Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Type 1 diabetes is not associated with an increased prevalence of hepatic steatosis.

AIM: Non-alcoholic fatty liver disease (NAFLD) is commonly associated with Type 2 diabetes. Recently, it has been suggested that NAFLD is also frequently associated with Type 1 diabetes and diabetic complications. In this study, we set out to determine whether Type 1 diabetes was associated with liver fat content measured using magnetic resonance imaging. METHODS: One hundred and twenty-eight patients with Type 1 diabetes, 264 patients with Type 2 diabetes and 67 participants without diabetes were included in this study. Hepatic steatosis was defined as a liver fat content > 5.5%. RESULTS: People with Type 1 diabetes and controls were similar for age and BMI. Liver fat content was significantly higher in patients with Type 2 diabetes than in patients with Type 1 diabetes and controls. In the control group, nine people (13.4%) had steatosis compared with six (4.7%) patients with Type 1 diabetes (P = 0.04). Among patients with Type 2 diabetes group, 166 (62.8%) had steatosis. In multivariate analysis that included patients with Type 1 diabetes and participants without diabetes, steatosis was associated only with BMI, whereas age, sex, statin therapy and Type 1 diabetes were not. In patients with Type 1 diabetes, there was no correlation between liver fat content and estimated glomerular filtration rate or carotid intima media thickness. CONCLUSIONS: Our data showed that Type 1 diabetes was not associated with an increased prevalence of steatosis. Moreover, our study provided no specific arguments concerning a link between liver fat content and diabetic complications in patients with Type 1 diabetes.

Epidemiology, Management, and Survival of Peritoneal Carcinomatosis from Colorectal Cancer: A Population-Based Study.

BACKGROUND: Modern chemotherapy aims to improve long-term survival for selected patients with peritoneal carcinomatosis. Publications suggest promising results, but the spread of these new aggressive treatment strategies in the general population is not well known. OBJECTIVE: The aim of this study was to draw a picture of epidemiology, management, and survival in synchronous and metachronous peritoneal carcinomatosis from colorectal cancer. DESIGN: The cumulative risk of metachronous peritoneal carcinomatosis was estimated in patients resected for cure. Net survival rates were calculated for synchronous and metachronous peritoneal carcinomatosis. SETTINGS: The study was conducted with the use of the Burgundy Digestive Cancer Registry. PATIENTS: Overall, 9174 primary colorectal cancers registered between 1976 and 2011 by the population-based digestive cancer registry were considered. RESULTS: In total, 7% of patients were diagnosed with synchronous peritoneal carcinomatosis. The 5-year cumulative risk of metachronous peritoneal carcinomatosis was 6%, and the stage of the colorectal cancer at diagnosis was the major risk factor. Other independent risk factors were mucinous adenocarcinoma, ulceroinfiltrating tumors, and diagnosis after obstruction or perforation. The proportion of patients resected for cure was 11% and 9% for synchronous and metachronous peritoneal carcinomatosis, and 3-year overall net survival was 8% and 5%. The corresponding rates after resection for cure were 21% and 17%. There was a dramatic increase in the proportion of patients receiving systemic chemotherapy: from 11% before 1997 to 48% in 2011 for synchronous peritoneal carcinomatosis and from 3% to 38% for metachronous peritoneal carcinomatosis. LIMITATIONS: This is a retrospective observational population-based study. CONCLUSION: Peritoneal carcinomatosis complicating colorectal cancer is a major reason for treatment failure. This study identified patients at a high risk of developing peritoneal carcinomatosis who may benefit from specific surveillance. New therapeutic modalities are also needed to improve the prognosis.

Management of colorectal cancer explains differences in 1-year relative survival between France and England for patients diagnosed 1997-2004.

