Effect of different glucose-lowering therapies on cancer incidence in type 2 diabetes: An observational population-based study.

AIM: To assess the effect of metformin on cancer incidence in type 2 diabetes (T2DM), considering possible interactions with other glucose-lowering drugs and diabetes duration. METHODS: Study cohort included diabetes patients aged 20-84 on December 2009, still alive and resident in Reggio Emilia province as of December 2011. Drug exposure was assessed for 2009-2011; subjects taking metformin continuously, with or without other hypoglycaemic drugs, were compared to subjects on diet-only therapy. The cohort was followed up from 2012 to 2014 through the cancer registry. Age- and sex-adjusted incidence rate ratios (IRRs) were computed using Poisson regression models for all sites, lung, breast, liver, colorectal, prostate and pancreatic cancer. RESULTS: The cohort includes 17,026 people with T2DM, 7460 taking metformin. 887 cancers occurred during follow-up, 348 among metformin users. Cancer risk was similar in T2DM patients using metformin and those on diet-only. The risk for prostate (IRR = 0.65; 95%CI:0.36; 1.17), liver (IRR = 0.82; 95%CI:0.36; 1.85) and breast (IRR = 0.77; 95%CI:0.43; 1.40) cancers only was slightly reduced; for lung (IRR = 1.52; 95%CI:0.92; 2.50), pancreas (IRR = 1.51; 95%CI:0.59:3.89) and colon-rectum (IRR = 1.71; 95%CI:0.94; 3.08) the risk was slightly increased. CONCLUSIONS: There is no evidence of antitumor effect of metformin. A possible decrease only for breast, liver and prostate cancer, is compatible with random fluctuations.

Cancer incidence following long-term consumption of drinking water with high inorganic selenium content.

Selenium, a trace element to which humans are exposed mainly through diet, has been involved in the etiology of human cancer. We investigated the long-term effects of selenium exposure on cancer incidence using data from a natural experiment in Northern Italy. During the 1970s-1980s, in a part of the Italian municipality of Reggio Emilia, residents were inadvertently exposed to unusually high levels of inorganic hexavalent selenium (selenate) through drinking water. We followed the exposed residents for 28years, generating data on incidence (when available) and mortality rates for selected cancer sites; the remaining municipal residents comprised the unexposed (reference) group. We observed no substantial difference in overall cancer incidence comparing exposed and unexposed cohorts. We detected, however, a higher incidence of cancer at some sites, and for a few of them, namely cancers of the buccal cavity and pharynx, melanoma, urinary tract and lymphoid tissue, the excess incidence was particularly evident in the first period of follow-up but decreased over time. Overall, these results suggest that consumption of water with levels of selenium in its inorganic hexavalent form close to the European standard, 10µg/L, may have unfavourable effects on cancer incidence.

Changes in mortality and incidence of prostate cancer by risk class in different periods in Italy: the possible effects of PSA spread.

PURPOSE: In Italy, the spread of prostate-specific antigen (PSA) testing varies in different areas. A peak of incidence was reached in 2003-2004 in some areas, while in others the incidence is still increasing. Mortality has declined since 1999 in some areas, while it remains stable in others. We compared mortality and the risk of advanced cancer over 2 periods (1996-1998; 2005-2007) and by geographic area characterized by a different spread of PSA, to understand the possible impact of PSA on the epidemiology of prostate cancer. METHODS: In 8 Italian Cancer Registries (CRs), 4,632 cases diagnosed over 2 periods, 1996-1998 and 2005-2007, were sampled to assess risk class. The CRs were classified into late and early phase of PSA testing depending on whether an incidence peak had been reached by 2008. Incidence by risk class was estimated based on overall incidence in each CR and on risk class distribution in the sample. We calculated standardized mortality (MRR) and risk class-specific incidence rate ratios (IRR) to compare the 2 periods. RESULTS: Incidence increased from 1996-1998 to 2005-2007 (IRR 1.5; 95% CI 1.4, 1.6). High-risk and metastatic cancer incidence decreased only in late-phase areas (IRR 0.78; 95% CI 0.69, 0.88; and 0.40; 95% CI 0.30, 0.54, respectively), while in early-phase areas, incidence remained virtually stable (IRR 1.2; 95% CI 1.0, 1.4; and 0.77; 95% CI 0.59, 1.0, respectively). Mortality decreased only in late-phase areas (MRR 0.81; 95% CI 0.85, 0.97; vs 1.1; 95% CI 0.92, 1.2) in early-phase areas. CONCLUSIONS: Mortality reduction and a decrease in high-risk and metastatic cases occurred simultaneously only in areas in late phase of PSA spread.

