Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype.

Gastric cancer incidence and mortality decreased substantially over the last decades in most countries worldwide, with differences in the trends and distribution of the main topographies across regions. To monitor recent mortality trends (1980-2011) and to compute short-term predictions (2015) of gastric cancer mortality in selected countries worldwide, we analysed mortality data provided by the World Health Organization. We also analysed incidence of cardia and non-cardia cancers using data from Cancer Incidence in Five Continents (2003-2007). The joinpoint regression over the most recent calendar periods gave estimated annual percent changes (EAPC) around -3% for the European Union (EU) and major European countries, as well as in Japan and Korea, and around -2% in North America and major Latin American countries. In the United States of America (USA), EU and other major countries worldwide, the EAPC, however, were lower than in previous years. The predictions for 2015 show that a levelling off of rates is expected in the USA and a few other countries. The relative contribution of cardia and non-cardia gastric cancers to the overall number of cases varies widely, with a generally higher proportion of cardia cancers in countries with lower gastric cancer incidence and mortality rates (e.g. the USA, Canada and Denmark). Despite the favourable mortality trends worldwide, in some countries the declines are becoming less marked. There still is the need to control Helicobacter pylori infection and other risk factors, as well as to improve diagnosis and management, to further reduce the burden of gastric cancer.

Patient, primary care physician and specialist expectations of primary care physician involvement in cancer care.

BACKGROUND: In Canada, many health authorities recommend that primary care physicians (PCP) stay involved throughout their patients' cancer journey to increase continuity of care. Few studies have focused on patient and physician expectations regarding PCP involvement in cancer care. OBJECTIVE: To compare lung cancer patient, PCP and specialist expectations regarding PCP involvement in coordination of care, emotional support, information transmission and symptom relief at the different phases of cancer. DESIGN: Canadian survey of lung cancer patients, PCPs and cancer specialists PARTICIPANTS: A total of 395 patients completed questionnaires on their expectations regarding their PCP participation in several aspects of care, at different phases of their cancer. Also, 45 specialists and 232 community-based PCP involved in these patients' care responded to a mail survey on the same aspects of cancer care. RESULTS: Most specialists did not expect participation of the PCP in coordination of care in the diagnosis and treatment phases (65% and 78% respectively), in contrast with patients (83% and 85%) and PCPs (80% and 59%) (p < 0.0001). At these same phases, the best agreement among the 3 groups was around PCP role in emotional support: 84% and more of all groups had this expectation. PCP participation in symptom relief was another shared expectation, but more unanimously at the treatment phase (p = 0.85). In the advanced phase, most specialists expect a major role of PCP in all aspects of care (from 81% to 97%). Patients and PCP agree with them mainly for emotional support and information transmission. CONCLUSION: Lung cancer patient, PCP and specialist expectations regarding PCP role differ with the phase of cancer and the specific aspect of cancer care. There is a need to reach a better agreement among them and to better define PCP role, in order to achieve more collaborative and integrated cancer care.

Therapeutic drug monitoring in cancer - Are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Cigarette smoking and endometrial cancer risk: the modifying effect of obesity.

The objective of this study was to evaluate the association between cigarette smoking and endometrial cancer risk by investigating potential modifying effects of menopausal status, obesity, and exogenous hormones. We pooled data from three case-control studies with the same study design conducted in Italy and Switzerland between 1982 and 2006. Overall, 1446 incident endometrial cancers and 4076 hospital controls were enrolled. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models, conditioned on study and centre, and adjusted for age, period of interview, age at menarche, parity, and body mass index. In comparison with never smokers, current smokers showed reduced endometrial cancer risk (OR: 0.80; 95% CI: 0.66-0.96), with a 28% decrease in risk for smoking >/=20 cigarettes/day. The association did not vary according to menopausal status, oral contraceptive use, or hormone replacement therapy. However, heterogeneity emerged according to body mass index among postmenopausal women, with obese women showing the greatest risk reduction for current smoking (OR: 0.47; 95% CI: 0.27-0.81). In postmenopausal women, obesity turned out to be an important modifier of the association between cigarette smoking and the risk of endometrial cancer. This finding calls for caution in interpreting the favorable effects of cigarette smoking, considering the toxic and carcinogenic effects of tobacco.