BACKGROUND: Few international population-based studies have provided information on potential determinants of international disparities in cancer survival. This population-based study was undertaken to identify the principal differences in disease characteristics and management that accounted for previously observed poorer survival in English compared with French patients with colorectal cancer. METHODS: The study population comprised all cases of colorectal cancer diagnosed between 1997 and 2004 in the areas covered by three population-based cancer registries in France and one in England (N=40 613). To investigate the influence of clinical and treatment variables on survival, we applied multivariable excess hazard modelling based on generalised linear models with Poisson error. RESULTS: Poorer survival for English patients was primarily due to a larger proportion dying within the first year after diagnosis. After controlling for inter-country differences in the use of chemotherapy and surgical resection with curative intent, country of residence was no-longer associated with 1-year survival for advanced colon cancer patients (excess hazard ratio (EHR)=0.99 (0.92-1.01), P=0.095)). Longer term (2-5 years) excess hazards of death for colon and rectal cancer patients did not differ between France and England. CONCLUSION: This study suggests that difference in management close to diagnosis of colon and rectum cancer is related to differences in survival observed between France and England. All efforts (collection and standardisation of additional variables such as co-morbidity) to investigate the reasons for these disparities in management between these two countries, and more generally across Europe, should be encouraged.

Management and prognosis of pancreatic cancer over a 30-year period.

BACKGROUND: The aim of this study was to report on changes in the diagnostic assessment, patterns of care and survival over time for pancreatic cancers. METHODS: A total of 2986 cases of pancreatic cancer from the Digestive Cancer Registry of Burgundy (France) over a 30-year period (1976-2005) were considered. Non-conditional logistic regressions were carried out to identify the factors associated with resection for cure and with the use of chemotherapy. A multivariate relative survival analysis was carried out. RESULTS: Diagnostic procedures have changed. Ultrasonography and computed tomography progressively have become the major diagnostic procedures. There was a slight improvement in stage: the proportion of stage I-II was 2.8% in the 1976-1980 period and 8.8% in the 2001-2005 period (P<0.001). There was a similar trend in the proportion of cases resected for cure, the corresponding percentages being 4.5 and 11.3%, respectively (P<0.001). The 5-year relative survival increased from 2.0 to 4.2% (P<0.001). In the multivariate relative survival analysis, the period remained a significant prognostic factor. Stage, sex, age and histology were independent prognostic factors. CONCLUSION: Over a 30-year period, there were minor changes in the stage at diagnosis, resection for cure and prognosis of pancreatic cancers, although there were improvements in the diagnostic modalities. Pancreatic cancer still represents a major challenge in oncology.

Epidemiology and prognosis of synchronous colorectal cancers.

BACKGROUND: The aim of this population-based study was to report on the incidence, treatment and prognosis of synchronous colorectal carcinomas. METHODS: Data were obtained from the population-based cancer registry of Burgundy. RESULTS: Between 1976 and 2004, 15 562 colorectal cancers were diagnosed. Some 3.8 per cent of patients had synchronous colorectal cancers. The risk of having synchronous cancers was higher in men (odds ratio (OR) 1.41 (95 per cent confidence interval (c.i.) 1.19 to 1.68)), when associated adenomas were present (OR 2.02 (95 per cent c.i. 1.69 to 2.41)), when there were adenomatous remnants on pathological examination (OR 2.10 (95 per cent c.i. 1.73 to 2.55)) and in patients aged over 75 years (OR 1.31 (95 per cent c.i. 1.08 to 1.59)). Synchronous tumours were more often located on the same intestinal segment, although the correlation was weak (kappa = 0.26). Resection for cure was performed in 74.8 per cent of synchronous cancers and 72.0 per cent of single cancers (P = 0.131). Five-year relative survival for synchronous (48.7 per cent) and single (48.3 per cent) cancers was almost identical. Stage, age, associated adenomas and adenomatous remnants were independent prognostic factors. CONCLUSION: Synchronous colorectal cancers convey a similar prognosis to single tumours. Men and patients aged over 65 years with associated adenomas are more prone to multiple colorectal cancers.

Time trends and short term projections of cancer prevalence in France.