Second malignancy risk in patients with bronchopulmonary carcinoids: epidemiological results from Italian Network of Cancer Registries.

PURPOSE: This epidemiological study aimed to determine the prevalence and characteristics of second tumors (STs) in patients with bronchopulmonary carcinoids (BCs). METHODS: Data on neuroendocrine carcinomas (NECs) from the AIRTUM registry (1975-2011) were used for the analysis. Among 32,325 NECs, we focused our analysis on 3,205 patients (9.9%) affected by BCs. The overall ST number and incidence were calculated. The number of STs was compared with the expected cancer number in the healthy Italian population, and the standardized incidence ratio (SIR) and 95% confidence intervals were calculated. RESULTS: The male/female ratio was 1.5:1 and the mean age 61.7 years (range: 7-94). A total of 640 STs were observed (overall incidence: 20%): 198 tumors were metachronous, 23 synchronous, and 419 occurred before the diagnosis of BC. The most common STs were bladder tumors (12.2%) followed by breast tumors (11.1%). We observed a large number of thyroid tumors (SIR = 3.88), with a remarkably higher frequency of thyroid tumors being synchronously detected with BC in female patients (SIR = 61.39). In male patients there was an increased frequency of urinary system tumors, in particular metachronous tumors of the kidney and renal pelvis (SIR = 3.34) and synchronous tumors of the urinary bladder (SIR = 11.48). CONCLUSIONS: A high frequency of STs is predictable in patients with BCs, with synchronous thyroid tumors being observed in women and kidney and urinary bladder tumors in men. However, these data should be interpreted with caution, considering that the diagnosis of such tumors often occurs as an incidental finding during investigations for other malignancies.

[The accuracy of the causes of death and the estimated trend: the case of cervix uteri]. / L'accuratezza delle cause di morte e la stima dei trend: il caso della cervice uterina.

BACKGROUND: reduction in cervical cancer mortality is the ultimate goal of the screening. Quality of death certificate reports has been improved over time, but they are still inaccurate, making it difficult to assess time trends in mortality. OBJECTIVES: to evaluate the accuracy of the topographic coding of causes of death and to estimate the mortality time trend for cervical cancer through the method of incidence-based mortality (IBM) using cancer registry (CR) data. DESIGN: from the mortality registry (MR), we extracted data on deaths for cervix uteri cancer, corpus uteri cancer, and uterus cancer not otherwise specified (NOS) referred to residents in Reggio Emilia (Emilia-Romagna Region, Northern Italy) from 1997 to 2013. Deaths were checked with the CR to verify the topographical site of the primary tumour. Furthermore, by using CR data, we constructed a cohort of incident cervical cancer cases diagnosed between 1997 and 2009 with a 5-year follow-up. We calculated cause-specific IBM (excluding ovary) and IBM for all cause, crude and standardized, and annual percentage change (APC). RESULTS: out of 369 deaths for uterine cancer, 269 were reported in the RT: 32 for cervix uteri cancer, 76 for corpus uteri cancer, 161 for uterus cancer NOS. 28 of the 32 persons who died for cervical cancer were incidents for cervix uteri cancer. 63 of the 76 who died for corpus uteri cancer were incidents for corpus uteri cancer. Of the 161 who died of uterus cancer NOS, 80 were incidents for corpus uteri cancer, 45 for cervix uteri cancer, 28 for uterus cancer NOS, 5 for vagina cancer, and 3 for cancer of other non-specified organs. Applying these proportions of misclassification, we can estimate that the real number of cervical cancer deaths is 2.4 folds the number of cases reported in the MR as cervical cancer. IBM for all causes decreased significantly over the years (APC: -9.5; 95%CI -17.1;-1.1); cause-specific IBM decreases, but not significantly (APC: -5.1; 95%IC -16.1;+7.3). There is no improvement in survival (r2=0.02; p=0.6), while the incidence shows a decrease (APC: -6.6;95%CI -10.0;-3.0). CONCLUSIONS: mortality for cervical cancer is still underestimated by deaths certificates: for each reported case, there are other 1.4 cases that are reported with other less specific causes.

