer

Eugene McCloskey, Alexander Paterson, John Kanis, Rita Tähtelä, Trevor Powles — 2009-12-25

Abstract: Breast cancer treatments have been associated with accelerated bone loss and increased osteoporosis risk. In a subgroup analysis of a randomised, double-blind, placebo-controlled study, we compared the changes in spine and total hip bone mineral density (BMD) and biochemical markers of bone turnover in women with primary breast cancer who had received standard therapy plus either oral clodronate 1600mg/d (n=419) or placebo (n=432) for 2years. After 2years, spine BMD was 1.92% higher in patients who received clodronate instead of placebo (P<0.0001) and total hip BMD was 1.29% higher (P=0.002 versus placebo). Patients who received clodronate had a median 26% reduction in levels of serum N-terminal pro-peptide of type I procollagen (PINP) – a marker of bone turnover – after 2years of therapy. This compares with a median 5% increase in patients who received placebo (P<0.0001). Effects on BMD, but not biochemical markers, persisted for up to 3years post-treatment. Early changes in PINP were associated with changes in BMD and the likelihood of developing bone metastases. This study shows the use of oral clodronate during primary breast cancer treatment is associated with reduced bone turnover and protection against bone metastases.

Factors related to being sunburnt in 7-year-old children in Sweden

Ylva E. Rodvall, Carl-Fredrik Wahlgren, Henrik T. Ullén, Kerstin E. Wiklund — 2009-10-08

Abstract: Background: Epidemiologic research shows that being sunburnt as a child is an important risk factor for cutaneous malignant melanoma (CMM). The purpose of this study was to investigate sunburn in relation to tanning habits and complexion among 7-year-old children living at different latitudes in Sweden.Methods: Two municipalities were chosen at latitudes 65°N and 68°N in the north of Sweden and two at latitude 57°N in the south. Children born in 1994 and registered in the municipalities were to be included (N=1676). A questionnaire was sent to their parents asking about their children’s tanning habits, and the children were examined. The analysis set comprised 1360 children who participated in the examination and whose parents answered the questionnaire (81.1%).Results: Twelve percent of all children had been sunburnt during the first 2 years of life compared to 44% between 2 and 4 years and 67% after 4. The children in the south at latitude 57°N compared to Kiruna at latitude 68°N and Piteå at 65°N had a higher risk of ever being sunburnt during the first 2 years of life OR=1.87 (95% confidence interval (CI) 1.11–3.14) and 1.66 (0.95–2.90), respectively. The differences diminished with age. Sunscreen was an independent risk factor of being sunburnt between 2 and 7 years of age (not or seldom using sun screen was protective). Photosensitive skin type was the main risk factor for sunburns.Conclusion: Swedish children are frequently sunburnt and children living in the south are more sunburnt than those in the north. Sunscreens that were seldom used or not used at all were found to be protective. These results support previous reports that photosensitive skin type is an important risk factor for suffering sunburn as a child and therefore increases the risk of cutaneous malignant melanoma.

Personality is associated with health status and impact of cancer among melanoma survivors

Floortje Mols, Cynthia Holterhues, Tamar Nijsten, Lonneke V. van de Poll-Franse — 2009-10-12

Abstract: Objective: We aimed to investigate the prevalence of Type D personality (the conjoint effects of negative affectivity and social inhibition) among melanoma survivors and to obtain insight into its effects on health status, impact of cancer and health care utilisation.Methods: We selected all patients diagnosed with melanoma between 1998 and 2007 from three large regional hospitals in the Netherlands. In total, 699 survivors, alive in January 2008, received a questionnaire including Type D personality scale (DS14), impact of cancer questionnaire (IOC) and SF-36 and 80% responded (n=562).Results: Twenty-two percent of survivors (n=125) were classified as Type D. They reported a clinically and statistically significant worse general health (57.8 versus 75.6), social functioning (73.1 versus 88.7), mental health (61.7 versus 80.6), more emotional role limitations (67.8 versus 89.4) and less vitality (54.5 versus 72.8) than non-Type D patients. Additionally, they reported a statistically and clinically relevant higher impact of cancer on body changes, negative self-evaluation, negative outlook on life, life interferences and health worry. Furthermore, they were more worried about the influence of the sun on their skin and acted accordingly. No differences were found in health care utilisation.Conclusions: Type D personality has a distinct negative impact on health status in melanoma survivors and is an important factor to screen for in clinical practice. Giving special attention to these patients is important while they are more likely to experience a strong impact of cancer which cannot be explained by socio-demographical or clinical characteristics.