BACKGROUND: This study analyzes time trends in cancer prevalence in France and provides short-term projections up to the year 2017. The 15-year prevalence for 24 cancers was estimated from the French cancer registries network (FRANCIM) incidence and survival data. METHOD: We estimated prevalence using the P = I × S relationship, with flexible modeling of incidence and survival. Based on observations of the incidence and survival up to 2010, different scenarios for evolution up to 2017 were studied, combining stable and dynamic incidence and survival. The determinants of variations in prevalence (incidence, survival and demography) were quantified. RESULTS: At the end of 2017, an estimated 1,396,000 men and 1,359,000 women having had cancer in the previous 15 years were alive, respectively 5.4% and 4.8% of the population. Twelve percent had been diagnosed in the preceding year and 23% between 10 and 15 years. Between 2010 and 2017, changes in incidence and survival depended on the cancer site. The effect of the demographic change was null for those under age 65, whereas above age 65, the contribution of this factor was 20% in men and 17% in women at 15 years. The different projection scenarios led to very different estimates for some cancers for which incidence strongly varied in the last decades. CONCLUSION: Prevalent cases are numerous in a country such as France, where incidence and survival are high. Due to the sensitivity of prevalence to changes in incidence and survival, we recommend that the results of projections are presented under different scenarios. We propose a robust and flexible prevalence estimate.

Prevalence and distribution of HPV genotypes and cervical-associated lesions in sexually active young French women following HPV vaccine.

BACKGROUND: Despite the availability of safe and effective HPV vaccines in France, more than 80% of girls remain unvaccinated. SETTING: A regional university hospital referral center in France. OBJECTIVE: To estimate the overall prevalence and distribution of HPV in vaccinated, sexually active young French women who were screened for cervical cancer by cytology and HPV testing. METHODS: High-risk HPV (HR-HPV) prevalence, genotype-specific prevalence and extent of multiple infections were assessed in 125 cervical samples from females with available vaccine data using hc2 assay and INNO-LiPA assay. HPV status was analyzed in accordance with cytological data. RESULTS: In our series, mean age was 23 years, overall prevalence of HR-HPV was 52% and was correlated with the lesion grade. The diversity of HPV genotypes was broad. Single HR-HPV infections were identified in 11%, 21% and 47% of women with NILM, ASC-US/-H and LSIL respectively. Multiple infections with HR-HPV were detected in 28% of the specimens. Only 24.5% of women with NILM presented infections with 2 genotypes or more, vs 28% of women with ASC-US/-H and 35% of women with LSIL. The overall prevalence of genotypes covered by the quadrivalent vaccine was low (5.9%); with 4.2%, 0%, 0.8% and 0.8% for HPV 16, HPV 18, HPV 6 and HPV 11 respectively. CONCLUSION: Among HPV-vaccinated young women, HR-HPV are detected at a high rate, and an association with the grade of cytological abnormalities was observed. However, HPV 16 and 18, both targeted by the vaccines, are remarkably rare among young French women since program implementation.

Is the management of hepatitis C patients appropriate? A population-based study.

BACKGROUND: In order for hepatitis C patients to receive antiviral treatment, they must reach medical care. AIM: To assess the proportion of patients reaching medical care after hepatitis C diagnosis in a general population (1 006 171 inhabitants) in France. METHODS: Between 1994 and 1999, 1508 cases were diagnosed, of which 1251 were eligible for the study. RESULTS: Two-hundred and two patients did not have any medical care; among them, 55.4% had normal alanine transferase, 58.4% had risk factors related to lifestyle and 22.8% were alcoholics. Amongst the 1049 other patients, 41.6% had a liver biopsy, 25.0% were treated. Treatment was more often carried out in males than in females (OR: 1.59; P = 0.001), and in patients under 65 than in older patients (OR: 2.22; P < 0.008). Among non-treatment reasons, alcoholism (P = 0.001), drug-addiction (P = 0.04) and escaping monitoring (P = 0.04) were more frequent in males than in females, whereas normal alanine transferase was more frequent in females than in males (P = 0.004). Amongst 278 patients with a Metavir score >A1F1, 71 (25.5%) did not undergo treatment. CONCLUSION: In a general population, one patient in six did not receive on-going health care; a quarter of patients with a Metavir score >A1F1 did not receive any treatment. These results showed insufficient clinical management, which could compromise the effectiveness of treatment in general population.

