Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial.

BACKGROUND: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS: Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. RESULTS: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). CONCLUSIONS: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.

Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs.

BACKGROUND: Cardiac sequelae from oncologic drugs are important in early cancer drug development. Prolongation of the corrected QT interval (QTc) by noncardiac drugs is the most common cause of drug development delays, nonapprovals and postmarketing withdrawals by the US Food and Drug Administration. PATIENTS AND METHODS: We analyzed 8518 electrocardiograms (ECGs) in 525 consecutive cancer patients enrolled in 22 industry-sponsored phase I clinical trials, starting 1 January 2006. RESULTS: Seventy-four patients [14%, 95% confidence interval (CI) 11% to 17%] with normal QTc at baseline had QTc intervals above upper limit of normal after treatment initiation; 33 (6%, 95% CI 4% to 9%) had prolonged QTc intervals at baseline, and only one (3%, 95% CI 0% to 16%) worsened after dosing. Seven of 33 patients (21%, 95% CI 9% to 39%) with prolonged baseline QTc had normalization of QTc intervals after dosing. All QTc prolongations were clinically insignificant; study drugs were continued uneventfully. Two of 525 patients (0.4%, 95% CI 0% to 1%) experienced cardiac serious adverse events (myocardial infarction possibly related to drug and unstable atrial flutter related to metastatic disease). Both cardiac events were detected by clinical assessment, not surveillance ECGs. CONCLUSION: Frequent ECG monitoring provided no clinically significant information in 525 patients in early phase trials.

Is cardiotoxicity being adequately assessed in current trials of cytotoxic and targeted agents in breast cancer?

The cardiotoxicity of anthracyclines, trastuzumab and other agents is of special importance to adjuvant breast cancer patients whose life expectancy is restored to normal but who may be left with cardiac abnormalities that can present years later. We systematically reviewed the design of current trials (including adjuvant studies) on the clinicaltrials.gov Web site. Surprisingly few specify primary or secondary cardiac end points. Although cardiac ultrasound (echocardiography) and multiple uptake gated acquisition scintigraphy remain the most frequent techniques for estimating left ventricular ejection fraction, there is no consistency in the degree of reduction from baseline or absolute value taken as indicating cardiotoxicity. The details given do not suggest that diastolic function (which may give earlier warning of problems) is a focus of interest. There is growing interest in troponin as a marker of myocyte death and brain natriuretic peptide as a marker of myocardial stress and possible heart failure (though their clinical usefulness has still to be adequately defined). The duration of follow-up in many adjuvant studies may not be sufficient to determine the risk of late cardiac events. The findings indicate a need to study and standardize cardiac toxicity assessments in oncology trials.

Cardiovascular complications of conventional and targeted adjuvant breast cancer therapy.

Adjuvant therapy has improved the survival of women with early breast cancer (BC). Meta-analyses suggest that anthracycline-based regimens reduced the annual BC death rate by ∼40% in women below the age of 50 and 20% in older women. Novel agents designed to modulate abnormal growth factor signaling in and around the BC cell further increase patients' chances of survival. However, both conventional chemotherapeutic agents as well as some of the novel signaling inhibitors can induce important cardiovascular side-effects, potentially attenuating the progress made in recent years. The mechanism of cancer drug-induced cardiovascular complications varies greatly with some compounds inducing irreversible myocardial cell damage, while others lead to temporary cell dysfunction. The challenge of the future will be to prospectively discriminate between irreversible damage which can lead to progressive cardiovascular disease and reversible cardiovascular dysfunctions without further prognostic implications. Since adjuvant therapy for BC is potentially curative, emphasis must be placed on finding treatments combining maximum efficacy with the minimum of long-term side-effects in order to achieve survival with preserved quality of life.

Characteristics of cardiac arrest in cancer patients as a predictor of survival after cardiopulmonary resuscitation.

