Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise.

BACKGROUND: Physical activity may increase the risk of cardiotoxicity (myocardial ischemia, major arrhythmias) of 5-Fluorouracil, but this risk has never been investigated for its prodrug capecitabine. PATIENTS AND METHODS: One hundred and ninety-two consecutive patients undergoing capecitabine chemotherapy from December 1, 2010 through July 31, 2016 were prospectively evaluated. The baseline evaluation included electrocardiography (ECG) and echocardiography (2DE); a follow-up evaluation, including ECG and exercise stress testing (2DE in case of ECG abnormalities), was done after ≥10 days of treatment. Cardiotoxicity was suspected from ischemic ECG changes, new kinetic abnormalities at 2DE, Lown classification ≥2 ventricular arrhythmia, symptomatic arrhythmias, or positive stress test, and confirmed by a negative stress test after capecitabine washout. RESULTS: Cardiotoxicity was diagnosed in 32 patients (16.7%): six at rest and 26 during exercise. All 32 patients had ECG abnormalities: ST-segment changes (24 patients), negative T-waves (2) and/or arrhythmias: ventricular arrhythmias (14 cases), supraventricular tachycardia (2), complete heart block (1). Eight patients had typical symptoms, 6 had atypical symptoms, 1 had syncope, 17 (53%) were asymptomatic. Cardiotoxicity was more common in patients with atypical symptoms during daily life (OR = 15.7) and in those on a therapeutic schedule of 5 days/week (OR = 9.44). CONCLUSION: Capecitabine cardiotoxicity is frequent, and often elicited by physical effort. Oncologists, cardiologists, and general practitioners should be aware of this risk. Active cardiotoxicity surveillance with ECG (and echocardiogram and/or stress testing in suspected cases) during therapy is recommended. CLINICAL TRIALS REGISTRATION NUMBER: CRO-2010-17.

Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B-cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi.

The purpose of this phase 2, multicenter study was to determine the activity and safety of nonpegylated liposomal doxorubicin as part of "R-COMP" combination in patients with diffuse large B-cell lymphoma and coexisting cardiac disorders. The study was conducted using a Bayesian continuing assessment method using complete remission rate and rate of cardiac events as study endpoints. Between November 2009 and October 2011, 50 evaluable patients were enrolled (median age, 76 years). Median baseline left ventricular ejection fraction (LVEF) was 60%. Ischemic cardiopathy was the most frequent preexisting cardiac disorder (35%), followed by atrial fibrillation (15%), left ventricular hypertrophy (13%), and baseline LVEF <50% (12%). Based on the intent to treat analysis, overall response rate was 72%, including 28 patients in complete remission (complete remission rate, 56%), and 8 in partial remission (16%). At the end of treatment, grades 3 to 4 cardiac events were observed in 6 patients. No significant modifications from baseline values of LVEF were observed during treatment and follow-up. Nonpegylated liposomal doxorubicin instead of doxorubicin in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is a feasible option for patients with diffuse large B-cell lymphoma presenting with concomitant cardiac disorders.

Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients.

BACKGROUND: Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients' immunological background to the induction of clinical responses. METHODS: Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab ± hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months. RESULTS: From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcγRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P ≤0.05). CONCLUSIONS: In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2-overexpressing BC. TRIAL REGISTRATION: Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).

The puzzling clinical presentation of fluoropyrimidines cardiotoxicity.

The cardiotoxicity of fluoropyrimidines (FP) [5-Fluorouracil and Capecitabine] is often reported as acute cardiac ischemia with rest typical angina, signs of ischemia at electrocardiogram (ECG), and ventricular kinetics abnormalities. However, silent ischemia, effort-related toxicity, and ventricular arrhythmias (VA) have been also described. The aim of this study is to report a consecutive series of 115 patients with FP cardiotoxicity observed in a single center both within clinical prospective studies and during the clinical routine. The clinical presentation widely varied as regards symptoms, ECG abnormalities, and clinical outcomes. We report also the strategies used to prevent cardiotoxicity in a subgroup of 35 patients who continued o rechallenged FP therapy after cardiotoxicity. In nearly half of the patients, the cardiotoxicity was triggered by physical effort. Typical angina was rare: the symptoms were absent in 51% of cases and were atypical in half of the other cases. ST-segment elevation and VA were the most frequent ECG abnormality; however, ST segment depression or negative T waves were the only abnormalities in 1/3 of the cases. Troponins essays were often within the normal limits, even in presence of extensive signs of ischemia. The most effective strategy to prevent cardiotoxicity at rechallenge was reducing FP dosage and avoiding physical effort. Anti-ischemic therapies were not always effective. Raltitrexed was a safe alternative to FP. Fluoropyrimidine cardiotoxicity shows a wide variety of clinical presentations in real life, from silent ischemia to atypical symptoms, acute coronary syndrome, left ventricular dysfunction (LVD), VA, or complete atrio-ventricular block. Physical effort is the trigger of cardiotoxicity in nearly half of the cases. The recognition of cardiotoxicity cannot rely on symptoms only but requires an active screening with ECG and stress test in selected cases.