The influence of geographical access to health care and material deprivation on colorectal cancer survival: evidence from France and England.

This article investigates the influence of distance to health care and material deprivation on cancer survival for patients diagnosed with a colorectal cancer between 1997 and 2004 in France and England. This population-based study included all cases of colorectal cancer diagnosed between 1997 and 2004 in 3 cancer registries in France and 1 cancer registry in England (N=40,613). After adjustment for material deprivation, travel times in England were no longer significantly associated with survival. In France patients living between 20 and 90min from the nearest cancer unit tended to have a poorer survival, although this was not statistically significant. In England, the better prognosis observed for remote patients can be explained by associations with material deprivation; distance to health services alone did not affect survival whilst material deprivation level had a major influence, with lower survival for patients living in deprived areas. Increases in travel times to health services in France were associated with poorer survival rates. The pattern of this influence seems to follow an inverse U distribution, i.e. maximal for average travel times.

Improvement in survival of metastatic colorectal cancer: are the benefits of clinical trials reproduced in population-based studies?

AIM OF THE STUDY: To describe trends in survival of non-resectable metastatic colorectal cancer (MCRC) over a 34-year period in a French population-based registry taking into account major advances in medical therapy. PATIENTS AND METHODS: 3804 patients with non-resectable metastatic colorectal cancer diagnosed between 1976 and 2009 were included. Three periods (1976-96, 1997-2004 and 2005-09) were considered. RESULTS: The proportion of patients receiving chemotherapy dramatically increased from 19% to 57% between the first two periods, then increased steadily thereafter reaching 59% during the last period (p<0.001). Median relative survival increased from 5.9 months during the 1976-96 period to 10.2 months during the 1997-2004 period but, despite the availability of targeted therapies, remained at 9.5 months during the 2005-09 period. During the last study period, less than 10% of elderly patients received targeted therapies compared to more than 40% for younger patients. Their median relative survival was 5.0 months compared to 15.6 months in younger patients. CONCLUSION: There was an improvement in survival in relation with the increased use of more effective medical treatment. However, at a population-based level, patients are not all treated equally and most of them, especially the elderly, do not benefit from the most up-to-date treatment options.

Increased erythrocytes n-3 and n-6 polyunsaturated fatty acids is significantly associated with a lower prevalence of steatosis in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome and type 2 diabetes. Although dietary fat contributes substantially to the accumulation of liver fat, the role of individual fatty acids in this accumulation is unclear. OBJECTIVE: In this study, we set out to determine whether liver fat content (LFC), was associated with red blood cell fatty acid (RBC-FA) composition in people with type 2 diabetes. DESIGN, SETTINGS, AND PARTICIPANTS: One hundred and sixty-two type 2 diabetic patients were included in this study. LFC was measured using (1)H-MR Spectroscopy. RBC-FA composition was measured by gas chromatography. RESULTS: One hundred and nine (67.2%) patients had steatosis. Patients with steatosis had a higher BMI (p = 0.0005), and higher plasma triglyceride levels (p = 0.009) than did patients without steatosis. We report a significant association between palmitic acid (16:0), palmitoleic acid (16:1n-7) concentrations and ratio of monounsaturated to saturated fatty acid (palmitoleic acid to palmitic acid) and higher liver fat content. Total polyunsaturated fatty acid (PUFA), homo-gamma-linolenic acid (20:3n-6), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4 n-6) were associated with lower LFC. CONCLUSIONS: Our data showed that an increased erythrocytes long-chain n-3 and n-6 fatty acids was associated with a lower prevalence of steatosis in patients with type 2 diabetes. These results suggest that n-3 and n-6 fatty acids supplementation could be a promising treatment for NAFLD in patients with type 2 diabetes.

Immunogenic death of colon cancer cells treated with oxaliplatin.

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

Time trends in first-diagnosis rates of colorectal adenomas: a 24-year population-based study.