Impact of Screening Program on Incidence of Colorectal Cancer: A Cohort Study in Italy.

OBJECTIVES: Colorectal cancer (CRC) screening using the fecal occult blood test (FOBT) has been shown to be effective in reducing cause-specific mortality. However, although it detects pre-cancerous adenomas, it is uncertain whether FOBT reduces the incidence of invasive cancer. The objective is to evaluate the impact of screening with immunochemical FOBT (FIT) on CRC incidence and mortality. METHODS: An organized screening program was implemented in 2005 in the province of Reggio Emilia (Northern Italy). The program invites the resident population aged 50-69 for FIT every 2 years. Subjects who test positive are referred for colonoscopy. Incidence was studied through cancer registry. Person-times of people aged 50-74 from 1997 to 2012 were classified for exposure to screening according to age and period. Furthermore, two open cohorts-one never screened (aged 50-69 in 1997) and one invited for screening (aged 50-69 in 2005)-were followed up for 8 years. RESULTS: A total of 171,785 people have been invited, and approximately 70% have undergone FIT at least once (272,197 tests). The rate of colonoscopy participation has been about 90%, and 2896 cancers have been recorded (1237 in the screening period). The age-adjusted and sex-adjusted incidence rate ratios as compared with pre-screening were 1.60 (95% confidence interval (CI), 1.43-1.79), 0.86 (95% CI, 0.78-0.94), and 0.59 (95% CI, 0.50-0.69) for the first round, subsequent rounds, and post screening, respectively. Cumulative incidence and incidence-based mortality decreased by 10% (95% CI, 3-17%) and 27% (95% CI, 15-37%), respectively. CONCLUSIONS: FIT screening leads to a decrease in the incidence of CRC and in its mortality.

The impact of immunochemical faecal occult blood testing on colorectal cancer incidence.

BACKGROUND: The efficacy of colorectal cancer screening based on faecal immunochemical test, in terms of reduction of colorectal cancer incidence, is under debate. In the district of Florence, an organized screening programme based on faecal immunochemical test has been running since the early 1990s. The aim of this study was to compare the risk of developing colorectal cancer for subjects undergoing faecal immunochemical test with those who did not undergo the test in the same period. METHODS: Two cohorts were analyzed: subjects who underwent an initial faecal immunochemical test between 1993 and 1999 ("attenders"), and unscreened residents in the same municipalities invited to perform the faecal immunochemical test in the same period ("non-attenders"). Kaplan-Meier and Cox regression analysis were performed to evaluate the risk of developing colorectal cancer. RESULTS: The attenders' and non-attenders' cohorts included 6961 and 26,285 subjects, respectively. Cox analysis showed a reduction in colorectal cancer incidence of 22% in the attenders' compared to the non-attenders' cohort (hazard ratio = 0.78, 95% Confidence Interval: 0.65-0.93). CONCLUSION: Our results support the hypothesis that screening based on a single faecal immunochemical test every 2 years produces a significant decrease in colorectal cancer incidence after an average follow-up observation period of 11 years.

Indicators of the standard of care for melanoma: Tuscany data.

