Maurizio Civelli

Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition

Background— An increase in troponin I soon after high-dose chemotherapy (HDC) is a strong predictor of poor cardiological outcome in cancer patients. This finding has important clinical implications and provides a rationale for the development of prophylactic strategies for preventing cardiotoxicity. Angiotensin-converting enzyme inhibitors slow the progression of left ventricular dysfunction in different clinical settings, but their role in the prevention of cardiotoxicity has never been investigated. Methods and Results— Of the 473 cancer patients evaluated, 114 (72 women; mean age, 45±12 years) who showed a troponin I increase soon after HDC were randomized to receive (angiotensin-converting enzyme inhibitor group; 20 mg/d; n=56) or not to receive (control subjects; n=58) enalapril. Treatment was started 1 month after HDC and continued for 1 year. Cardiological evaluation was performed at baseline and at 1, 3, 6, and 12 months after HDC. The primary end point was an absolute decrease >10 percent units in left ventricular ejection fraction, with a decline below the normal limit value. A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients. According to the Kaplan-Meier analysis, the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; P<0.001). Conclusions— In high-risk, HDC-treated patients, defined by an increased troponin I value, early treatment with enalapril seems to prevent the development of late cardiotoxicity.

Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy

Background—In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously. Methods and Results—In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values ≥0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were <0.08 ng/mL (TnI−/− group); in 145, there was only an early increase (TnI+/− group); and in 63 patients, both values increased (TnI+/+ group). In the TnI−/− group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI+/+ group (84% versus 37% in the TnI+/− group; P <0.001). Conclusions—TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter. This stratification allows us to differentiate the monitoring program and to plan, in selected patients, preventive strategies aimed at improving clinical outcome.

Anthracycline-Induced Cardiomyopathy: Clinical Relevance and Response to Pharmacologic Therapy

OBJECTIVES The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy. BACKGROUND The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking. METHODS We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF) <or=45% due to AC-CMP. Enalapril and, when possible, carvedilol were promptly initiated after detection of LVEF impairment. LVEF was measured at enrollment, every month for the first 3 months, every 3 months during the first 2 following years, and every 6 months afterward (mean follow-up 36 +/- 27 months). Patients were considered responders, partial responders, or nonresponders according to complete, partial, or no recovery in LVEF, respectively. Major adverse cardiac events during follow-up were also evaluated. RESULTS Eighty-five patients (42%) were responders; 26 patients (13%) were partial responders, and 90 patients (45%) were nonresponders. The percentage of responders progressively decreased as the time from the end of chemotherapy to the start of HF treatment increased; no complete recovery of LVEF was observed after 6 months. Responders showed a lower rate of cumulative cardiac events than partial and nonresponders (5%, 31%, and 29%, respectively; p < 0.001). CONCLUSIONS In cancer patients developing AC-CMP, LVEF recovery and cardiac event reduction may be achieved when cardiac dysfunction is detected early and a modern HF treatment is promptly initiated.

Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation

PURPOSE Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated. PATIENTS AND METHODS In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%. RESULTS TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio [HR], 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001). CONCLUSION TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy

OBJECTIVES We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). BACKGROUND High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. METHODS We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. RESULTS In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). CONCLUSIONS The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.

Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy

Background— Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. Methods and Results— We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and <50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase >5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6–8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3–6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33–1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04–1.15 for each 50 mg/m2 increment) were independent correlates of cardiotoxicity. Conclusions— Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

Increased Perioperative N-Terminal Pro-B-Type Natriuretic Peptide Levels Predict Atrial Fibrillation After Thoracic Surgery for Lung Cancer

Background— Postoperative atrial fibrillation (AF) is a complication of thoracic surgery for lung cancer, with a reported incidence that can run as high as 42%. Recently, it has been observed retrospectively that B-type natriuretic peptide predicts AF after cardiac surgery. We performed a prospective study to evaluate the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a marker for risk stratification of postoperative AF in patients undergoing thoracic surgery for lung cancer. Methods and Results— We measured NT-proBNP levels in 400 patients (mean age, 62±10 years; 271 men) 24 hours before and 1 hour after surgery. The primary end point of the study was the incidence of postoperative AF. Overall, postoperative AF occurred in 72 patients (18%). Eighty-eight patients (22%) showed an elevated perioperative NT-proBNP value. When patients with either preoperatively or postoperatively elevated NT-proBNP were pooled, a greater incidence of AF was observed compared with patients with normal values (64% versus 5%; P<0.001). At multivariable analysis, adjusted for age, gender, major comorbidities, echocardiography parameters, pneumonectomy, and medications, both preoperative and postoperative NT-proBNP values were independent predictors of AF (relative risk, 27.9; 95% CI, 13.2 to 58.9; P<0.001 for preoperative NT-proBNP elevation; relative risk, 20.1; 95% CI, 5.8 to 69.4; P<0.001 for postoperative NT-proBNP elevation). Conclusions— Elevation of perioperative NT-proBNP is a strong independent predictor of postoperative AF in patients undergoing thoracic surgery for lung cancer. This finding should facilitate studies of therapies to reduce AF in selected high-risk patients.