[Long QT and torsade de pointes in a patient with acquired human immunodeficiency virus infection in multitherapy with drugs affecting cytochrome P450]. / Allungamento del QT e torsione di punta in un paziente con immunodeficienza virale acquisita in multiterapia con farmaci utilizzatori del citocromo P450.

In acquired human immunodeficiency virus (HIV) infection, a long depolarization period at ECG may be the consequence of cardiac complications due to viral myocarditis or cardiomyopathy or indirectly due to autonomic neuropathy, or sometimes resulting from pharmacological treatments. Several drugs administered for direct treatment of HIV disease or its complications, such as antiretrovirus, fluconazole, and antibiotics, may induce ventricular arrhythmias due to long QT prolonged depolarization period. Also methadone, frequently associated with HIV therapy to treat patients with opiate addiction, is described in the literature to have cardiac inotropic effects. It has also the potential to increase the QT period and to develop ventricular torsade de pointes, primarily through interference with the rapid component of the delayed rectifier potassium ion current. Moreover, the use of methadone associated with other inhibitors of cytochrome P450 might increase plasma concentrations and contribute to methadone cardiac toxicity. We report the case of an HIV patient receiving antiretroviral treatment, fluconazole and high-dose methadone, who suddenly complained of vertigo, dizziness, pre-syncope and syncope due to severe ventricular arrhythmias that disappeared after discontinuation of all treatments.

Neoplastic pericardial disease in lung cancer: impact on outcomes of different treatment strategies. A multicenter study.

BACKGROUND: Local (intrapericardial) chemotherapy has been reported to be useful for the treatment of neoplastic pericardial disease, but it has never been compared to systemic chemotherapy, a combination of the two and simple pericardial drainage or sclerosis. METHODS: We analyzed the clinical and echocardiographic data of 119 patients, suffering of neoplastic pericarditis due to lung cancer (97 with non-small-cell), comparing the outcomes of four different treatment strategies (extended catheter drainage/sclerosis, systemic chemotherapy, local chemotherapy, and combined - local plus systemic - chemotherapy) at the last available follow-up or at the change of therapy after a treatment failure. The outcomes (based on semiquantitative evaluation of pericardial disease) were classified as complete, partial, no response and progressing disease. RESULTS: A complete response was achieved in 37/53 of patients with combined, in 12/22 with local, in 5/27 with systemic chemotherapy, respectively, and in 4/17 after drainage/sclerosis (p<0.001). Overall response was achieved in 51/53 with combined, 18/22 and 16/27 with local or systemic chemotherapy, respectively, and in 5/17 with drainage/sclerosis only (p<0.001). Survival was significantly better after combined chemotherapy (p<0.001) and 12/53 patients (23%) in this subgroup survived more than 1 year. The overall response rate was higher with intrapericardial cisplatinum than with other agents (98% vs 80%, χ(2)=7.69, p<0.01). CONCLUSIONS: Local chemotherapy, alone or with systemic chemotherapy, is effective in treating pericardial metastases from lung carcinoma, leading to a good control of pericardial effusion in 92% of cases, and to complete disappearance of effusion and masses in 65%. Combined therapy is significantly better than any other treatment. Pericardiocentesis and intrapericardial chemotherapy should be used whenever possible in lung cancer neoplastic pericardial disease, not only in case of tamponade.

Capecitabine cardiac toxicity presenting as effort angina: a case report.

We report a case of capecitabine-induced cardiotoxicity (effort angina) in a woman with metastatic breast carcinoma. Due to cancer progression, rechallenge of therapy with capecitabine was attempted, using several strategies in order to prevent cardiotoxicity. The most (even if not fully) effective strategy was reducing capecitabine dosage together with nitrates, calcium-channel blockers and trimetazidine therapy.

Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cis-platin.

The antimetabolite 5-fluorouracil is frequently used in the therapy of various malignancies. Cardiotoxicity has frequently been described during treatment, but there is no common agreement on the need to perform cardiovascular monitoring of patients during 5-fluorouracil administration. We report the case of a young patient with an head-neck cancer on whom a continuous electrocardiogram recording was performed, documenting serious ventricular dysrhythmias in the presence of myocardial ischemia during 5-fluorouracil and cis-platin infusion.