Formal indicators for the evaluation of the quality of melanoma care are needed. We identified 13 process indicators, which encompassed early diagnosis, pathology reporting and surgical treatment. We evaluated the adherence to these indicators using a population-based series on incident skin melanomas (only primary melanomas) for the year 2004 (687 cases) and for the first semester of 2008 (539 cases). We compared the indicators for these 2 years. The melanoma incidence increased between 2004 and 2008. There were statistically significant increases in the percentage of thin (≤1 mm) melanomas (from 50.7 to 61.3%) and in the number of pathology reports that mentioned ulceration (from 61.4 to 84.6%) and margin status (from 76.8 to 84.3%). The percentage of patients staged by sentinel lymph node biopsy was stable (63%) and was higher for patients younger than 75 years of age (74%). The number of nodes almost invariably exceeded the proposed site-specific cutoff reference and, in 2008, the number of nodes removed was always reported for lymphadenectomy. From 2004 to 2008, surgical and pathological waiting times increased. Collection and analysis of these indicators would enable continuous evaluation of the quality of melanoma care in Tuscany and provide sources for a comparative study between Italy and elsewhere.

Consistency and inconsistency in testing biomarkers in breast cancer. A GRELL study in cut-off variability in the Romance language countries.

PURPOSE: Biological markers are crucial factors in order to differentiate female breast cancers and to determine the right therapy. This study aims at evaluating whether testing for biomarkers for female breast cancer has similar frequency and characteristics across and within countries. METHODS: Population-based cancer registries of the Association for cancer registration and epidemiology in Romance language countries (GRELL) were asked to complete a questionnaire on biomarkers testing. The data collected referred to invasive female breast cancer cases diagnosed between 2004 and 2009. The investigation focused on 1) the overexpression and amplification of the human epidermal growth factor receptor 2 oncogene (HER2); 2) the expression of oestrogen (ER) and progesterone (PgR) receptors; and 3) the proliferation index (PI). Weighted percentages, the heterogeneity among and within countries, and the correlation between responses and calendar years were evaluated. The study was based on 19,644 breast cancers. RESULTS: Overall, 85.9% of the cases were tested for HER2, 91.8% for both ER and PgR, and 74.1% for proliferative markers. For HER2 and ER-PgR, the frequency of testing increased from 2004 to 2009. Testing varied among countries (HER2 from 82.0% to 95.9%, ER-PgR from 89.3% to 98.9%, PI from 10% to 92%) and also within the same country (e.g. HER2 in Italy from 51% to 99%) as well as within single cancer registries. The most relevant differences were in the scores for positive/negative/not clearly defined HER2 (e.g. HER2 was defined positive if IHC 3+ in 21/33 registries), and in the cut-off of positive cells for ER/PgR (from >0% to >30%) and PI positivity (from >0% to >20%). CONCLUSIONS: Biological markers are widely tested in the Romance language countries; however, the parameters defining their positivity may vary, raising concerns about homogeneity in breast cancer classification and treatment.

Estimating all cancers incidence with the MIAMOD model: a new method to include multiple tumors.

AIMS AND BACKGROUND: The MIAMOD method has been widely applied to derive regional and national cancer burden estimates. The method is based on a back-calculation approach using cancer-specific mortality and relative survival to derive expected incident and prevalent cases. Multiple tumors occurring in the same site for the same person (for example colon-colon) can be estimated just once. This has little effect on cancer-specific estimates, whereas it limits all cancers-combined estimates, where only cancer cases, rather than cancer diagnoses, can be accounted for by the method. The aim of this article is to present a specific strategy of application of the MIAMOD method to all cancers sites, which better approximates an estimate of 'cancer diagnoses'. METHODS: The strategy consists of breaking down the estimation process in separate applications to the most frequent cancer sites and to a 'remainder-site', given by all malignant sites except the previous ones. The separate estimates are then summed up to derive the overall quantities for all cancers combined. Cancer-specific mortality in the years 1985-2004 in the Tuscany cancer registry area (about 1,200,000 inhabitants) and relative survival data in the same area and periods (end of follow-up, 31 December 2006) were used to produce the estimates, which were then tested using observed incidence data in the same area and period. RESULTS: The standard application of the MIAMOD method underestimates all cancer incidence for both sexes. The mean relative difference between observed and expected incident cases is -14.8% for males and -17.2% for females. With the alternative method, the same mean relative difference drops to -8.2% for males and -6.1% for females. CONCLUSIONS: The study provides a strategy to reduce a structural limit of the MIAMOD method in estimating the total burden of cancer disease.