BACKGROUND: Despite advances in cardiopulmonary resuscitation and the education of its providers, survival remains dismal for cancer patients suffering in-hospital cardiac arrest. In an effort to determine if characteristics of cardiac arrest would represent a useful parameter for prognostication and recommendations regarding the suitability of ongoing resuscitation for various groups, this review was undertaken for patients who experienced in-hospital cardiac arrest. METHODS: A retrospective study of data gathered between January 1993 and December 1997 was undertaken in a 518-bed comprehensive cancer center. The records of 243 inpatients who experienced cardiac arrest and received cardiopulmonary resuscitation were reviewed, and their course observed until hospital discharge or death. RESULTS: Sixteen of 73 patients (22%) who had sudden, unanticipated cardiac arrests survived to be discharged from the hospital; however, none (0 of 171) of the patients who experienced an anticipated cardiac arrest survived (P < 0.001). Logistic regression analysis revealed that anticipated cardiac arrest associated with metabolic derangement was an independent predictor of hospital mortality. CONCLUSIONS: Patients experiencing an anticipated cardiac arrest, the course of which could not be interrupted through aggressive management in an intensive care unit, have an extremely poor prognosis. Ongoing resuscitative measures in these patients need not be routinely provided. The authors suggest an algorithm for resuscitation that evaluates the characteristics of the arrest as a prognostic factor. This algorithm should be implemented once progressive deterioration spirals toward cardiac arrest that cannot be prevented. Such an approach should avoid painful and costly interventions that are futile with the present techniques of cardiopulmonary resuscitation.

Doxorubicin cardiotoxicity in children: reduced incidence of cardiac dysfunction associated with continuous-infusion schedules.

We retrospectively reviewed the medical records of 97 children (59 boys and 38 girls) with a median age of 13 +/- 4 years who had been treated with continuous infusion of doxorubicin at a dosage of 60 mg/m2 over 24 h (61 patients) or at a dosage of 75 mg/m2 over 72 h (36 patients). The drug was administered every 3 weeks. The cardiac status of patients was evaluated as a baseline and every 6 months during, and following therapy (median, 30.5 months). The evaluations included M-mode and two-dimensional echocardiography. Congestive heart failure developed in only one patient in this series, an 8-year-old girl who ultimately died of her cardiac complication. This incidence of doxorubicin-induced cardiotoxicity was compared with that seen in a control group of pediatric patients previously treated with doxorubicin at similar dosages but with a rapid infusion. The result compared favorably to the 13% incidence of cardiotoxicity (p = 0.03) and 7% mortality (p < 0.01) in the control group. No changes in the levels of tumor response were noted in children treated by continuous infusion when compared with historical controls. Continuous-infusion schedules of doxorubicin thus result in fewer incidences of cardiotoxicity in children and should be considered for wider application in pediatric cancer patients receiving doxorubicin.

Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact?

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest in innovative therapeutic modalities designed to target tumor cells demonstrating such overexpression. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody developed to target the HER2 receptor, is the most widely studied example of such a modality. In early clinical studies with trastuzumab, cardiomyopathy was observed with a clinical expression similar to that seen with the anthracyclines (ie, a potentially progressive decrease in cardiac systolic function). A number of possible explanations for this cardiotoxicity are explored in this report. The first is that trastuzumab has inherent toxicity. This consideration has some theoretical interest, since fetal myocardial cells exhibit HER2 receptors and the adult myocardium expresses HER3 receptors. A second possibility is that sequential stresses following doxorubicin administration contribute to cardiac dysfunction. A third explanation is that observational artifacts lead to an overestimation of trastuzumab cardiotoxicity. Approaches for additional study of the extent and severity of trastuzumab cardiotoxicity are briefly addressed.

Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration.

BACKGROUND: Doxorubicin cardiotoxicity remains a serious problem in children with malignancy. The present study was undertaken to determine if the administration of consecutive divided daily doses of doxorubicin would significantly reduce the likelihood of cardiotoxicity in children compared with a single dose administration regimen. PROCEDURE: One hundred thirteen children (60 boys and 53 girls) received doxorubicin either by single dose infusion or by a consecutive divided daily dose schedule. The divided dose patients received one third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single dose schedule received the cycle dose as a 20-minute infusion. The mean doxorubicin dose was 341 mg/m2. Patients were followed up for 4-180 months. There were 60 boys and 53 girls in the series. RESULTS: Fifteen patients developed cardiacdysfunction, eight of whom died of progressive cardiac failure. There was no significant difference in the incidence of cardiac dysfunction between the divided and single dose infusion groups. More girls than boys developed cardiac dysfunction and more girls died of progressive cardiac failure; this difference was not statistically significant. The median time to the development of cardiac failure was 2 months. CONCLUSIONS: The divided dose regimen did not alter the incidence of cardiotoxicity. Other schedules should therefore be investigated. Our data suggest that, at similar cumulative doses, girls are more likely to develop cardiac dysfunction than are boys. If the sex-related difference is proved in larger series of patients, it may be prudent to lower the recommended cumulative doses for girls.

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE: To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS: Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS: The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION: DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy.