Previous thyroid disease and risk of thyroid cancer in Switzerland

A hospital-based case-control study of 86 cases of thyroid cancer and 317 controls was done in the Swiss Canton of Vaud. Patients with thyroid cancer tended to be better educated (odds ratio [OR] 2.1 for greater than or equal to 14 vs. less than or equal to 8 years of education 95% CI 1.1-4.1) and of higher social class than controls. Cases more often had a history of benign thyroid nodules (OR 25.2, 95% CI 7.6-83.6) and non-toxic goitre (OR 5.3, 95% CI 2.5-11.2). Furthermore, patients with thyroid cancer were more likely to have resided in endemic goitre areas (OR 1.7, 95% CI 1.0-3.0) and to have had first-degree relatives affected by benign thyroid disease (OR 3.9, 95% CI 2.1-7.1). Therefore, this study offers quantitative evidence of the association between various thyroid diseases and the risk of thyroid cancer which, despite difficulties in the classification of benign and malignant thyroid diseases, is remarkably consistent in studies from different countries.

The stomach cancer pooling (StoP) project: study design and presentation.

Gastric cancer affects about one million people per year worldwide, being the second leading cause of cancer mortality. The study of its etiology remains therefore a global issue as it may allow the identification of major targets, besides eradication of Helicobacter pylori infection, for primary prevention. It has however received little attention, given its comparatively low incidence in most high-income countries. We introduce a consortium of epidemiological investigations named the 'Stomach cancer Pooling (StoP) Project'. Twenty-two studies agreed to participate, for a total of over 9000 cases and 23 000 controls. Twenty studies have already shared the original data set. Of the patients, 40% are from Asia, 43% from Europe, and 17% from North America; 34% are women and 66% men; the median age is 61 years; 56% are from population-based case-control studies, 41% from hospital-based ones, and 3% from nested case-control studies derived from cohort investigations. Biological samples are available from 12 studies. The aim of the StoP Project is to analyze the role of lifestyle and genetic determinants in the etiology of gastric cancer through pooled analyses of individual-level data. The uniquely large data set will allow us to define and quantify the main effects of each risk factor of interest, including a number of infrequent habits, and to adequately address associations in subgroups of the population, as well as interaction within and between environmental and genetic factors. Further, we will carry out separate analyses according to different histotypes and subsites of gastric cancer, to identify potential different risk patterns and etiological characteristics.

Cigarette smoking and the risk of endometrial cancer.

The risk of endometrial cancer in relation to cigarette consumption was evaluated in a hospital-based case-control study of breast and genital neoplasms conducted in Milan, northern Italy. For the present analysis, 357 women (cases) with histologically confirmed endometrial cancer were compared to a group of 1122 women (controls) admitted for a large spectrum of acute conditions unrelated to smoking or to any of the known or potential risk factors for endometrial cancer. Compared with never-smokers, the multivariate relative risk estimates were for current 0.45 [95% confidence interval (CI) = 0.30-0.70] and 0.86 (95% CI = 0.50-1.46) for ex-smokers. The negative association of endometrial cancer with current smoking was not influenced by menopausal status as well as by other major identified potential confounding factors, i.e. menstrual and reproductive history, body mass index, oral contraceptive or estrogen replacement therapy use and family gynecologic cancer history. However, there was no evidence of a dose-risk effect, since the relative risks were similar in moderate and heavy smokers. The present study confirms that smoking is less frequent in cases hospitalized for endometrial cancer than in a comparison group of patients with non-smoking-related acute conditions. This negative association is perhaps explained in terms of reduced estrogen levels in smokers, though the influence and the importance of some uncontrolled selection bias (due, for instance, to longer hospital stay of smokers even when admission diagnosis was for non-smoking-related conditions) cannot be ruled out.