[Suicide mortality among cancer patients]. / Decessi per suicidio in pazienti con tumore.

OBJECTIVE: to evaluate the excess risk in the deaths due to suicide in a huge case-series of cancer patients and in particular in a group with recent diagnosis. DESIGN: observational cohort. SETTING AND PARTICIPANTS: population-based study based on 136,105 patients of the cancer registry of Tuscany Region, incident during 1985-2005, 42,321 of whom diagnosed during 2000-2005. MAIN OUTCOME MEASURES: standardised mortality ratio (SMR) of suicide by sex, age, prognosis, time since diagnosis and period of incidence. RESULTS: deaths due to suicide were 0.2% of all the deaths observed in the cohort of patients. Overall cases, 1985-2005, showed a SMR of 1.47 (p<0.05), it was higher than expected for men (SMR =1.50), for subjects older that 54 years, especially for cancers with poor prognosis (SMR=2.27), particularly during the first year after diagnosis (SMR=2.87) but also in the following years. Cases diagnosed in 2000-2005 had a SMR=1.19 (n.s.), confirmed the high risk for the age 55-64 years (SMR=2.27), for cancers with worse prognosis (SMR=3.23) and during the first year after diagnosis (SMR=2.64). Trend analysis showed that the excess in the risk of suicide death among cancer patients decreased over time (p=0.042). CONCLUSION: although suicide is not one of the major cause of death among cancer patients, we confirmed that those patients had a higher risk than the general population. SMR higher than expected were documented for the age 55-64 years, for cancers with poor prognosis and during the first year after diagnosis. Trend analysis shows that excess in the risk of suicide death among cancer patients is decreasing over time. This may be due, among other possible explanations, to the relevant development of the palliative care system in the area based both on hospices and on home care. Although suicide deaths are rather rare, their prevention among cancer patients is still a priority, due to its likely depressive etiology and to the effects on the family and on the health system.

[Socio-economic determinants of cancer survival in the municipality of Florence]. / I determinanti socio-economici della sopravivenza per i principali tumori nel comune di Firenze.

OBJECTIVE: The aim of the present paper is to evaluate cancer survival in patients resident in the municipality of Florence according to different deprivation levels. DESIGN: We used data from the Tuscan Cancer Registry and data from the national census 2001. We used a deprivation index, measured as a continue variable, classified in tertiles according to the distribution of the resident population. We compared more deprived patients (category 3) vs less deprived ones (category 1-2). MAIN OUTCOME MEASURES: 10-year relative survival has been computed for patients diagnosed with 27 different cancer sites during 1997-2002, for different deprivation categories. Cancer sites were split into three groups of the same dimension, on the basis of 10-year survival (bad, intermediate and good prognosis). For each category the relative excess risk of death (RER) for most deprived patients has been computed using a Generalized Liner Model. We evaluated also the effect of marital status, classified as married and non-married. RESULTS: We analysed 14 549 invasive cancer cases (out of skin epithelioma). Overall bad prognosis cancers did not show any RER of dying for most deprived patients. For intermediate prognosis cancers RER was 1.13 (1.02 ; 1.24). A excess occurs in the most disadvantaged tertile for tumors diagnosed under 50 years. For good prognosis cancers the RER was 1.06 (0.89 ; 1.26). We found a relative excess of mortality for non-married vs married. CONCLUSIONS: In the area of Florence there is an effect of deprivation level of survival for median-better prognosis cancers, for tumours diagnosed under 50 years and for unmarried people compared to unmarried ones.

[Cancer incidence in Italian natives and in first-generation immigrants to Italy]. / L'incidenza dei tumori in cittadini nati in Italia e in immigrati di prima generazione.