PURPOSE: To assess whether dexrazoxane (DZR) given after a cumulative doxorubicin dose of 300 mg/m2 confers cardioprotection in patients with advanced breast cancer treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC). PATIENTS AND METHODS: In two multicenter studies (088001 and 088006), patients were randomized to receive FAC and placebo (PLA) versus FAC and DZR. After a protocol amendment, all patients received open-label DZR after they had reached a cumulative doxorubicin dose of 300 mg/m2. Two groups were compared: 99 patients randomized to the PLA arms before the amendment who received FAC and PLA for at least seven courses (PLA group), and 102 patients randomized to the PLA arms after the amendment who received FAC and PLA for six courses followed by open-label DZR (PLA/DZR group). RESULTS: The hazards ratio of PLA to PLA/DZR was 3.5 (95% confidence interval [CI], 2.2 to 5.7; P < .001, logrank and generalized Wilcoxon tests) for the doxorubicin dose at any cardiac event, ejection fraction changes, or congestive heart failure (CHF). The hazards ratio of PLA to PLA/DZR was 13.1 (95% CI, 3.7 to 46.0; P < .001, logrank and generalized Wilcoxon tests) for the doxorubicin dose at the development of CHF. The overall incidence of CHF in the PLA/DZR group was 3%, compared with 22% in the PLA group (P < .001, Fisher's exact test). Twenty-six percent of PLA/DZR patients received at least 15 courses of therapy, compared with 5% of patients in the PLA group. These results do not appear to be attributable to a time trend. CONCLUSION: DZR is a highly effective cardioprotective agent when used in patients with advanced breast cancer who continue to receive doxorubicin-based chemotherapy after a cumulative doxorubicin dose of 300 mg/m2 has been reached.

Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia.

PURPOSE: To estimate the incidence of idarubicin (IDA)-related cardiomyopathy in acute myeloid leukemia (AML) and myelodysplasia (MDS). PATIENTS AND METHODS: We analyzed a group of 127 AML/MDS patients who received IDA-based induction and postremission or salvage therapy and achieved a complete remission (CR) that lasted > or = 12 weeks for the development of IDA-related congestive heart failure (CHF). CHF was defined as definite if a resting left ventricular ejection fraction (LVEF) of < or = 45% measured by radionuclide ventriculogram (RV) accompanied the clinical diagnosis of CHF, which had to be made during or within 6 months of receiving IDA and for which no other cause was apparent; without RV confirmation, the diagnosis was considered probable. Patients who had RVs performed were evaluated for decreasing LVEF. Older age (> or = 70 years), prior/sequential anthracycline/mitoxantrone (anthraquinone) therapy, and cardiac disease/hypertension were evaluated as risk factors for the development of CHF. RESULTS: One hundred fifteen patients were assessable (median age, 40 years; median dose, 96 mg/m2). Sixty-five had RVs performed during therapy; 43 had risk factors. The probability of IDA-related cardiomyopathy was 5% at a cumulative IDA dose of 150 to 290 mg/m2, with 18 patients receiving doses greater than 150 mg/m2. At a cumulative IDA dose of 150 mg/m2, the probability of a mild or greater asymptomatic decrease probability of a mild or greater asymptomatic decrease in LVEF (> or = 10% to a level < or = 50%) was 18%, whereas the probability of a moderate or greater asymptomatic decrease in LVEF (> or = 15% to a level < or = 45%) was 7%. No patient with asymptomatic LVEF decreases developed CHF. CHF was more frequent in patients with prior/sequential exposure to anthracyclines/mitoxantrone (P = .01). CONCLUSION: In this patient group, IDA-related cardiomyopathy was uncommon with cumulative IDA doses of up to 290 mg/m2. Asymptomatic LVEF decreases were more frequent, but their predictive value for the development of CHF is unclear.

Advance directives in the intensive care unit of a tertiary cancer center.

BACKGROUND: Advance directives are associated with considerable controversy. The goal of this study was to evaluate the outcomes of critically ill patients with cancer who were admitted to the intensive care unit and who previously had executed an advance directive. The problems associated with interpreting and honoring such documents in a tertiary cancer center also were reviewed. METHODS: A prospective observational study of patients with cancer with advance directives who were admitted to the intensive care unit of a major cancer hospital was undertaken. Twenty-six patients with directives were followed from the time of admission to the intensive care unit or, in the case of patients who presented their directives after admission, from the time of presentation of the directive until either discharge or death. RESULTS: Twenty four of the 26 patients were placed on mechanical ventilators. Eight patients died while on the ventilator, nine were terminally weaned, and seven were weaned and survived for at least 24 hours. Of these seven patients, six died before being discharged from the hospital and one was discharged home. Delay in presenting the advance directive, conflict between the dictates of the living will and the wishes of the person named in the durable power of attorney, and controversy among health-care providers as to when in the course of disease the spirit of the advance directive had been met were the most frequent problems encountered; a number of other concerns were also identified. CONCLUSIONS: Considerable controversy exists regarding advance directives, and such documents often leave room for confusion about patients' desires in particular clinical situations. Many of the problems identified in this study might be avoided and considerable cost savings achieved by the timely presentation of documents and by the evaluation of clinical goals on an ongoing basis.

