Adverse reactions to oncologic drugs: spontaneous reporting and signal detection

Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting

Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer

Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy.In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m(2) intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles.Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported.Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients.NCT02131506 (ClinicalTrials.gov identifier)

Bowel preparation for CT colonography

Bowel preparation represents an essential part of CT colonography, as the accuracy of the exam is strongly related to the adequacy of colonic cleansing, and a poor bowel preparation may compromise the diagnostic quality even despite optimization of all other acquisition parameters. Residual stool and fluid in the large bowel may affect the interpretation of the exam and may increase the number of false positives and false negatives. In this regard, the majority of patients having undergone CT colonography state that bowel preparation is the most unpleasant part. Unfortunately, to date no definite consensus has been reached about the ideal bowel preparation technique, and there is great variability in preparation strategies across diagnostic centers. The purpose of this review article is to describe the development and evolution of bowel preparation techniques in order to choose the best approach for optimizing the diagnostic quality of CT colonography in each patient

Acute portal vein thrombosis precipitated by indomethacin in a HCV-positive elderly patient

BACKGROUND: An increased risk of venous thromboembolism has been reported in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We describe a case of acute portal vein thrombosis (PVT) in a hepatitis C virus (HCV)-positive elderly patient following administration of indomethacin. CASE PRESENTATION: A 79-year-old HCV-positive man was hospitalized for severe abdominal pain, nausea and vomiting, 15 days after starting indomethacin for back pain. Clinical signs and imaging evaluations disclosed a picture of PVT. Indomethacin was discontinued, and the patient was started on fondaparinux and antithrombin. He was discharged 15 days later due to improvement of his clinical conditions. Thirty days later, a follow-up ultrasound did not show appreciable signs of PVT. The time elapsing between the start of analgesic therapy and PVT onset suggests a role of indomethacin as the triggering agent. Indomethacin could have precipitated PVT by a combination of at least two detrimental mechanisms: 1) direct action on liver vascular endothelium by inhibition of prostacyclin biosynthesis; 2) damage to the intestinal mucosa, followed by inflammatory and pro-coagulant activation of portal endothelium upon exposure to bacterial endotoxins. CONCLUSIONS: This case can be of interest to physicians, who should exert caution when prescribing NSAIDs for inflammatory pain in patients with background inflammatory dysfunctions of the portal vein endothelium

Autoimmune haemolytic anaemia following MF59-adjuvanted influenza vaccine administration: a report of two cases

OBJECTIVE: To describe 2 cases of autoimmune hemolytic anemia (AIHA) following the administration of MF59-adjuvanted influenza vaccine. CASE SUMMARY: An 83-year-old white woman developed persistent hyperpyrexia, polyarthralgia, and lower limb hypostenia about 2 days after receiving influenza vaccine. Clinical signs and laboratory evaluations suggested AIHA. The patient was treated with high-dose corticosteroids and immunoglobulins, and her clinical condition improved. A 74-year-old white woman developed severe abdominal pain and asthenia 3 days after the administration of influenza vaccine. Clinical signs and laboratory evaluations disclosed AIHA. She was treated with corticosteroids, rehydration, and blood transfusion; however, she died about 48 hours after hospitalization. DISCUSSION: AIHA has been rarely described following influenza vaccine administration. In the cases described here, the causal relationship between influenza vaccination and the occurrence of AIHA, assessed by means of World Health Organization criteria, was scored as probable. It has been proposed that the mechanism whereby vaccines induce autoimmune responses can be molecular mimicry, although a possible role of other vaccine constituents, with particular regard for adjuvants, such as MF59, can not be excluded. Squalene, a constituent of MF59, has been suggested as a causative agent of autoimmune reactions. However, it is not clear how and under what conditions squalene can cause immune responses. CONCLUSIONS: Influenza vaccination may rarely trigger severe AIHA, shortly after vaccine administration. A mechanism of molecular mimicry is probably involved in the development of these reactions, although the possible role of adjuvants can not be excluded. Patients should be instructed to report signs and symptoms of autoimmune disorders occurring in the first weeks after administration of influenza vaccine