Macronutrients, fatty acids, cholesterol and pancreatic cancer

2009-10-22

Abstract: A role of diet and nutrition in pancreatic carcinogenesis has been suggested, but the association between selected macronutrients, fatty acids, cholesterol and pancreatic cancer remains controversial. We analysed data from a hospital-based case-control study conducted in Italy between 1991 and 2008, including 326 cases (174 men and 152 women) with incident pancreatic cancer, and 652 controls (348 men and 304 women) frequency-matched to cases by sex, age and study centre. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression models conditioned on age, sex and study centre, and adjusted for year of interview, education, tobacco smoking, history of diabetes and energy intake. A positive association was found for animal proteins (OR=1.85 for the highest versus the lowest quintile of intake; 95% CI: 1.15–2.96; p for trend=0.039), whereas a negative association was observed for sugars (OR=0.52; 95% CI: 0.31–0.86; p for trend=0.003). Non-significant negative associations emerged for vegetable proteins (OR=0.69) and polyunsaturated fatty acids (OR=0.67). In conclusion, a diet poor in animal proteins and rich in sugars (mainly derived from fruit) appears to have a beneficial effect on pancreatic cancer risk.

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe

2009-10-26

Abstract: Introduction: In the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year – more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet.Patients and methods: A multicentre case–control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression.Results: When controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR=1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators – comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR=1.60 (1.28, 2.00); and for unemployment OR=1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR=1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community).Conclusion: Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

Cancer incidence among Iranian immigrants in Sweden and Iranian residents compared to the native Swedish population

2009-11-05

Abstract: Background and goals: Comparing cancer incidence by migrant studies is one of the main approaches to generate hypotheses on the aetiology of cancer. Immigrant studies are most informative when cancer incidence data are available from both the source and the host country.Methods: The age standardised incidence rate (ASR) and standardised incidence ratio (SIR) of cancers among the Iranian immigrants were compared to the native Swedish population as the standard population by using the Swedish Family-Cancer Database (FCD) from 1958 to 2006. We also compared SIRs between Iranian immigrants and Iranian residents for whom the data were derived from the Iranian national cancer registry report of 2006.Results: Among the 65,501 Iranian immigrants, the median age at immigration was 26 years and the median length of stay was 16 years. Their all-cancer ASR was 175.3 and 153.1 per 100,000 person years for males and females, respectively, during the period from 1996 to 2006, higher than for the Iranian residents. The ASRs increased among the male Iranian immigrants during the past two decades but were stable among females. The risk for all-cancers among Iranian immigrants was lower than that for the native Swedish population. The Iranian immigrants had a significantly increased risk for male urinary bladder (SIR=1.40) and thyroid cancers (2.64) compared to the Swedes.Conclusion: The reasons for the decreased risk for all-cancers among the Iranian immigrants remain to be established. The ASR difference between the Iranian immigrants and the Iranian residents may be due to the differences between the registry systems, selected immigrant groups and environmental exposures.