OBJECTIVE: The aim of this study was to evaluate differences in cancer incidence in populations born in different countries in the area covered by the Tuscan Cancer Registry. SETTING: We selected cancer cases diagnosed during the period 1998-2005 in the population resident in the provinces of Firenze and Prato. Each case was classified according to the place of birth: a) born in Italy, b) born in countries with high migration (PFPM), born in other highly developed countries (PSA).To compute incidence rates we used as denominator the health regional registry. MAIN OUTCOME MEASURES: We used the European standard population in computing standardized incidence rates (restricted to the age group 20-59 years) and the standardized rate ratio (SRR) in order to compare subjects born in different countries. RESULTS: During the period 1998-2005, 14 791 invasive cancers were diagnosed (non-melanoma skin excluded) in subjects aged 20-59 years old, 4.2% in subjects born in countries outside Italy (1.2% in other PSA e 3.0% in PFPM). Incidence in subjects born in PSA did not differ significantly from incidence in subjects born in Italy. Incidence rates among subjects born in PFPM were statistically lower, both in men (151.2 per 100 000) and women (199.3 per 100 000), than in subjects born in Italy (243.5 men e 337.5 women). On the contrary, liver and cervix uteri cancer incidence showed higher rates among subjects born in PFPM (liver: SRR=2.13, p=0.007; cervix uteri: SRR=1.88, p=0.0095). CONCLUSION: Subjects born in countries with high migration showed a level of incidence lower than subjects born in Italy (healthy migration effect). Incidence was higher among subjects born in PFPM only for liver and cervix uteri, cancers with a virological aetiology. The migration phenomena open new study prospectives, but also methodological questions (definition of immigrants and of reference populations).

[Automatic coding of pathologic cancer variables by the search of strings of text in the pathology reports. The experience of the Tuscany Cancer Registry]. / Codifica automatica di variabili patologiche tumorali tramite la ricerca di stringhe di testo nei referti anatomo-patologici. L'esperienza del Registro tumori toscano.

The present study evaluates the application of an automatic system for variables coding by means of strings reading in the text of the pathology reports, in the database of the Tuscany Cancer Registry. Incidence data for the years 2000 (n. 6297) and 2001 (n. 6291) for subjects for whom computerised pathology reports were available were included. The system is based on Queries (SQL language) linked to Functions (Visual Basic for Applications) that work on Windows Access. The agreement between original data inputted by the registrars and variables coded by means of automatic reading has been evaluated by means of Cohen's kappa. The following variables were analysed: cancer site (kappa = 0.87 between "manual" and automatic coding, for cases incident in the year 2001), morphology (kappa=0.75), Berg's morphology groups (kappa=0.87), behaviour (kappa=0.70), grading (kappa=0.90), Gleason (kappa=0.90), focality (kappa=0.86), lateralily (kappa=0.36), pT (kappa=0.92), pN (kappa=0.76), pM (kappa=0.28), number of lymph nodes (kappa=0.69), number of positive lymph nodes (kappa=0.70), Breslow thickness (kappa=0.94), Clark level (kappa=0.91), Dukes (kappa=0.74). The system of automatic reading of strings allows to collect a very huge amount of reliable information and its use should be implemented by the Registries.

Cancer trends in Italy: figures from the cancer registries (1986-1997).

The Italian Network of Cancer Registries analyzed incidence and mortality cancer trends during the period 1986-1997 Overall, 525,645 incident cancers and 269,902 cancer deaths (in subjects 15 years and older) were included. Age-adjusted rates, joinpoints (points in time where trend significantly changes from linearity) and estimated annual percent changes in rates (EAPC) were computed. Overall cancer incidence was significantly increasing in both sexes and cancer mortality was significantly decreasing (since 1991 among males). Incidence and mortality trends are summarised for single cancer sites. Crude rates are also showed to evaluate the effect of population ageing in terms of diagnostic and therapeutic burden for the National Health System.

Italian Network of Cancer Registries. Methods.

The trend analysis of the data base of the Italian Network of Cancer Registries has had a descriptive approach. The period of study has been from 1986 to 1997. Within this period we have included only nine Registries that were active for at least ten years (pool AIRT). For three Registries few lacking incidence years have been estimated according to their observed data. For the pool of Registries standardised (standard = European population) incidence and mortality rates have been computed with the direct method. The so called joinpoint analysis has been used to detect temporal points of trend change. Trends have been summarised by means of estimated annual percent change (EAPC) of the rate. Age-specific and birth cohort-specific rates have been also computed.