Late doxorubicin-associated cardiotoxicity in children. The possible role of intercurrent viral infection.

BACKGROUND: The most frequently encountered doxorubicin related cardiac toxicity is a dose-related myocardial dysfunction occurring 1-6 months after chemotherapy. Recently, late cardiotoxicity has been the focus of interest. This paper explores the possibility that acute intercurrent viral illness may trigger late cardiotoxicity. METHODS: Thirty selected pediatric patients were followed for changes in their echocardiographically measured fractional shortening (FS) for 2-10 years after completion of their doxorubicin chemotherapy. They were divided according to the dose of doxorubicin they received (< 300 mg/m2 or > or = 300 mg/m2) and to whether the manifestations of an acute intercurrent viral illness during the observation period were documented. Eleven patients experienced such infections. RESULTS: Changes in FS demonstrated two different responses. The usual response to doxorubicin was a gradual, dose-related fall in FS, followed by recovery; while the second response included an unexpected, late, sudden decrease in FS. Four patients in the low dose subgroup experienced an acute intercurrent viral illness, but none of these demonstrated the unexpected decrease. Of the seven patients who acquired such illness in the high dose subgroup, five demonstrated the sudden, late decrease in FS, with two of them developing severe, reversible congestive heart failure. CONCLUSIONS: The most likely explanation for the late, sudden decrease in FS is an additional stress in patients who already have sustained subclinical cardiac damage as a result of their doxorubicin chemotherapy. An acute intercurrent viral illness may have triggered late cardiac dysfunction in some of these patients.

Assessment of anthracycline cardiomyopathy by endomyocardial biopsy.

Ultrastructural evaluation of endomyocardial biopsy specimens is a sensitive and effective method with which to detect and quantitate cardiotoxicity produced by anthracylines. The procedure and grading system used at the M.D. Anderson Cancer Center are described, and some of the pitfalls that may be encountered by the electron microscopist are reviewed.

Cardiac diastolic function in pediatric patients receiving doxorubicin.

The purpose of the study was to compare systolic and diastolic function in pediatric patients treated with doxorubicin. Left ventricular function was evaluated in 61 children prior to and following chemotherapy. None had clinical evidence of cardiac decompensation prior to treatment. All received relatively low cumulative doses of doxorubicin; the majority received the drug by continuous infusion. Systolic function was estimated using fractional shortening; diastolic function was estimated using A wave velocity, E wave velocity, E to A ratio, and deceleration time. There was a small but significant decline in systolic cardiac function as estimated from changes in fractional shortening that could not be appreciated in any of the measured parameters of diastolic function. A variety of reasons that could be responsible for the absence of significant changes in diastolic function are discussed. For the present, estimations of systolic function are preferred over the studied parameters of diastolic function in the evaluation of cardiac status in pediatric patients receiving doxorubicin containing regimens.

Cardiac emergencies in the cancer patient.

Cardiac emergencies may be encountered during the management of patients with cancer, both in those with underlying cardiovascular disease and those with no previous history of cardiac problems. Both surgical and medical cancer treatment modalities may exacerbate preexisting cardiac conditions. Some antineoplastic agents can adversely affect the coronary arteries, myocardium, or pericardium. It has also been recognized that cardiac damage due to radiotherapy and chemotherapy may become clinically significant many years after therapy has been completed. Treatment of urgent cardiac problems in the cancer patient may differ from that recommended for other patient groups, since many cancer patients are not ideal candidates for some of the newer cardiac agents. Management of these conditions must therefore be tailored to the individual patient.

Nodus migrans: the case of the migrating knot.

Flow-directed pulmonary artery catheters provide important information regarding intravascular volume status, cardiac function and vascular resistance. We describe an unusual complication of pulmonary artery catheterization in which a knot formed at the distal end was torn away from the catheter body and migrated from its original position in the right subclavian vein to a distal branch of the right pulmonary artery. Careful attention to insertion and withdrawal techniques could prevent this potentially serious complication.