Mary Kathryn Pierri

Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience

PURPOSE This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. RESULTS Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). CONCLUSION Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.

Clinical cardiotoxicity of 5-fluorouracil.

5‐Fluorouracil is widely known to be toxic to the hematopoietic and gastrointestinal systems. It also has cardiac toxicity, but this is perceived to be rare. During a 16‐month period from January 1990 through April 1991, approximately 910 patients were treated with 5‐fluorouracil. Five of these developed life‐threatening toxicity consistent with coronary artery spasm for an incidence of .55%. The acute events occurred on the third or fourth day of the 5‐day infusion and after the fourth intravenous bolus in the patient on bolus therapy. Each of the patients had ST elevation and ventricular arrhythmias, four had acute myocardial infarction, and two had cardiac arrests. In these cases and those previously reported, cardiac toxicity is consistent with drug‐ or metabolite‐mediated increases in coronary vasomotor tone and spasm, leading to the full spectrum of signs and symptoms of myocardial ischemia in susceptible individuals.

Isoflurane versus fentanyl: hemodynamic effects in cancer patients treated with anthracyclines.

Cancer patients treated with anthracycline derivatives are at risk for perioperative cardiovascular decompensation. The authors studied hemodynamic performance before, during, and after laparotomy in 14 anthracycline-treated patients with ovarian carcinoma. General anesthesia was maintained with 70% N2O in O2, and patients were randomized to receive supplementation with either isoflurane, 0.59% end-tidal +/- 0.04 (mean +/- SE), or fentanyl, 2.67 micrograms/kg +/- 0.49 as a loading dose, and a total dose of 7.16 micrograms/kg +/- 0.71. The degree of hemodynamic stability relative to the baseline was assessed. There was no obvious superiority of either technique prior to the skin incision. However, during and immediately after surgery, a clearer tendency for isoflurane-N2O to result in better hemodynamic stability was found. Isoflurane-N2O demonstrated significantly smaller change scores in systemic vascular resistance (SVR) and cardiac index (CI). At the start of surgery, the isoflurane-N2O change in SVR was 228.08 dyne.sec.cm-5 compared to 479.58 for the fentanyl patients, (P = 0.002); at the end of surgery the corresponding means were -12.09 and 703.14 dyne.sec.cm-5, respectively, (P = 0.002). Isoflurane-N2O was associated with significantly greater CI stability in the early postoperative period: the isoflurane-N2O mean change was -0.081 L/min/m2, versus -0.993 for the fentanyl-N2O patients, (P = 0.005). The authors conclude that anthracycline-treated patients who do not have overt evidence of cardiomyopathy can be safely anesthetized with either anesthetic technique. However, during surgery and in the early postoperative period, an isoflurane-N2O technique appears to offer better hemodynamic stability.

Evaluation of Suspected Deep Venous Thrombosis in Oncologic Patients

Impedance plethysmography (IPG) and duplex scanning with color flow Doppler were performed in 100 consecutive high-risk patients with clinically suspected deep venous thrombosis. Risk factors included recent surgery (<three weeks) in 23%, malignant disease in 91%, clotting abnormalities in 32%, and limited activity in 70%. Lower limb findings of either edema, calf tenderness, or both occurred in 92%. There was agreement between the two tests in 76 patients (29 positive and 47 negative). In 12 patients the IPG was positive and the duplex negative. Four of these had extensive pelvic disease, 2 had lung cancer with an obstructive profile, and 2 had heart failure, all of which are known to cause false-positive IPG results. In the other 12 patients the IPG was negative and the duplex positive; however, 3 of these patients had nonocclusive thrombi, 5 had pelvic disease, and 1 had a hemiparesis of the involved lower limb. In 15 patients (11 with positive duplex studies and 4 with negative) a venogram was obtained and confirmed the results. All patients were followed up clinically and none developed complications suggesting inaccurate duplex results. In conclusion, the IPG is of limited utility in this population with a sensitivity of 71%, specificity of 80%, and false-negative rate of 29% when duplex Doppler and clinical outcome are used as the standard. Where available, duplex Doppler should be preferred for evaluation of suspected deep venous thrombosis in patients with extensive medical disease.

Haemodynamic effects of recombinant interleukin-2 administered by constant infusion

Adoptive immunotherapy with recombinant interleukin-2 (rhIL-2) has been reported to induce tumour regression in some patients with refractory cancer. However, the cardiovascular toxicity of bolus therapy requires invasive monitoring of patients in the intensive care unit (ICU). In an effort to examine the haemodynamic alterations caused by a constant infusion of IL-2, as opposed to bolus therapy, we studied the haemodynamic variables of 10 patients, with no evidence of heart disease, receiving 3 x 10(6) IU/m2 per day of rhIL-2 as a continuous infusion for 5 days. Measured and derived haemodynamic variables were obtained immediately prior to, at 2, 24, and 48 h during, and upon termination of the infusion. There was no evidence of clinical haemodynamic instability in these patients. Except for development of fever and tachycardia, there were no clinically significant differences in any measured or derived haemodynamic parameter. Moreover, continuous electrocadiographic monitoring of these patients during the infusion did not reveal any abnormalities. Invasive haemodynamic monitoring in an ICU is not necessary in carefully selected patients receiving constant infusion rhIL-2, at the described dose and schedule.

Tricuspid valve thromboembolus with recurrent pulmonary embolism--a case report.

The authors describe a fifty-one-year-old man with multiple pulmonary emboli in whom two-dimensional echocardiography clearly showed a large mobile thrombus transiently entrapped in the chordal apparatus of the tricuspid valve, a location rarely noted except in autopsy specimens. Subsequent lung scan and echocardiograms documented clinically silent nonfatal embolization of this large thrombus to the lungs. Whereas most patients with this form of thromboembolic disease come to either surgery or autopsy, this case demonstrates how the combination of echocardiography and lung scanning can be used to differentiate the etiology of some right-heart masses.