Atrial fibrillation after operation for lung cancer: clinical and prognostic significance

BACKGROUND Atrial fibrillation is a common complication of early postoperative period in lung cancer thoracotomy. Its clinical incidence and short- and long-term impact on overall mortality has never been definitely assessed; moreover, it is unclear whether the arrhythmia represents an independent cardiac risk factor. METHODS We prospectively studied 233 consecutive patients undergoing operation for lung cancer (170 with non-small-cell lung cancer). Postoperative atrial fibrillation incidence was related to different clinical factors possibly involved in its occurrence and to both short- and long-term survival. RESULTS Atrial fibrillation occurred in 28 patients (12%) (same percentage in non-small-cell lung cancer); a strong relationship was observed between arrhythmia and age, history of hypertension and associated lymph node resection. The mean hospitalization time was 14 +/- 4 days in patients developing atrial fibrillation and 13 +/- 4 days in those who did not (p = not significant). No difference was observed between the two groups with regard to short- or long-term mortality or to long-term atrial fibrillation recurrences, also when considering the entire population and only non-small-cell lung cancer, separately. CONCLUSIONS At our institution, early atrial fibrillation occurrence after operation for lung cancer does not show any negative impact on short- and long-term mortality or on recurrence rate.

Intrapericardial Treatment of Neoplastic Pericardial Effusions

Pericardial effusion and cardiac tamponade are known complications of many advanced malignancies as lung cancer, breast cancer, lymphomas and leukemias. Initial relief can be easily obtained with percutaneous echo-guided pericardiocentesis, without significant mortality and morbidity and well-tolerated even in critically ill patients. Effusion recurrences can be observed, however, in up to 40% of cases if only simple pericardial drainage is performed.Effective management can be obtained by instillation in the pericardial sac of different agents, with sclerosing or cytostatic activity, like tetracyclines, bleomycin, thiotepa or radionuclides. Intrapericardial sclerotherapy is associated to good results in terms of recurrence prevention and survival improvement. Absence of pericardial effusion at 30 days after drainage can be observed in 70 to 90% of all treated patients, without significant variations among different treatments. No significant side effects are observed, with the exclusion of chest pain during tetracyclines instillation.In our opinion pericardiocentesis associated to intrapericardial sclerotherapy with thiotepa is the best compromise in terms of recurrence prevention, tolerability and costs. Real randomized, case-control studies are moreover required to assess the gold standard of malignant pericardial effusions treatment.ZusammenfassungPerikarderguss und Herzbeuteltamponade finden sich nicht selten als Folge fortgeschrittener maligner Erkrankungen, wie zum Beispiel bei Bronchial- und Mammakarzinomen sowie bei Lymphomen und Leukämien. Eine vorübergehende Entlastund kann durch die perkutane ultraschall- oder durchleuchtungskontrollierte Perikardpunktion erreicht werden. Dieses Vorgehen wird auch von schwer kranken Patienten gut toleriert und ist mit keiner nennenswerten Morbidität oder Mortalität verbunden. Allerdings werden Rezidive in bis zu 40% der Fälle beobachtet.Deshalb wurden bislang drei wesentliche alternative Vorgehensweisen entwickelt: 1. eine Perikardpunktion mit intraperikardialer Sklerotherapie, 2. eine perkutane Ballonperikardiotomie und 3. die operative Perikardfensterung entweder als subxyphoidale oder transthorakale Perikardiotomie oder als thorakoskopische Perikardfensterung. Zwar wird das chirurgische Vorgehen in der chirurgischen Literatur favorisiert, dagegen empfehlen kardiologische Zentren vor allem bei kritisch kranken Patienten ein kardiologisches Vorgehen mit Perikardpunktion und Sklerotherapie. Offensichtlich ist eine intraperikardiale