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.

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.

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.

Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study.

One hundred patients with non-small cell lung cancer were entered into a randomized evaluation of two schedules of doxorubicin combined with ftorafur, cyclophosphamide, and cisplatin (FACP). Doxorubicin was given either weekly at 20 mg/m2, or every three weeks (standard) at 60 mg/m2. Fifty-two patients were randomized to the FACP/weekly doxorubicin arm and 48 patients to the FACP/standard doxorubicin arm. The FACP/weekly doxorubicin regimen was associated with higher complete and partial remission rates (31% versus 19%), longer response duration (median, 33 versus 21 weeks), and longer survival duration for responders (median, 58 versus 50 weeks). These differences were not significant. Less neutropenia (p = 0.01) and less infectious morbidity (p = 0.05) were observed in the FACP/weekly doxorubicin arm. Twenty-eight patients underwent 35 endomyocardial biopsies to assess doxorubicin-induced cardiotoxicity. Sixteen biopsies were performed in 12 patients receiving cumulative doxorubicin doses ranging from 250 to 1,190 mg/m2 within the FACP/weekly doxorubicin arm. Nineteen biopsies were performed in 16 patients receiving cumulative doxorubicin doses ranging from 250 to 540 mg/m2 within the FACP/standard doxorubicin regimen. The FACP/weekly doxorubicin regimen was associated with significantly lower cardiotoxicity scores (p = 0.01). This study indicates that weekly administered doxorubicin is as effective and less cardiotoxic than the standard schedule.

A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.

One hundred fifty-eight patients receiving Adriamycin underwent 226 transjugular biopsy procedures. The specimens were evaluated by electron microscopy for evidence of drug-related cardiotoxicity. Ejection fraction determinations using echocardiographic or nuclear techniques at rest were available for 69% and 81% of the patients, respectively. Analysis of the data revealed a correlation between cumulative Adriamycin dose and biopsy grade (p less than 0.02). No similar relationship existed between cumulative Adriamycin dose and ejection fractions obtained at rest or between biopsy grades and ejection fractions. In patients who underwent serial endomyocardial biopsies and serial ejection fraction determinations, the correlation between changes in biopsy grade and ejection fraction was poor. A change in resting ejection fraction detected by either method did not reliably predict a change in biopsy grade. The poor correlation between ejection fractions and biopsy grades could be due in part to the sensitivity and specificity of the Adriamycin-related structural changes in contrast to the wider range of disease processes that can affect myocardial function, and to the fact that structural changes often precede the ejection fraction abnormalities. The greater sensitivity and specificity of the biopsy grade should prove useful in reducing the risks associated with evaluating new anthracyclines and potential myocardial protectors of Adriamycin toxicity.

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.

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.

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.

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.

Syncope and hypotension due to carcinoma of the breast metastatic to the carotid sinus.

Tumors involving the carotid sinus and glossopharyngeal nerve may produce syncope due to bradycardia and hypotension. Carotid sinus syncope unrelated to cancer is usually caused by bradycardia and responds to control of the heart rate. When neoplastic disease involves the carotid sinus, vasodepressor hypotension, with or without bradycardia, is more common. Control of the heart rate alone is not effective. Although this syndrome is not common, it is probably not recognized in milder forms. Most patients in whom this syndrome develops have cancer of the head and neck. A patient with breast carcinoma metastatic to the neck and carotid sinus is described in whom syncope with hypotension and bradycardia developed. Although a temporary cardiac pacemaker controlled bradycardia, severe hypotensive episodes recurred despite treatment with anticholinergic and sympathomimetic drugs. The pathophysiology and therapy of this syndrome in patients with cancer are reviewed.

Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma.

Studies of regional pulmonary function using radioactive 133xenon gas and spirometric tests (forced vital capacity and forced expiratory volume in the first second) were performed before and after unilateral pulmonary resection for cancer of the lung. Ninety-one patients were evaluated; 47 underwent total pneumonectomy, and 44 underwent lobectomy. The postoperative serial evaluations were classified into short-term and long-term studies (less than or more than three months, respectively). The preoperative and postoperative data were utilized to derive formulas for predicting an estimate of the overall functional loss after pulmonary resection based on the number of segments removed. The correlation between the predicted and measured postoperative values was good for resections involving more than three segments (r = 0.83). Prediction for smaller resections was unreliable. While both regional and overall pulmonary functions were relatively stable after pneumonectomy, there was a disproportionate early loss, followed by significant functional improvement with time following lobectomy. The anticipation of and preparation for this early loss of function may be crucial in the treatment of these patients.

