Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial.

BACKGROUND: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. METHODS: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. FINDINGS: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. INTERPRETATION: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.

Reliability of Left Ventricular Ejection Fraction from Three-Dimensional Echocardiography for Cardiotoxicity Onset Detection in Patients with Breast Cancer.

BACKGROUND: Cardiotoxicity is a well-known adverse effect of various chemotherapeutic agents that can be monitored by echocardiography. A decrease in left ventricular ejection fraction (LVEF) triggers consideration for therapy modification or interruption. The aim of this study was to evaluate how variability in LVEF estimates computed using three-dimensional echocardiography could influence cardiotoxicity onset detection. METHODS: One hundred eighty one patients with breast cancer treated with anthracycline and trastuzumab were analyzed. LVEF was computed using two commercial software packages. In a subgroup of 40 patients, three-dimensional echocardiographic data were reanalyzed to assess intra- and interobserver variability by two expert investigators using both packages. Global longitudinal strain (GLS) imaging was evaluated in 64 patients. RESULTS: End-diastolic volume, end-systolic volume, and LVEF measurements obtained applying the two software packages were in good agreement, with small bias and acceptable limits of agreement. Intra- and interobserver variability was smaller using one of the two software packages. However, for both packages, variability indexes were in the range of affecting LVEF estimates at a level that could lead to an inaccurate assessment of cardiac adverse effects of cancer therapeutic drugs. On the basis of LVEF, 11 of 181 patients (6.1%) had cardiotoxicity at 3-month follow-up. The absolute value of GLS was smaller in 16 of 64 patients (25%) thought to have cardiotoxicity on the basis of GLS results, including six of seven patients who had cardiotoxicity considering LVEF in this subgroup. CONCLUSIONS: Following clinical definition of cardiotoxicity onset, variability in LVEF computation by three-dimensional echocardiography could be a confounding factor for cardiotoxicity diagnosis, and different software packages should not be used interchangeably for LVEF monitoring. GLS confirms its predictive value for subsequent cardiotoxicity.

Paraneoplastic hypocalcemia-induced heart failure in advanced breast cancer: A case report and literature review.

Hypocalcemia is an uncommon clinical symptom of patients with malignant tumors, and a number of factors may be involved in its development. The present study describes the case of a 67-year-old Caucasian female, presenting with severe refractory hypocalcemia and heart failure. The patient was subsequently diagnosed with breast cancer and bone metastases. The paraneoplastic origin of the syndrome was confirmed by its complete resolution once the tumor responded to specific antineoplastic treatments, comprising weekly paclitaxel and aromatase inhibitor administration. The present case report suggested the need for greater awareness of the possibility of paraneoplastic hypocalcemia in breast cancer patients, and suggested that this condition may also contribute to the occurrence of heart failure. The mechanisms potentially responsible for this event were discussed and a brief review of the literature presented.

Taxanes as a risk factor for acute adverse reactions to iodinated contrast media in cancer patients.

BACKGROUND: The impact of cytotoxic agents on the risk of acute allergy-like adverse reactions (ARs) to intravenous iodinated contrast media (ICM) injections is unknown. METHODS: We retrospectively reviewed 13,565 computed tomography (CT) scans performed in a consecutive cohort of cancer patients from January 1, 2010 to December 31, 2012. Episodes of acute ICM-related ARs were reported to the pharmacovigilance officer. The following matched comparisons were made: tax code, gender, primary tumor, antineoplastic therapy, and date of last cycle. Concomitant antineoplastic treatment was classified into five groups: platinum, taxane, platinum plus taxane, other, and no treatment group (no therapy had been administered in the previous 24 months). Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) to evaluate the risk of acute ICM-related ARs. RESULTS: Of 10,472 contrast-enhanced CT scans, 97 (0.93%; 95% CI: 0.74-1.11) ICM-related ARs were reported, 11 of which (0.1%) were severe, including one fatality. The overall incidence was significantly higher in patients aged <65 years (p = .0062) and in the platinum plus taxane and taxane groups (p = .007), whereas no correlation was found with gender, number of previous CT scans, site of disease, or treatment setting. Multivariate analysis confirmed an increased risk for patients aged <65 years (OR: 1.73; 95% CI: 1.14-2.63) and for the taxane group (in comparison with the no treatment group; OR: 2.06; 95% CI: 1.02-4.16). CONCLUSION: Among cancer patients, concomitant treatment with taxanes and younger age would seem to be risk factors for ICM-related ARs.