Skerotherapie wesentlich schonender als das chirurgische Vorgehen. Außerdem wird hierdurch auch die Verschleppung von Tumorzellen in Pleura und Peritoneum vermieden.Unter intraperikardialer Sklerotherapie versteht man die Instillation von Substanzen, die sklerosierende und zytostatische Aktivität besitzen, wie zum Beispiel Tetracycline, Bleomycin, Thiotepa, Cisplatin oder Radionuklide.Tetracycline: Maher et al. konnten in einer größeren retrospektiven Studie zeigen, dass von 85 mittels Sklerotherapie behandelten Patienten 79% in den ersten 30 Tagen ohne Rezidiv blieben. Die Therapie mit Tetracyclinen ist allerdings mit einer hohen Nebenwirkungsrate verbunden: Fieber und Vorhofarrhythmien werden in 10%, retrosternale Schmerzen in 20% der Fälle beobachtet. Deshalb wird zur pH-Neutralisierung die Beimengung von Blut in das intraperikardiale Instillat empfohlen.Bleomycin: Liu et al. untersuchten 29 Patienten retrospektiv, die mit Bleomycin oder Doxycyclin behandelt wurden. Die Wirksamkeit beider Substanzen war ähnlich, Bleomycin wurde aber besser toleriert. Größere prospektive Studien fehlen.Thiotepa (Triethylenphosphoramid): Thiotepa ist eine alkylierende Substanz, die über lange Zeit in der Therapie von soliden Tumoren und Pleuraergüssen eingesetzt wurde, da sie sowohl sklerosierende als auch zytostatische Eigenschaften besitzt. Girardi et al. und Colleoni et al. behandelten insgesamt 60 Patienten mit verschiedenen Therapieregimen. Wesentliche Komplikationen oder Nebenwirkungen wurden nicht berichtet. Die Rezidivrate 30 Tage nach der Behandlung betrug 83%.Cisplatin: Zahlreiche Studien zeigen einen Therapieerfolg bei malignen intraperitonealen Ergüssen. Mehrere Studien wurden auch zur Behandlung von Perikardergüssen publiziert. Die Wirksamkeit mit rezidivfreien Intervallen von zwei bis 24 Monaten (Median zwei bis drei Monate) ist gut, die Nebenwirkungsrate sehr niedrig.Andere Medikamente: Weitere Therapievorschläge umfassen die Immunmodulatoren (IFN, Il-2, OK 432) oder anderen zytostatischen Substanzen (5-FU oder Aclarubicine).Radiotherapie: Insbesondere für die Therapie radiosensitiver Tumoren wurde eine externe Radiotherapie vorgeschlagen. Auch die intraperikardiale Applikation von 32P-Kolloid ist mit sehr guten Ansprechraten (komplette Remission in 95% im Mittel für acht Monate) ohne signifikante Nebenwirkungen vergesellschaftet.Aufgrund der Datenlage kann eine allgemeine Empfehlung zur Therapie maligner Perikardergüsse gegenwärtig noch nicht gegeben werden. Dazu fehlen randomisierte, kontrollierte Multicenterstudien mit ausreichend großen Fallzahlen. Unserer Auffassung nach ist aber die Perikardpunktion in Kombination mit einer intraperikardialen Sklerotherapie, zum Beispiel mit Thiotepa oder Cisplatin, den chirurgischen Verfahren vorzuziehen, da Rezidiv- und Komplikationsraten sowie die Kosten gering sind.

Cardio-oncology: a new medical issue

Due to the increasing number of long-term cancer survivors, the ageing of the population, as well as the increased incidence and prevalence of oncologic and cardiovascular diseases, the number of patients presenting oncologic and cardiologic co-morbidities are increasing. Accordingly, there is a rapidly growing need for a comprehensive and proficient management of patients in whom the two co-morbidities exist, and for cancer patients whose clinical history and oncologic treatment put them at higher risk for developing cardiovascular problems, in order to provide the optimal treatment in every situation, and to avoid the possibility that the development of the second disease does not lead to a reduction of therapeutic opportunities for the patient. A new discipline, cardio-oncology, has been created to deal with this need. Its aim is to investigate new strategies, collect new evidence-based indications and develop interdisciplinary expertise in order to manage this growing category of patients. Cardio-oncology deals with the following main clinical and research areas: early diagnosis of cardiotoxicity, risk stratification and preventions, treatment and monitoring of cardiotoxicity.