Two Signatures For A New Blood-Based Test For Colorectal Cancer Screening

Background: Detection rates for adenoma and early colorectal cancer (CRC) are unsatisfactory due to low compliance towards invasive screening procedures such as colonoscopy. There is a large unmet screening need calling for an accurate, non-invasive and cost-effective test to screen for early neoplastic and pre-neoplastic lesions. Our goal is to identify effective biomarker combinations to develop a screening test aimed at detecting precancerous lesions and early CRC stages, based on a multigene assay performed on peripheral blood mononuclear cells (PBMC).Methods: A pilot study was conducted on 92 subjects. Colonoscopy revealed 21 CRC, 30 adenomas larger than 1 cm and 41 healthy controls. A panel of 103 biomarkers was selected by two approaches: a candidate gene approach based on literature review and whole transcriptome analysis of a subset of this cohort by Illumina TAG profiling. Blood samples were taken from each patient and PBMC purified. Total RNA was extracted and the 103 biomarkers were tested by multiplex RT-qPCR on the cohort. Different univariate and multivariate statistical methods were applied on the PCR data and 60 biomarkers, with significant p-value (< 0.01) for most of the methods, were selected.Results: The 60 biomarkers are involved in several different biological functions, such as cell adhesion, cell motility, cell signaling, cell proliferation, development and cancer. Two distinct molecular signatures derived from the biomarker combinations were established based on penalized logistic regression to separate patients without lesion from those with CRC or adenoma. These signatures were validated using bootstrapping method, leading to a separation of patients without lesion from those with CRC (Se 67%, Sp 93%, AUC 0.87) and from those with adenoma larger than 1cm (Se 63%, Sp 83%, AUC 0.77). In addition, the organ and disease specificity of these signatures was confirmed by means of patients with other cancer types and inflammatory bowel diseases.Conclusions: The two defined biomarker combinations effectively detect the presence of CRC and adenomas larger than 1 cm with high sensitivity and specificity. A prospective, multicentric, pivotal study is underway in order to validate these results in a larger cohort.

Mediastinal reinforcement after induction therapy and pneumonectomy: comparison of intercostal muscle versus diaphragm flaps.

OBJECTIVE: Prospective non-randomised comparison of full-thickness pedicled diaphragm flap with intercostal muscle flap in terms of morbidity and efficiency for bronchial stump coverage after induction therapy followed by pneumonectomy for non-small cell lung cancer (NSCLC). METHODS: Between 1996 and 1998, a consecutive series of 26 patients underwent pneumonectomy following induction therapy. Half of the patients underwent mediastinal reinforcement by use of a pedicled intercostal muscle flap (IF) and half of the patients by use of a pedicled full-thickness diaphragm muscle flap (DF). Patients in both groups were matched according to age, gender, side of pneumonectomy and stage of NSCLC. Postoperative morbidity and mortality were recorded. Six months follow-up including physical examination and pulmonary function testing was performed to examine the incidence of bronchial stump fistulae, gastro-esophageal disorders or chest wall complaints. RESULTS: There was no 30-day mortality in both groups. Complications were observed in one of 13 patients after IF and five of 13 after DF including pneumonia in two (one IF and one DF), visceral herniations in three (DF) and bronchopleural fistula in one patient (DF). There were no symptoms of gastro-esophageal reflux disease (GERD). Postoperative pulmonary function testing revealed no significant differences between the two groups. CONCLUSIONS: Pedicled intercostal and diaphragmatic muscle flaps are both valuable and effective tools for prophylactic mediastinal reinforcement following induction therapy and pneumonectomy. In our series of patients, IF seemed to be associated with a smaller operation-related morbidity than DF, although the difference was not significant. Pedicled full-thickness diaphragmatic flaps may be indicated after induction therapy and extended pneumonectomy with pericardial resection in order to cover the stump and close the pericardial defect since they do not adversely influence pulmonary function.

Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide.

Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response.

Validation of the 34-item Supportive Care Needs Survey and 8-item Breast module French versions (SCNS-SF34-Fr and SCNS-BR8-Fr) in breast cancer patients.

This study aimed to assess the psychometric robustness of the French version of the Supportive Care Needs Survey and breast cancer (BC) module (SCNS-SF34-Fr and SCNS-BR8-Fr). Breast cancer patients were recruited in two hospitals (in Paris, France and Lausanne, Switzerland) either in ambulatory chemotherapy or radiotherapy, or surgery services. They were invited to complete the SCNS-SF34-Fr and SCNS-BR8-Fr as well as quality of life and patient satisfaction questionnaires. Three hundred and eighty-four (73% response rate) BC patients returned completed questionnaires. A five-factor model was confirmed for the SCNS-SF34-Fr with adequate goodness-of-fit indexes, although some items evidenced content redundancy, and a one-factor was identified for the SCNS-BR8-Fr. Internal consistency and test-retest estimates were satisfactory for most scales. The SCNS-SF34-Fr and SCNS-BR8-Fr scales demonstrated conceptual differences with the quality of life and satisfaction with care scales, highlighting the specific relevance of this assessment. Different levels of needs could be differentiated between groups of BC patients in terms of age and level of education (P < 0.001). The SCNS-SF34-Fr and SCNS-BR8-Fr present adequate psychometric properties despite some redundant items. These questionnaires allow for the crucial endeavour to design appropriate care services according to BC patients' characteristics.

Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93.

INTRODUCTION: International Breast Cancer Study Group (IBCSG) Trial 11-93 is the largest trial evaluating the role of the addition of chemotherapy to ovarian function suppression/ablation (OFS) and tamoxifen in premenopausal patients with endocrine-responsive early breast cancer. METHODS: IBCSG Trial 11-93 is a randomized trial comparing four cycles of adjuvant chemotherapy (AC: doxorubicin or epirubicin, plus cyclophosphamide) added to OFS and 5 years of tamoxifen versus OFS and tamoxifen without chemotherapy in premenopausal patients with node-positive, endocrine-responsive early breast cancer. There were 174 patients randomized from May 1993 to November 1998. The trial was closed before the target accrual was reached due to low accrual rate. RESULTS: Patients randomized tended to have lower risk node-positive disease and the median age was 45. After 10 years median follow up, there remains no difference between the two randomized treatment groups for disease-free (hazard ratio=1.02 (0.57-1.83); P=0.94) or overall survival (hazard ratio=0.97 (0.44-2.16); P=0.94). CONCLUSION: This trial, although small, offers no evidence that AC chemotherapy provides additional disease control for premenopausal patients with lower-risk node-positive endocrine-responsive breast cancer who receive adequate adjuvant endocrine therapy. A large trial is needed to determine whether chemotherapy adds benefit to endocrine therapy for this population.

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Lung cancer treatment strategy relies on an accurate staging of the disease and a careful evaluation of patient characteristics, including capability of undergoing and tolerating a defined treatment plan. Therefore, a solid knowledge on all intervention-related adverse events and drug toxicities is essential for a reliable decision-making process. Most lung cancer patients are diagnosed at an advanced stage of the disease, correlated with a dismal prognosis. Systemic therapy is the mainstay, and drug selection still strongly relies on expected toxicity profile. This chapter first describes the drug standard options and their respective toxicities in this context. Side effects of more complex multimodality combined treatments of early non-small-cell lung cancer as well as small-cell lung cancer, usually involving use of the same cytotoxic agents jointly with surgery and radiotherapy, are discussed in the second part of this chapter.

Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991.

INTRODUCTION: This trial randomly assessed short-term adjuvant hormonal therapy added to radiotherapy (RT) for intermediate- and high-risk (UICC 1997 cT2a or cT1b-c with high PSA or Gleason score) localised prostate cancer. We report acute toxicity (CTCAE v2) assessed weekly during RT in relation to radiation parameters. PATIENTS AND METHODS: Centres selected the RT dose (70, 74 or 78Gy) and RT technique. Statistical significance is at 0.05. RESULTS: Of 791 patients, 652 received 3D-CRT (70Gy: 195, 74Gy: 376, 78Gy: 81) and 139 received IMRT (74Gy: 28, 78Gy: 111). During RT, grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were reported by 7 (0.8%) and 50 (6.3%) patients, respectively. No grade 4 was reported. The risk of grade 2 GI toxicity increased significantly with increasing D50%-rectum (p=0.004) and that of grade 2 GU toxicity correlated only to Dmax-bladder (p=0.051). 3D-RT technique, increasing total dose and V95% >400 cc increased D50% and Dmax. One month after RT, only 14 patients (1.8%) reported grade 3 toxicity. AST did not seem to influence the risk of GU or GI acute toxicity. CONCLUSION: RT up to 78Gy was well tolerated. Dmax-bladder and D50%-rectum influenced the risk of grade 2 GU toxicity and GI toxicity, respectively. Both were lower with IMRT but remained high for an irradiated RT volume>400 cc for 3D-RT and for a dose of 78Gy. Hormonal treatment did not influence acute toxicity.

Empirical use of anti-Gram-positive antibiotics in febrile neutropaenic cancer patients with acute leukaemia

Gram-positive infections including those due to methicillin-resistant staphylococci occur frequently in febrile neutropaenic patients. Although few data support the empirical addition of a glycopeptide antibiotic to the standard broad-spectrum antibiotic regimen, these agents are often used in many cancer centres. The emergence of infections due to vancomycin- resistant enterococci and glycopeptide-intermediate staphylococci has led to recommendations for a restricted use of glycopeptide antibiotics. The objective of the present work was to formulate evidence-based guidelines for the empirical use of anti- Gram-positive antibiotics in neutropaenic patients with acute leukaemia.