Separate episodes of capillary leak syndrome and pulmonary hypertension after adjuvant gemcitabine and three years later after nab-paclitaxel for metastatic disease.

BACKGROUND: Systemic capillary leak syndrome is a rare disease with a high mortality rate. This syndrome is characterised by generalised edema, hypotension, hemoconcentration, and hypoproteinemia. The cause is the sudden onset of capillary hyperpermeability with extravasations of plasma from the intravascular to the extravascular compartment. We present the case of a patient who experienced two episodes of systemic capillary leak syndrome and pulmonary hypertension; the first after gemcitabine in an adjuvant setting and the second three years later after treatment with nab-paclitaxel for metastatic disease. CASE PRESENTATION: A 65-year-old patient underwent a pancreatectomy in January 2010 for ductal carcinoma (pT3 N0 M0, stage IIa), followed by adjuvant chemotherapy. Seven days after the last cycle, she developed dyspnea associated with orthopnea and cough. A transthoracic cardiac ecocolordoppler was performed, with evidence of pulmonary hypertension (58 mmHg). Blood tests showed an increase in creatinine, pro-BNP and D-Dimer. She began high-dose diuretic therapy combined with cortisone. After a month, the patient was eupneic and the anasarca had resolved. We decided gradually to reduce the steroid and diuretic therapy. After ten days of the reduction, the patient began to re-present the same symptoms after treatment with gemcitabine. Corticosteroid therapy was restored with rapid clinical benefit and decreased pro-BNP after a week of treatment. After two years, the disease returned. As a first line treatment, it was decided to use nab-paclitaxel 100 mg/m2 weekly. After two doses, followed by approximately 14 days of treatment, the patient developed acute respiratory distress syndrome. The clinical suspicion was a relapse of capillary leak syndrome and treatment with a high-dose diuretic (furosemide 250 mg daily) was started combined with cortisone (40 mg methylprednisolone). The patient showed a progressive clinical benefit. CONCLUSIONS: In patients treated with gemcitabine and nab-paclitaxel who experience a sudden onset of diffuse edema with respiratory distress, capillary leak syndrome should be suspected. Immediate treatment with corticosteroids may be life-saving.

Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors.

OBJECTIVE: Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. DESIGN: Retrospective study. SETTING: Institute for Cancer Research and Treatment, Medical Oncology Department. PATIENTS: Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. MAIN OUTCOME: Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥ 15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (ß-blockers, ACE inhibitors and/or angiotensin receptor blockers). RESULTS: Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m(2) of doxorubicin or >500 mg/m(2) of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). CONCLUSIONS: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

A phase IB dose-finding trial of liposomal doxorubicin in combination with capecitabine in patients with pretreated metastatic breast cancer.

PURPOSE: Anthracyclines and fluoropyrimidines are very active in breast cancer, while liposomal doxorubicin has low cardiotoxicity. We conducted a dose-finding study of the combination of liposomal doxorubicin and capecitabine in patients with pretreated metastatic breast cancer. PATIENTS AND METHODS: Patients received liposomal doxorubicin 60 mg/m2 on day 1 plus capecitabine 825 mg/m2 bid (level 0) or 1,000 mg/m2 bid (level 1) on days 1-14 of each 21-day cycle to establish the maximum tolerated dose (MTD) and cardiac safety. RESULTS: Nine patients were enrolled and a total of 52 courses were delivered (median 6 cycles per patient [range 4-7]). Grade 4 neutropenia occurred in 15% of cycles, with one episode of febrile neutropenia; most nonhematological toxicities were mild or moderate. No formal MTD was established, and the study was closed because two cardiac events were observed at dose level 1 and another at dose level 0 in patients pretreated with epirubicin > or = 560 mg/m2. CONCLUSIONS: The recommended dose for phase II studies is liposomal doxorubicin 60 mg/m2 on day 1 plus capecitabine 825 mg/m2/bid on days 1-14 of each 21-day cycle. Despite the lower cardiotoxicity of liposomal doxorubicin, the risk of cardiac damage persists in anthracycline-pretreated individuals and mandates close cardiac monitoring and careful evaluation of the overall cumulative dose.

