Matteo Franchi

Trastuzumab-Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

BACKGROUND Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women. METHODS Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model. RESULTS Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5-36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1-9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease. CONCLUSIONS Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.

Bevacizumab in Clinical Practice: Prescribing Appropriateness Relative to National Indications and Safety

The aim of this study was to describe the clinical use of bevacizumab in Lombardy (9.5 million inhabitants), Italy, during 2006-2007 in patients with metastatic colorectal cancer (mCRC) to evaluate compliance with the Italian Medicine Agency (AIFA) indications, the incidence of adverse events, and the survival rate. We performed computerized record linkage among three different Lombardy health care databases: File F registry, Regional discharge database, and Registry Office records. Patients were classified into approved and off-label uses according to the AIFA indications. Treatment with bevacizumab was administered to 780 patients, of whom 81.7% (n = 637) had mCRC. Among these, 37.8% (n = 241) of patients received the drug in observance of AIFA indications. Overall, ∼10% of patients had serious treatment-related toxicities (fistula, 3.5%; venous thromboembolism, 2.8%; hemorrhage, 1.9%; intestinal perforation and arterial thromboembolism, <1%). The 1-year survival rate was 74.3% and the 2-year survival rate was 39.2%. The median survival time was 20.5 months, and there were no meaningful differences between gender and age groups. There was a gap between the bevacizumab approved indication and clinical practice pattern: overall, less than one half of the patients received bevacizumab in observance with the regulatory indication. The main reason for nonadherence to the indication was use as a second-line or advanced line of therapy. The incidence of serious adverse events and the survival rates of mCRC patients were similar to those reported in clinical trials.

Effectiveness of Trastuzumab in First-Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

BACKGROUND The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting. MATERIALS AND METHODS By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006-2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis. RESULTS Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50-1.26). CONCLUSION Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials.

Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case-control study in Italy

Background:Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells.Methods:In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case–control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors.Results:Women in the highest quartile category of proanthocyanidins with ⩾3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48–0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m−2, and, for flavanones, among parous or non-users of hormone-replacement therapy women.Conclusion:High consumption of selected proanthocyanidins may reduce endometrial cancer risk.

Trastuzumab for HER2+ metastatic breast cancer in clinical practice: Cardiotoxicity and overall survival

The evidence on efficacy and safety of trastuzumab in metastatic breast cancers (MBC) mainly derives from randomized clinical trials. We assessed short- and long-term overall survival (OS) and cardiotoxicity in a large cohort of women with MBC treated with trastuzumab in clinical settings. Using healthcare administrative data of Lombardy (10 millions inhabitants), we identified a cohort of women receiving trastuzumab for MBC between 2006 and 2009. The cumulative risk of severe cardiac events and the OS from the first trastuzumab administration were estimated using the Kaplan-Meier method. Their predictors were assessed using Cox regression models. We found 681 trastuzumab MBC users. Thirty two (4.7%) women experienced severe cardiac adverse events. The cumulative risk increased sharply, reaching a value of 2.4% and 4.3% during the first and second year; thereafter it increased of about 1% per year. Age was a strong predictor of cardiotoxicity. The OS was 81.8%, 64.0%, 50.2%, 41.1% and 37.2% at 1, 2, 3, 4 and 5 years, respectively. Independent predictors of worse OS were: age, brain liver or lung metastasis compared to other metastasis, use of taxanes and other chemotherapies, a cardiac adverse event after trastuzumab use, and a higher time between metastasis and BC diagnoses. The incidence of cardiotoxicity among women treated with trastuzumab for HER2-positive MBC appeared higher than that reported in RCTs, particularly in elder patients. In spite of this, median survival, was, if anything, better.

Long term survival of HER2-positive early breast cancer treated with trastuzumab-based adjuvant regimen: A large cohort study from clinical practice

Trastuzumab-based regimens for the adjuvant treatment of HER2-positive early breast cancer significantly prolonged overall survival (OS) and disease free survival (DFS) in large randomized trials, with sustained benefits at four-year follow-up. We assessed long-term survival estimates and predictors in a large cohort of Italian women with early breast cancer treated with trastuzumab in clinical practice. Through a record linkage between five regional healthcare databases, we identified women treated with trastuzumab for early breast cancer in Lombardy (2006-2009). DFS and OS were estimated using the Kaplan-Meier method, and independent predictors were assessed using proportional hazard models. 2046 women received trastuzumab in early breast cancer adjuvant setting. Overall, the proportion of patients surviving free of disease was 93.9% at one year, 85.8% at 2 years, 79.4% at 3 years, and 75.0% at 4 years. OS estimates were 98.7%, 95.4%, 91.5% and 89.4% at 1, 2, 3 and 4 years, respectively. Significant independent predictors of worse survival outcomes were age <40 or ≥70 years compared to age 40-69 years, positive nodal status, radical breast surgery, combination therapy with paclitaxel, having at least one comorbidity (i.e. diabetes, cardiovascular disease), and a trastuzumab-based regimen lasting less than six months. Long term survival rates of women treated with trastuzumab for early breast cancer in clinical practice were consistent with estimates from clinical trials testing the drug in the adjuvant setting.

Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases.

Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics.

Why do smokers start

Most studies investigating the reasons for smoking initiation are based on adolescents or young individuals. We considered the issue in a large dataset on the general Italian population. Six population-based surveys on smoking were conducted annually from 2005 to 2010 on representative samples of Italian individuals aged 15 years or over, involving more than 3000 individuals each year. A specific question on the main reason to start smoking was asked to 7469 ever smokers. Overall, 59.9% of ever smokers started smoking before 18 years of age and 33.6% started smoking before 16 years of age. Among ever smokers, 61.1% reported having started smoking because of the influence of friends, 15.6% for enjoyment and satisfaction, 9.0% to feel mature and independent, 6.6% because of the influence of partner/family, 2.5% because of stress, 1.9% to feel more secure and 1.8% for curiosity. The finding that the majority of Italian men and women – particularly those who started smoking at a young age – started smoking because of the influence of friends suggests that antismoking campaigns should consider social influence, resistance and the dimension of self-esteem. An improvement in the legislation prohibiting the purchase of tobacco products by minors aged less than 18 years and a smoking ban in school courtyards are urgently required in Italy.

Prevalence and incidence of psoriatic arthritis: A systematic review and meta-analysis

BACKGROUND Psoriatic arthritis (PsA) is a specific form of inflammatory arthritis associated with psoriasis affecting in the same measure men and women but with a consistent geographic variability. Since the burden of PsA frequency has important implications in the definition of the healthcare policies, it is important to measure the frequency of disease in the general population. OBJECTIVE To quantify the global health burden of PsA summarizing the data provided by the population-based available studies investigating prevalence and incidence of the disease. METHODS A MEDLINE search was performed to identify all studies reporting the prevalence or incidence of PsA. Fixed- and random-effect models were fitted to estimate the prevalence and incidence pooled estimates. Between-study heterogeneity was evaluated using the Q statistic and the I2 index and Publication bias using Eggers asymmetry test. RESULTS Twenty-eight studies were included in the meta-analysis, 17 retrieved from the literature search and 11 from the meta-analysis of Alamanos et al. The random effect pooled PsA prevalence and incidence rates are respectively 133 every 100,000 subjects (95% CI, 107-164 every 100,000 subjects) and 83 every 100,000 PY (95% CI, 41-167 every 100,000 PY). High between-study heterogeneity was found for both prevalence and incidence estimates. CONCLUSIONS This study allowed the estimation of a global average prevalence and incidence rates of PsA and the evaluation of the geographic variability. The high between-study heterogeneity suggests the importance to look not only at the pooled estimates but also at the study-specific estimate.

Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies

OBJECTIVE Concerns have been raised about a possible increased risk of pancreatic cancer associated with incretin-based therapies. We examined the risk of pancreatic cancer among patients with diabetes prescribed incretin drugs. RESEARCH DESIGN AND METHODS With the use of public health insurance databases of Belgium and the Lombardy Region, Italy, we created two retrospective cohorts that included adult patients who were first prescribed an incretin drug or another noninsulin antidiabetic drug (NIAD) from 1 July 2008 to 31 December 2013 in Belgium and from 1 January 2008 to 31 December 2012 in the Lombardy Region. The risk of pancreatic cancer was evaluated by multivariate-adjusted Cox models that included time-dependent variables. Adjusted hazard ratios (aHRs) from Belgium and Italy were pooled by using fixed-effects meta-analyses. RESULTS The cohorts included 525,733 patients with diabetes treated with NIADs and 33,292 with incretin drugs. Results in both cohorts were similar. Eighty-five and 1,589 subjects who developed pancreatic cancer were registered among the incretin and NIAD new users, respectively, which represented an aHR of pancreatic cancer of 2.14 (95% CI 1.71–2.67) among those prescribed an incretin compared with an NIAD. The aHR with a drug use lag exposure of 6 months was 1.69 (1.24–2.32). The aHR decreased from 3.35 (2.32–4.84) in the first 3 months after the first incretin prescription to 2.12 (1.22–3.66) in months 3–5.9, 1.95 (1.20–3.16) in months 6–11.9, and 1.69 (1.12–2.55) after 12 months. Among those prescribed an NIAD, pancreatic cancer occurred mostly within the year after the first prescription. The risk of pancreatic cancer among patients subsequently prescribed insulin was 6.89 (6.05–7.85). CONCLUSIONS The recent prescription of incretin therapy is associated with an increased risk of pancreatic cancer. The reason for such an increase is likely the consequence of an occult pancreatic cancer that provokes or aggravates diabetes. Studies are warranted for assessing the risk of pancreatic cancer associated with long-term use of incretin drugs.