Regional and overall pulmonary function changes in lung cancer. Correlations with tumor stage, extent of pulmonary resection, and patient survival.

Spirometry and regional pulmonary function studies using xenon 133 gas were performed in 251 patients who had primary lung cancer. Surgical resection was undertaken in 150 while the remainder were treated with nonsurgical modalities. Pulmonary function studies were repeated postoperatively in 54 patients. Regional ventilation and perfusion of the tumor-bearing lung were decreased in patients with larger primary tumors and in those with involvement of ipsilateral hilar lymph nodes. Reduced regional function was also directly related to the proximity of the primary tumor to the hilum. Significant hypoperfusion did not contraindicate operation in 14 patients; however, 13 of them required pneumonectomy. Estimated postoperative forced expiratory volume in 1 second (FEV1.0), derived from preoperative spirometry and regional function of the tumor-bearing lung, correlated well with the measured postoperative values. These estimations were valuable in determining the extent of safe resection and correlated well with short-term survival. Long-term survival correlated better with the stage of disease.

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.

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.

A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer.

Seventy-seven patients with progressive metastatic breast cancer refractory to prior therapy participated in a prospective randomized trial designed to compare the efficacy and toxicity of doxorubicin and epirubicin administered as single agents. In arm 1, 60 mg/m2 of doxorubicin and, in arm 2, 90 mg/m2 of epirubicin were administered by 48-h continuous i.v. infusion every 3 weeks. In arm 3, 90 mg/m2 of epirubicin was administered by bolus every 3 weeks. Patients in the three groups had similar characteristics, except that in arm 3 more patients were premenopausal, had more extensive disease, and fewer patients had been exposed to doxorubicin. Objective remission rates were 29, 26, and 13%, respectively for the three arms. Median response durations ranged from 4-6 months. No significant differences occurred in response rate, remission duration, or survival among patients in the three arms. The incidence of gastrointestinal toxicity and alopecia was evenly distributed. Hematologic toxicity was more severe in arms 2 and 3, and there was a higher incidence of infectious complications in arms 2 and 3 compared to arm 1 (p = 0.05). Two episodes of congestive heart failure occurred in arm 1, one in arm 2, and three in arm 3. Although the total cumulative anthracycline dosage was highest in the arm 2 group, they had the lowest incidence of cardiac toxicity. Epirubicin by bolus and doxorubicin administered by continuous infusion have similar potential for cardiac toxicity. Epirubicin administered by continuous infusion appears less cardiotoxic than doxorubicin by either method of administration or epirubicin given by bolus. Epirubicin appears equally active and less cardiotoxic than the parent compound doxorubicin in patients with metastatic breast cancer.

Philosophy of care, decision making, and ethical considerations.

The very nature of critical care opens the door to controversy, for it is in the intensive care unit that staggering amounts of money and human resources are expended. The outcome is frequently suboptimal, and the feeling often persists that our patients, who should be the beneficiaries of our efforts, are paying a tremendous price in the form of isolation from loved ones, life-support systems that do not allow them to communicate with their families or caretakers, and the physical pain of multisystem failure. As Carlon has recently asked, are we allocating our limited resources inappropriately because we are unable to select patients who will not survive despite our intensive care units? This concern may be justified. However, the work we do in the intensive care unit has another, more positive intangible result. Many of the breakthroughs in medicine have been achieved by dedicated pioneers who tried to accomplish something that had not been accomplished before. At first their efforts were often challenged as being useless or overly extravagant or were even opposed as a violation of God's will or the laws of nature. Developing new forms of treatment, some of which can only be tested in an intensive care unit, is a challenge for all of us. We must, of course, balance what we are trying to accomplish with what we spend, since too much as well as too little emphasis on new techniques is suboptimal. If we persevere, some of what we find impossible to achieve today will become possible tomorrow, will become the norm of the future, and will, we hope, give way to still better innovations as medicine continues to evolve.

Critical cardiologic considerations in the cancer patient.

Aggressive treatment modalities for patients with cancer are often associated with complications or side effects, frequently involving the cardiovascular system. Longer survival of cancer patients can lead to the development of related or unrelated cardiac problems. This article reviews the major cardiac entities necessitating transfer of cancer patients to intensive care facilities and addresses specific management strategies.

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.