The association between atrial septal aneurysm and mitral valve prolapse in patients with recent stroke and normal carotid arteries.

BACKGROUND: The association between mitral valve prolapse (MVP) and cryptogenic stroke is controversial. The Atrial Septal Aneurysm Multicenter Italian (ASA-MI) Study is a prospective multicenter study evaluating the prevalence of atrial septal aneurysm (ASA) in patients with a recent stroke and normal carotid arteries. The aim of the present research was to evaluate the frequency of ASA and its association with MVP in the stroke population and in the subgroup of young patients (< 55 years) included in the ASA-MI Study. METHODS: The study group included 245 of the 606 patients referred for transesophageal echocardiography (168 men and 77 women, mean age 65.7 +/- 21 years). All patients were selected on the basis of a recent episode of unexplained cerebral ischemia and were included in the study if they had normal carotid arteries. The control population included 245 patients (mean age 64.7 +/- 23 years) who underwent transesophageal echocardiographic evaluation during the same period for indications other than cerebral ischemia. The subgroup of young patients (< 55 years) included 90 patients (61 men and 29 women, mean age 49 +/- 5 years). RESULTS: The prevalence of MVP was 18% (95% confidence interval 8 to 21%) in the stroke population and 15% (95% confidence interval 7 to 20%) in the control population (chi 2 = 2.1, p = NS). The prevalence of MVP did not differ between young stroke patients (28.8%) and young controls (20%) (chi 2 = 0.835, p = 0.3). MVP was not significantly associated with stroke. We found an association between ASA and MVP: there was a higher incidence of MVP in stroke patients with an ASA than in patients without stroke or an ASA (40.9 vs 25%, p < 0.05). There was also a higher frequency of MVP associated with ASA in the group of young patients than in all patients of the ASA-MI Study (28.8 vs 18%, chi 2 = 20.313, p < 0.001). CONCLUSIONS: We found an association between ASA and MVP in patients with recent stroke and this association bore a higher risk of cerebral events than in patients without these abnormalities.

Association between atrial septal aneurysm and patent foramen ovale in young patients with recent stroke and normal carotid arteries.

BACKGROUND: Atrial septal aneurysm (ASA) has been considered a potential source of cardiogenic embolism for many years. The ASA Multicenter Italian (ASA-MI) Study evaluated the prevalence and characteristics of ASA in patients with stroke and normal carotid arteries compared with control patients without stroke. The purpose of the present study was to evaluate the frequency of ASA and the association with patent foramen ovale (PFO) in the subgroup of younger patients (aged less than 55 years) included in the ASA-MI Study. METHODS: The ASA-MI Study included 606 patients, enrolled between November 1990 and December 1996: 245 patients with a previous cerebral embolic attack and normal carotid study and a control group of 316 patients. They all underwent transthoracic and transesophageal echocardiography. The subgroup of younger patients aged less than 55 years included 90 patients (61 men and 29 women of mean age 49 +/- 5 years) (group AY). This group was evaluated and compared with an age- and sex-matched control population (61 men; of mean age 48 +/- 6 years) (group BY). RESULTS: The prevalence of ASA was 48.8% (95% confidence interval 40-61) in group AY and 22.2% in the group BY (95% confidence interval 18-33) (chi(2) = 5.968; p = 0.01). Morphological features were similar in the 2 groups of patients. ASA involved the entire septum in 52% of patients of group AY, and in 47.2% of group BY. The prevalence of PFO was 58.8% (95% confidence interval 43-62) in group AY and 28.8% in group BY (95% confidence interval 17-35) (chi(2) = 5.811; p = 0.01). A strong association was found between ASA and PFO. Of the 90 younger patients with stroke, 39 of 44 (88.6%) with ASA also had PFO, compared with 14 of 46 (30.4%) without ASA (chi(2) = 7.370; p = 0.007). CONCLUSION: We found that ASA and PFO were independent predictive factors for stroke in younger patients with stroke and normal carotid arteries and that the association between ASA and PFO bore an increased odds risk.