Eugenio Carrani

Multiple tumours in survival estimates.

In international comparisons of cancer registry based survival it is common practice to restrict the analysis to first primary tumours and exclude multiple cancers. The probability of correctly detecting subsequent cancers depends on the registrys running time, which results in different proportions of excluded patients and may lead to biased comparisons. We evaluated the impact on the age-standardised relative survival estimates of also including multiple primary tumours. Data from 2,919,023 malignant cancers from 69 European cancer registries participating in the EUROCARE-4 collaborative study were used. A total of 183,683 multiple primary tumours were found, with an overall proportion of 6.3% over all the considered cancers, ranging from 0.4% (Naples, Italy) to 12.9% (Iceland). The proportion of multiple tumours varied greatly by type of tumour, being higher for those with high incidence and long survival (breast, prostate and colon-rectum). Five-year relative survival was lower when including patients with multiple cancers. For all cancers combined the average difference was -0.4 percentage points in women and -0.7 percentage points in men, and was greater for older registries. Inclusion of multiple tumours led to lower survival in 44 out of 45 cancer sites analysed, with the greatest differences found for larynx (-1.9%), oropharynx (-1.5%), and penis (-1.3%). Including multiple primary tumours in survival estimates for international comparison is advisable because it reduces the bias due to different observation periods, age, registration quality and completeness of registration. The general effect of inclusion is to reduce survival estimates by a variable amount depending on the proportion of multiple primaries and cancer site.

The EUROCARE-5 study on cancer survival in Europe 1999–2007: Database, quality checks and statistical analysis methods

BACKGROUND Since 25years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. METHODS In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to data on nearly nine million cancer patients diagnosed in 2000-2007 and followed up to 2008. Survival time trends were analysed applying the period approach to data on about 10 million cancer cases diagnosed from 1995 to 2007 and followed up to 2008. Differently from EUROCARE-4, multiple primary cancers were included and relative survival was estimated with the Ederer II method. RESULTS EUROCARE-5 covered a population of 232 million resident persons, corresponding to 50% of the 29 participating countries. The population coverage increased particularly in Eastern Europe. Cases identified from death certificate only (DCO) were on average 2.9%, range 0-12%. Microscopically confirmed cases amounted to over 85% in most CRs. Compared to previous methods, including multiple cancers and using the Ederer II estimator reduced survival estimates by 0.4 and 0.3 absolute percentage points, on average. CONCLUSIONS The increased population size and registration coverage of the EUROCARE-5 study ensures more robust and comparable estimates across European countries. This enlargement did not impact on data quality, which was generally satisfactory. Estimates may be slightly inflated in countries with high or null DCO proportions, especially for poor prognosis cancers. The updated methods improved the comparability of survival estimates between recently and long-term established registries and reduced biases due to informative censoring.

A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies myhre syndrome

Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.

A wide difference in cancer survival between middle aged and elderly patients in Europe

Nowadays the burden of cancer in elderly people has reached an alarming extent. The purpose of this study is comparing cumulative and conditional relative survival in elderly patients between 65 and 84 years and younger adults aged from 55 to 64. Fifty‐three cancer registries of 22 European countries, participating in the EUROCARE‐3 programme, collected information on the cases diagnosed over the period 1990–1994. We computed cumulative and conditional relative survival for 16 cancer sites. Middle aged patients experienced a better prognosis than the elderly for all cancer sites, in both sexes and the differences were more marked at 1 than 5 years since diagnosis. The very large differences noted in the first period after cancer detection declined in the subsequent years and, when 5‐years conditional survival was considered, for several cancers the elderly and younger adults had the same probabilities of surviving. The death relative excess risks (RERs) in the elderly with respect younger individuals were really very high and markedly larger at 1 than 5 years, and in women than men. Genitourinary and gynaecological cancers showed the highest RERs, around 2.0 and between 1.5 and 2.5 respectively. This very high early mortality could be due not only to clinical aspects: the barriers to health care access and a consequent late diagnosis might represent for elderly patients the main determinant of this very large prognostic disadvantage. In conclusion, clinical management of cancer in the elderly remains a major issue to be faced with complex social and health care policies.

Trends in net survival lung cancer in six European Latin countries: results from the SUDCAN population-based study.

Survival is a key measure of the effectiveness of a healthcare system. European Latin countries have some similarities in their health systems; it is thus interesting to examine their differences in survival from cancer, here, lung cancer. The aim of the SUDCAN collaborative study was to compare the trends in the 1- and 5-year net survival from lung cancer and the trends in the excess mortality rates between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. First, the net survival was studied over the 2000–2004 period using Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modelling. Overall, the 1-year net survival from lung cancer ranged between 36 (Spain) and 43% (Belgium and Switzerland) and the 5-year net survival ranged between 11 (Spain) and 15% (Belgium and Switzerland). Between 1992 and 2004, the age-standardized survival increased considerably at 1 year, but increased less at 5 years after diagnosis. This increase was observed at ages 60 and 70, but was less obvious at age 80. There was little difference in net survival from lung cancer between European Latin countries, particularly in the more recent years. However, survival was slightly lower in Spain and Portugal than in France, Italy, Belgium and Switzerland. High-resolution studies with data on treatment, stage at diagnosis and comorbidities are needed to understand the reasons for these differences.

Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN population-based study

Pancreatic cancer represents a real clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from pancreatic cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000–2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modelling strategy. There were little differences between countries in age-standardized net survivals (2000–2004). The 5-year net survival was poor (range: 6–10%). The changes in net survival from 1992 to 2004 were mostly related to early survival and patients aged 60 years. A slight decrease in the excess mortality rate between 1992 and 2004 was observed, limited to the 18 months after diagnosis. This study confirmed that, despite some improvement, survival from pancreatic cancer is still poor throughout European Latin countries. The major improvements in clinical imaging did not result in improvements in prognosis. Development of truly innovative treatments is highly needed to improve prognosis.

Trends in net survival from head and neck cancer in six European Latin countries: results from the SUDCAN population-based study.

Cancer survival is a key measure of the effectiveness of a healthcare system. As differences in healthcare systems are present among European Latin countries, it is of interest to look specifically at their similarities and differences in terms of cancer survival. Incident cases were extracted from the EUROCARE-V database for France, Italy, Spain, Switzerland, Portugal, and Belgium. One and 5-year net survivals (NS) were calculated for the period 2000–2004 using the Pohar-Perme estimator. Trends in NS over the 1992–2004 period and changes in the pattern of cancer excess mortality rate until 5 years after diagnosis were examined using a multivariate excess mortality rate model. There were moderate differences in age-standardized NS between countries (5-year NS range: 83–88%), but significant differences in the age groups 15–54 and 55–74 years (at 5 years up to +16 and +18% between any two countries). During the study period, excess mortality and NS improved in Italy, Spain, and Portugal. In Italy and Portugal, this improvement was slightly similar at ages 40, 55, and 70 whereas, in Spain, there was a sharp increase in NS at age 55. Because of this improvement, excess mortality and NS were similar in all six countries in 2004. Excess mortality peaked around 1 year after diagnosis in the youngest ages, but decreased gradually in the elderly. Detailed analyses showed differences in excess mortality and NS from cervical cancer between European Latin countries. However, these differences decreased over the study period because of the considerable improvement in Spain, Italy, and Portugal.

Trends in net survival from skin malignant melanoma in six European Latin countries: Results from the SUDCAN population-based study

In Europe as a whole, survival from skin malignant melanoma (SMM) has increased constantly since the 1980s. The aim of the SUDCAN collaborative study was to compare the trends in the 5-year net survival from SMM and in related excess mortality rate between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland). The data were extracted from the EUROCARE-5 database (end of follow-up: 01 January 2009). First, the net survival was studied over the 2000–2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modeling. Over the 2000–2004 period, the 5-year net survival from SMM ranged from 79 (Portugal) to 90% (Switzerland). In all countries, net survival was higher in women versus men and in young versus old age groups. From 1992 to 2004, the 5-year net survival increased the most in the countries with the lowest survivals in 1992 (+9% in Italy and Spain vs. +2% in Switzerland or +4% in France). The differences between countries decreased between 1992 and 2004. Although survival increased to a lower or higher extent in all countries during the period studied, significant differences in net survival from SMM persisted among the six countries studied. Health policies should mainly enhance early diagnosis by increasing public awareness and with screening campaigns. Furthermore, new immunotherapies, which will be approved soon hopefully, should also be used to improve the outcomes of SMM treatment.

New insights into survival trend analyses in cancer population-based studies: The SUDCAN methodology

The main objective of the SUDCAN study was to compare, for 15 cancer sites, the trends in net survival and excess mortality rates from cancer 5 years after diagnosis between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. The study period ranged from 6 (Portugal, 2000–2005) to 18 years (Switzerland, 1989–2007). Trend analyses were carried out separately for each country and cancer site; the number of cases ranged from 1500 to 104 000 cases. We developed an original flexible excess rate modelling strategy that accounts for the continuous effects of age, year of diagnosis, time since diagnosis and their interactions. Nineteen models were constructed; they differed in the modelling of the effect of the year of diagnosis in terms of linearity, proportionality and interaction with age. The final model was chosen according to the Akaike Information Criterion. The fit was assessed graphically by comparing model estimates versus nonparametric (Pohar-Perme) net survival estimates. Out of the 90 analyses carried out, the effect of the year of diagnosis on the excess mortality rate depended on age in 61 and was nonproportional in 64; it was nonlinear in 27 out of the 75 analyses where this effect was considered. The model fit was overall satisfactory. We analysed successfully 15 cancer sites in six countries. The refined methodology proved necessary for detailed trend analyses. It is hoped that three-dimensional parametric modelling will be used more widely in net survival trend studies as it has major advantages over stratified analyses.

Trends in net survival from liver cancer in six European Latin countries: Results from the SUDCAN population-based study

Liver cancer represents a major clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from liver cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000–2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess-rate modeling strategy. There were little differences between the six countries in the 5-year age-standardized net survival (2000–2004): it ranged from 13% (France and Portugal) to 16% (Belgium). An increase in the net age-standardized survival was observed in all countries between 1992 and 2004, both at 1 year and at 5 years (the highest in Spain, the lowest in France). Generally, patients aged 60 years showed the highest increase. There was a progressive decrease in EMR over the 5-year- period following diagnosis. The study confirmed the poor prognosis of liver cancer. Innovative treatments might improve the prognosis as well as preventive screening of cirrhotic patients with good liver function. Efforts are also needed to improve registration practices.