Estimation of Theoretical Cost Preventability Achievable with an Effective Pharmacovigilance Activity in a Pharmacovigilance Regional Centre in Italy

Introduction: The management of patients with adverse drug events (ADEs) has a significant economic impact owing to hospitalization and treatment costs. Recently, social and healthcare costs related to ADEs have become a relevant issue, and they are increasingly being included in budget estimations for health resource allocations. Aim: To evaluate the costs of ADEs and their predictability, and to estimate the impact of a pharmacovigilance facility on ADE-related cost savings within a regional healthcare system. Methods: A systematic review of English medical literature quoted in PUBMED (January 2005–March 2015) was conducted. We included all studies performed in Western Europe, USA and Canada about direct costs of ADEs in inpatient settings, for which the mean cost of serious and/or not-serious ADEs could be estimated. Studies on specific side-effects or drug-classes were excluded. The following data were extracted: mean cost of ADEs; percentage of preventable ADEs; charges for outpatient care and medications. The mean cost (into Euros) of serious and not-serious ADEs and the mean percentage of preventable ADEs were estimated. Based on spontaneous ADE reports recorded by the Tuscan Pharmacovigilance Centre in 2014, the theoretical cost of ADEs in Tuscany (3,704,152 inhabitants) was calculated. A sensitivity analysis was performed about cost (mean cost ±standard deviation ±50 %), and preventability (the maximum and minimum percentage estimated). The resulting range of ADE costs and the theoretically costs-saving that can be achieved with the implementation of pharmacovigilance activities were assessed. Results: Fourteen studies were analyzed: 13 on serious ADEs; 3 on costs of not-serious ADEs; 8 on percentage of preventability. The mean cost of an ADE was: €3526 ± 1927 for serious and €172 ± 93 for not serious. We estimated a mean preventability of 51.3 ± 21 %. In 2014, the Italian National Network of Pharmacovigilance database accounted for 1498 serious ADEs and 2997 not-serious ADEs in Tuscany (1214 ADEs/million- inhabitants). The overall costs of ADEs incurred by the Tuscan Regional Healthcare System was: €5281,948 (€1,425,953/million-inhabitants; sensitivity analysis: €3304,827–322,957/million-inhabitants) for serious ADEs; €515,484 (€139,164/million-inhabitants; sensitivity analysis: €321,094 32,117/million-inhabitants) for not-serious ADEs. Based on the estimated preventable costs in Tuscany, an effective pharmacovigilance system could allow to save €2,974,083 (€802,905/million-inhabitants; sensitivity analysis: €1,697,370–237,115/million-inhabitants) over one-year. Conclusion: Resource allocations to improve the regional pharmacovigilance systems might increase appropriateness and safety of therapies, thus reducing the costs incurred by regional healthcare systems. It could be obtained through: ADE evaluation systems; computerized prescription systems with alerts; continuing education of health professionals; multidisciplinary support to medical therapies

Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer

Trastuzumab prolongs survival in women with HER2-positive breast cancer, but may increase the risk of heart disease. The occurrence of severe cardiotoxicity, however, is not defined in real-life settings. We performed a meta-analysis of clinical trials and cohort studies to estimate the frequency of cardiotoxicities following trastuzumab treatment. We searched MEDLINE, EMBASE, and the Cochrane Library (1996\u2013January 2014). The primary outcome was the frequency of severe cardiotoxicities up to 3-years after trastuzumab initiation. Among 58 studies (29,598 patients), severe cardiotoxicity occurred in 3.00\ua0% (95\ua0% CI 2.41\u20133.64), 2.62\ua0% (95\ua0% CI 1.97\u20133.35), and 3.14\ua0% (95\ua0% CI 2.12\u20134.37) of overall, early (EBC) and metastatic (MBC) breast cancer patients, respectively. In EBC, the proportion increased from 2.40\ua0% at the first year to a plateau of approximately 3\ua0% after the second year. In MBC, the proportion increased from 3.00 to 3.68\ua0% when trastuzumab was used as first line or further lines of therapy, respectively. In EBC, cardiotoxicity occurred in 2.90\ua0% of patients treated with taxanes and anthracyclines compared to 0.92\ua0% in patients treated with taxanes without anthracyclines. The occurrence of cardiotoxicity varied according to age, increasing from 2.31\ua0% in individuals 60\ua0years of age. Cardiotoxicity was higher in smokers (5.3\ua0%), dyslipidemic patients (3.9\ua0%), BMI 6525 (6.5\ua0%), diabetes (6.2\ua0%), hypertension (5.5\ua0%), or positive history of cardiac disease (19.1\ua0%). RCTs consistently report lower cardiac toxicity rates than observational studies (EBC: 1.7 versus 3.2; MBC: 2.8 versus 4.4). Following trastuzumab initiation, approximately three in 100 patients develop severe cardiotoxicity after 2\ua0years. Patients enrolled in cohort studies, who more closely reflect women treated for breast cancer in real-life settings compared to RCTs, are at higher risk of developing cardiac events