BACKGROUND: Little is known about the descriptive epidemiology of colorectal adenomas diagnosed in the population. AIM: To describe time trends in the rate of first diagnosis of colorectal adenomas and estimate the proportion of adenoma-bearing individuals detected over a 24-year period. METHODS: A total of 11,027 patients were first-diagnosed with colorectal adenomas among Côte-d'Or residents (France) between 1976 and 1999. Annual percentage changes were estimated using a Poisson regression model. The proportion of diagnosed adenoma-bearing individuals was estimated using the prevalence of adenomas in an autopsy study performed in the area. RESULTS: Standardized diagnosis rates were 89.6/100,000 men and 50.3/100,000 women. During the period 1976-1993, diagnosis rates significantly increased with annual percentage changes in men and women of respectively +17.1% and +22.3% for proximal adenomas, +7.5% and +9.1% for distal adenomas and +7.2% and +8.0% for advanced adenomas. Changes were less marked during the period 1994-1999. The estimated proportion of adenoma-bearing individuals diagnosed during the 24-year period was 20.0% in men and 16.0% in women. CONCLUSION: Despite a marked increase in the rate of first adenoma diagnosis, the proportion of diagnosed adenoma-bearing individuals seems too low to induce a significant decrease in colorectal cancer incidence.

Empirical study of the dependence of the results of multivariable flexible survival analyses on model selection strategy.

Flexible survival models, which avoid assumptions about hazards proportionality (PH) or linearity of continuous covariates effects, bring the issues of model selection to a new level of complexity. Each 'candidate covariate' requires inter-dependent decisions regarding (i) its inclusion in the model, and representation of its effects on the log hazard as (ii) either constant over time or time-dependent (TD) and, for continuous covariates, (iii) either loglinear or non-loglinear (NL). Moreover, 'optimal' decisions for one covariate depend on the decisions regarding others. Thus, some efficient model-building strategy is necessary.We carried out an empirical study of the impact of the model selection strategy on the estimates obtained in flexible multivariable survival analyses of prognostic factors for mortality in 273 gastric cancer patients. We used 10 different strategies to select alternative multivariable parametric as well as spline-based models, allowing flexible modeling of non-parametric (TD and/or NL) effects. We employed 5-fold cross-validation to compare the predictive ability of alternative models.All flexible models indicated significant non-linearity and changes over time in the effect of age at diagnosis. Conventional 'parametric' models suggested the lack of period effect, whereas more flexible strategies indicated a significant NL effect. Cross-validation confirmed that flexible models predicted better mortality. The resulting differences in the 'final model' selected by various strategies had also impact on the risk prediction for individual subjects.Overall, our analyses underline (a) the importance of accounting for significant non-parametric effects of covariates and (b) the need for developing accurate model selection strategies for flexible survival analyses.

A population-based assessment of the prognostic value of the CD19 positive lymphocyte count in B-cell chronic lymphocytic leukemia using Cox and Markov models.

No population-based study has assessed the prognostic impact on survival of the CD19 positive lymphocyte count, evaluated by immunophenotyping at diagnosis, in B-cell chronic lymphocytic leukemia (B-CLL). Aiming at addressing this issue, we investigated the clinical outcome of a well-defined population of B-CLL patients. Survival of B-CLL patients, diagnosed between 1990 and 1999 and recorded by the Registry of Hematological Malignancies of the Côte d'Or, was analysed applying Cox's regression model to the 237 included cases and to the 195 Binet stage A patients. To assess simultaneously the predictive value of each parameter on the risk of disease progression and on the risk of death, we completed this analysis by applying a three-states homogeneous Markov model to the whole study population. Analysis of the entire population showed that age (p < 0.001), Binet stage (p = 0.008) and CD19 positive lymphocyte count (p = 0.038) were three independent prognostic factors. However, in stage A patients, only progression into a more advanced stage, analysed as a time-dependent variable, and age had a clear impact on survival (p < 0.001 for both). Markov model revealed that an increased CD19 positive lymphocyte count increased the risk of disease progression in stage A patients (p = 0.002) but did not have direct impact on survival of either stage A patients with stable disease or stage B or C patients. An increased CD19 positive lymphocyte count at diagnosis is a marker of an increased risk of disease progression in stage A patients. Thus, it can be a useful tool for the clinical management of these patients.