Self-reported symptoms of faecal incontinence among long-term gynaecological cancer survivors and population-based controls

2009-11-19

Abstract: Aim of the study: To make a comprehensive, detailed inventory of gastrointestinal symptoms reported by gynaecological cancer survivors and control women from the general population.Method: We identified a cohort of 789 eligible women in the Stockholm and Gothenburg areas, treated with pelvic radiotherapy during the period 1991–2003, alone or as combined treatment, for gynaecological cancer. As controls, we randomly recruited 478 women, frequency matched by age and residence from the Swedish Population Registry. We collected data in 2006 by means of a study-specific, validated, postal questionnaire including 351 questions covering symptoms from the pelvic region. We asked about demographics, psychological and quality-of-life issues as well as social functioning.Results: Participation was 78% for cancer survivors and 72% for controls. Mean follow-up was 7.2years. In this large, population-based study, the greatest age-adjusted absolute risk difference between cancer survivors and control women was observed for the symptom defaecation urgency with faecal leakage and the highest age-adjusted relative risk for emptying of all stools into clothing without forewarning.Conclusions: Cancer survivors having undergone pelvic radiotherapy alone or as part of combined treatment between the period 1991–2003 for a gynaecological malignancy had a higher occurrence of long-lasting gastrointestinal symptoms as compared to population controls.

COX-2 expression in chondrosarcoma: A role for celecoxib treatment?

2009-12-10

Abstract: Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth.COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E2 (PGE2) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice.High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. In vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group.We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation.

Multimodal approach using oncolytic adenovirus, cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures

2009-12-14

Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common and often devastating disease without curative treatment when advanced or recurrent. The aim of this study was to assess whether capsid-modified oncolytic adenoviruses have therapeutic efficacy in HNSCC low passage tumour cell cultures and if it could be further improved by combination with cetuximab, radiotherapy and chemotherapy. We investigated which adenoviral capsid modifications allow best gene transfer and cell killing of HNSCC substrates. Gene transfer was assessed using replication-deficient adenoviruses expressing luciferase. Cell killing was studied in vitro and in vivo using oncolytic adenoviruses, which kill tumour cell by viral replication. The most effective capsid-modified oncolytic adenoviruses were combined with HNSCC standard therapies and their efficacy was assessed in vitro as well as in vivo. Cell killing was assessed in vitro by MTS assay and in vivo by HNSCC subcutaneous tumour growth follow-up in nude mice. Cetuximab treatment was found to enrich CD133+ and CD44+ tumour-initiating type cells in tumours grown in mice. Capsid-modified viruses showed increased transduction and oncolysis of HNSCC substrates in comparison to Ad5-based agents. Polylysine (pK7)-modified oncolytic virus resulted in significant tumour growth reduction in vivo. Combination of chemotherapy (cisplatin and 5-fluorouracil), radiotherapy and cetuximab with oncolytic adenovirus therapy resulted in further increases in cell killing effect in vitro and complete eradication of tumours in vivo. Our pre-clinical data suggest that it is feasible and efficacious to combine oncolytic adenoviruses with HNSCC standard therapies into a multimodality treatment regimen for clinical testing in HNSCC patients.

Non-receptor tyrosine kinase Etk regulation of drug resistance in small-cell lung cancer

Linlang Guo, Yuanyuan Zhou, Yanqin Sun, Fan Zhang — 2009-12-11

Abstract: Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase), plays an important role in the apoptosis of epithelial cells. The aim of this study was to investigate whether Etk is involved in the chemoresistance of small cell lung cancer (SCLC) and to correlate the drug resistance associated proteins such as bcl-2, bcl-XL and p53. Drug-resistant small lung cancer cells (H69AR) which were originally developed by ADM and which demonstrated multi-drug resistance to chemotherapeutic agents were used in the study. Western blot analysis revealed that H69AR cells over-expressed the proteins Etk and bcl-XL, but not bcl-2 and p53 when compared to parent H69 cells. Knockdown of Etk expression by Etk-specific small interfering RNA sensitised H69AR cells to chemotherapeutic drugs and inhibited bcl-XL expression but not bcl-2 and p53. Co-immunoprecipitation was performed to further evaluate the relationship between Etk and bcl-XL with anti-Etk and anti-phospho-Etk antibodies. The bcl-XL was accompanied with a robust increase of Etk and tyrosine phosphorylated Etk at Tyr-40 in H69AR cells. In conclusion, our results suggest that non-receptor tyrosine kinase Etk is involved in drug resistance to SCLC by mediating bcl-XL via Tyr(P)-40. The potential approach for downregulation of Etk activity on expression would be a novel, potentially clinically practical strategy for interfering with chemoresistance in SCLC.

Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients

2009-12-14

Abstract: Background: Human prominin-1 (CD133) is a novel pentaspan membrane protein which was originally classified as a marker of primitive haematopoietic and neural stem cells. Cancer stem cells have been isolated and expanded from leukaemia and several solid tumours, and have been associated with metastasis, chemoresistance and relapse. CD133 is recognised as a stem cell marker and is capable of identifying a tumour-initiating subpopulation in brain, colon, melanoma and other solid tumours.Methods: We assessed CD133 mRNA expression levels by RT-QPCR in tumour and matched normal tissue from 64 stages I–III colorectal cancer (CRC) patients and correlated tumour CD133 levels with clinicopathological characteristics and clinical outcome.Results: In four patients, CD133 mRNA was not expressed in tumour or in normal tissue. In the remaining 60 patients, expression levels were higher in tumour than in normal tissue (p=0.001). Higher levels of CD133 expression were associated with shorter relapse-free interval (RFI) (p=0.004) and overall survival (OS) (p<0.0001). In the multivariate analyses, CD133 levels emerged as a prognostic marker for RFI and OS.Conclusions: We have observed longer RFI and OS in patients with lower levels of CD133, regardless of adjuvant treatment and other clinical characteristics. If these findings are confirmed in larger prospective studies, CD133 assessment may prove useful for new diagnostic and therapeutic procedures for CRC patients.

Antitumour activity of NK012, SN-38-incorporating polymeric micelles, in hypovascular orthotopic pancreatic tumour

2009-12-16

Abstract: Human pancreatic cancer is refractory to chemotherapy partly because of blockage to penetration of anticancer agents. This issue must be taken into account particularly for the drug delivery system (DDS). The aim of the present study is to investigate how NK012 (SN-38-incorporating polymeric micelles) categorised as DDS exerts its antitumour effect in an orthotopic pancreatic tumour model compared with gemcitabine and irinotecan hydrochloride (CPT-11), a low-molecular-weight prodrug of a 7-ethyl-10-hydroxy-camptothecin (SN-38).The maximum tolerated doses (MTDs) of NK012 (30mg/kg/d), CPT-11 (66.7mg/kg/d) and gemcitabine (16.5mg/kg/d) were administered to mice bearing human pancreatic cancer cell (SUIT-2) xenografts implanted orthotopically. Antitumour effects of these compounds were evaluated. Drug distribution within the tumour was examined by fluorescence microscopy and high performance liquid chromatography (HPLC).NK012 exerted potent antitumour effects compared with CPT-11 and gemcitabine. A high concentration of NK012 and SN-38 released from NK012 had been observed until 192h. On the other hand, SN-38 converted from CPT-11 was detected only 1h postinjection. Fluorescence from NK012 was detected up to 48h, whereas that from CPT-11 almost disappeared by 24h postinjection.NK012 appeared to exert potent antitumour activity against intractable stroma-rich orthotopic pancreatic tumour xenografts due to its sufficient accumulation followed by the effective sustained release of SN-38 from NK012.