Giant fibrovascular polyp of the esophagus-imaging techniques for proper treatment planning: report of two cases

Giant fibrovascular polyps of the esophagus are rare, benign mesenchymal intraluminal lesions that arise from the cervical esophagus and can reach a very large size. Surgical excision is the treatment of choice, since endoscopic removal alone is not always feasible due to the presence of a very much vascularized stalk in most cases. We present two archetypal cases emphasizing the fact that these lesions can grow to huge masses with various and bizarre clinical presentation and they can arise (although rarely) at the level of the hypopharynx. We also aim to point out the role of imaging in defining the exact origin and characteristics of the stalk (width, vascularization) and the polyp structure (tissue components), thus providing useful information for planning the most appropriate surgical approach

Muscular adverse drug reactions associated with proton pump inhibitors: a disproportionality analysis using the Italian National Network of Pharmacovigilance database

Introduction: After cerivastatin marketing withdrawal for rhabdomyolysis’s fatal cases [1], statins represent the drug class most commonly associated with muscular adverse drug reactions (ADRs) [2]. However, also proton pump inhibitors (PPIs) have been related to myopathies [3]. Unfortunately, these potential signals may be under-detected due to the statins masking effect. Aim: To assess the reporting risk of muscular ADRs with PPIs on spontaneous reports in the Italian Pharmacovigilance Network database. Methods: A case/non-case analysis on data from July 1983 to May 2016 was performed. Published case reports, reports on adverse events following immunization, low-quality reports and duplicate reports were excluded [4]. Cases were identified by reports containing at least one muscular ADR. Non-cases were all reports containing ADRs other than muscular ones. In the primary analysis, reports with at least one suspected PPI were classified as index group while all other reports were the reference. Reporting odds ratio (ROR) and 95% confidence intervals (CIs) were calculated [5]. A sub-analysis only on rhabdomyolysis reports in the cases group was performed. In a secondary and tertiary analysis, we explored the association of PPIs with muscular ADRs after removing the statins masking effect [6]. The unmasking was performed by excluding reports with suspected statins and by including cases with at least one PPI (both suspected and concomitant). Moreover, a possible PPIs-statins interaction was also tested. The RORs were adjusted for age, gender, number of drugs and thyroid diseases by logistic regression. Results: Overall 274,108 reports were analysed. In the primary analysis, the RORs of muscular ADRs for PPIs, adjusted for age and gender, was 1.484 (95% CI 1.204–1.829; p.001), whereas the adjusted ROR for rhabdomyolysis was 0.621 (95% CI 0.258–1.499). In the secondary analysis, similar results were obtained (adjusted ROR 1.200; 95% CI 0.447–3.224). A potential association of rhabdomyolysis-PPIs was detected in the tertiary analysis, where PPIs were considered independently from their role (adjusted ROR: 1.667, 95% CI 1.173–2.369; p.01). No potential signal with PPI-statin interaction and muscular ADR/rhabdomyolysis was observed. Discussion: RORs for rhabdomyolysis did not reach the minimum criteria for signal detection. Only in the tertiary analysis, the rhabdomyolysis frequency related to PPIs was higher than any other ADRs, when compared to reports not including PPIs or statins. However, this finding should be confirmed by further investigations. Conclusion: A potential signal of disproportionate reporting for muscular ADRs related to the whole PPI class was identified and this was enhanced after the unmasking