High metastatic efficiency of human sarcoma cells in Rag2/γc double knockout mice provides a powerful test system for antimetastatic targeted therapy

2009-12-23

Abstract: Immunodeficient animal models are invaluable tools to investigate the metastatic propensity of human tumours. However residual immune responses, in particular natural killer (NK) cells, severely hamper the traffic and growth of human tumour cells. We studied whether a genetically modified mouse host lacking T, B and NK immunity allowed an improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lines was studied in double knockout Rag2–/–;γc–/– mice in comparison with NK-depleted nude mice. Rag2–/–;γc–/– mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2–/–;γc–/– was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2–/–;γc–/– mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2–/–;γc–/– mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lines failed to colonise the liver of Rag2–/–;γc–/– mice, independently of their metastatic spread to other sites. In vitro analysis of the molecular mechanisms of liver metastasis of sarcomas implicated liver-produced growth and motility factors, in particular the insulin-like growth factor (IGF) axis. NVP-BEZ235, a specific inhibitor of downstream signal transduction targeting PI3K and mTOR, strongly inhibited liver metastasis of human sarcoma cells. In conclusion, the Rag2–/–;γc–/– mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies.

Informed decision making on PSA testing for the detection of prostate cancer: An evaluation of a leaflet with risk indicator

2009-12-18

Abstract: Background: Population-based screening for prostate cancer (PCa) remains controversial. To help men making informed decisions about prostate specific antigen (PSA) screening a risk indicator (www.uroweb.org) was developed. This risk indicator is embedded in a leaflet that informs men about the pros and cons of PCa screening and enables calculation of the individual risk of having a biopsy detectable PCa.Aim: To assess the effect of providing a leaflet including individualized risk estimation on informed decision making of men, i.e. knowledge about PCa and PSA screening, attitude towards undergoing a PSA test and intention to have a PSA test.Methods: An intervention study among 2000 men, aged 55–65years, randomly selected from the population registry of the city of Dordrecht, the Netherlands, in 2008. Men were sent a questionnaire on knowledge of PCa, attitude and intention to have a PSA test. Men without a history of (screening for) PCa were sent the leaflet and Questionnaire 2 within 2weeks after returning Questionnaire 1. Validated health and anxiety measures were used.Results: One thousand and twenty seven of 2000 men completed Questionnaire 1 (51%), of whom 298 were excluded due to a history of (screening for) PCa. Of the 729 remaining men, 601 completed Questionnaire 2 as well. At the second assessment significantly more men met the requirements of informed decision making (15% versus 33%, p<0.001), more men had relevant knowledge (284/601, 50% versus 420/601, 77%, p<0.001) and the intention to have a PSA test had increased (p<0.001).Conclusions: Providing information on PCa screening combined with individualized risk estimation enhanced informed decision making and may be used for shared decision making on PSA screening of physicians and patients.

89Zr-trastuzumab PET visualises HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft

2009-12-25

Abstract: NVP-AUY922, a potent heat shock protein (HSP) 90 inhibitor, downregulates the expression of many oncogenic proteins, including the human epidermal growth factor receptor-2 (HER2). Because HER2 downregulation is a potential biomarker for early response to HSP90-targeted therapies, we used the 89Zr-labelled HER2 antibody trastuzumab to quantify the alterations in HER2 expression after NVP-AUY922 treatment with HER2 positron emission tomography (PET) imaging.The HER2 overexpressing human SKOV-3 ovarian tumour cell line was used for in vitro experiments and as xenograft model in nude athymic mice. In vitro HER2 membrane expression was assessed by flow cytometry and a radio-immuno assay with 89Zr-trastuzumab. For in vivo evaluation, mice received 50mg/kg NVP-AUY922 intraperitoneally every other day. 89Zr-trastuzumab was injected intravenously 6d before NVP-AUY922 treatment and after 3 NVP-AUY922 doses. MicroPET imaging was performed at 24, 72 and 144h post tracer injection followed by ex-vivo biodistribution and immunohistochemical staining.After 24h NVP-AUY922 treatment HER2 membrane expression showed profound reduction with flow cytometry (80%) and radio-immuno assay (75%). PET tumour quantification, showed a mean reduction of 41% (p=0.0001) in 89Zr-trastuzumab uptake at 144h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo 89Zr-trastuzumab biodistribution and HER2 immunohistochemical staining.NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with 89Zr-trastuzumab PET. This technique is currently under clinical evaluation and might serve as an early biomarker for HSP90 inhibition in HER2 positive metastatic breast cancer patients.

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