Cumulative Dose Of Doxorubicin Research Articles

A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin.

We have treated 14 cancer patients with liposome-encapsulated doxorubicin (LED) at doses of 30, 45, 60, and 90 mg/m2. Nausea and vomiting, phlebitis, and stomatitis were minimal or absent at each dose, but dose-limiting granulocytopenia occurred at 90 mg/m2. Thrombocytopenia and/or anemia also occurred in all patients treated at 60 or 90 mg/m2. Complete alopecia was seen in one of three cases at 60 mg/m2 and all cases at 90 mg/m2. No hepatic, renal, or other major organ toxicities were encountered. Clinical cardiac toxicity did not occur in any patient, but the cumulative doxorubicin doses in 13 cases were less than 400 mg/m2. The plasma elimination of LED out to 24 hours was analyzed in terms of a two-compartment model. Depending upon the dose and the infusion time, maximum plasma concentrations ranged from 2.6 mumol/L to 36.89 mumol/L and the area under the plasma concentration x time curve (AUC) values ranged from 1.86 mumol/L x h/L to 49.57 mumol x h/L. These values are significantly higher than those expected for free doxorubicin. Urinary excretion of LED was approximately 10% after 24 hours. Doxorubicinol and doxorubicinone appeared at low levels in plasma 12 to 24 hours after injection. LED pharmacokinetics differ from those of free drug by the higher plasma levels and AUC of doxorubicin achieved, and by the low conversion of LED to metabolites. Overall, LED was well tolerated and produced only moderate nausea and vomiting and little stomatitis at myelosuppressive doses. The study also suggested that LED produces less venous sclerosis than free doxorubicin, but this requires further clinical verification.

Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation

In order to evaluate the possible cardiosparing effect of a prolonged infusion of doxorubicin as compared with the standard mode of administration 62 consecutive patients with metastatic carcinoma of the breast or carcinoma of the ovary Stage III or IV were prospectively randomized to receive doxorubicin either as a rapid infusion over 15 to 20 minutes at 8 AM or as a continuous infusion over 6 hours, 8 AM to 2 PM. The remaining protocol was identical for the two groups. The cardiotoxic effect of doxorubicin was evaluated by history and physical examination and by the decline in resting ventricular ejection fraction (LVEF) as determined by gated pool radionuclide angiography with technetium 99m (99mTc) and by the decline in the height of the QRS complexes in the standard leads of the echocardiogram (ECG). Initially there were 31 patients in each group. The cumulative dose of doxorubicin, was 410 mg/m2 +/- 42 SD in the standard infusion group and 428 mg/m2 +/- 48 SD in the 6-hour infusion group. The mean decline in LVEF after a cumulative doxorubicin dose of 300 mg/m2 was 17% in the first group and only 4.1% in the second. After 400 mg/m2 the mean fall in LVEF was 21% in the first group and 6% in the second. The mean decline in QRS voltage after 300 mg/m2 was 29% and 1.5%, respectively. Four patients, all in the standard infusion group, developed congestive heart failure. These data suggest that slow infusion of doxorubicin is associated with reduced cardiotoxicity.

Current Status of Epirubicin (Farmorubicin) in the Treatment of Solid Tumours

Epirubicin (Farmorubicin) is a drug of significant interest in the treatment of a variety of solid tumours and a comprehensive review of reported investigations is given. From experimental and clinical studies it appears that in general doxorubicin and epirubicin exhibit no qualitative, but only some quantitative, differences. Thus, the pharmacokinetic and pharmacodynamic characteristics of the two drugs are essentially similar, as are the tumour spectrum and the level of their clinical efficacies. To achieve haematological equitoxicity of the two drugs the dose of epirubicin should be approximately 20% higher than that of doxorubicin, giving rise to a higher cumulative dose of epirubicin. On the other hand, epirubicin is significantly less cardiotoxic than doxorubicin. Thus, the recommended cumulative dose of doxorubicin is 500 mg/m2 and the corresponding figure for epirubicin is 1,000 mg/m2. For either drug a number of questions are still left open, the most important of which include the questions about optimal treatment schedules and the existence of a clinical relevant dose/efficacy relationship.

Acute effects of doxorubicin on human left ventricular systolic and diastolic function

Although the long-term cardiotoxic effects of cumulative doses of doxorubicin are well established, the short-term effects on cardiac function are uncertain. Therefore we examined the short-term effects of doxorubicin on left ventricular systolic and diastolic function following a total of 56 doses of doxorubicin in 15 patients with normal resting left ventricular function. Resting radionuclide ventriculography was performed 1 hour before and 4 hours after each dose of doxorubicin. Left ventricular ejection fraction increased significantly from 64 ± 1% to 67 ± 1% ( p < 0.001) after doxorubicin. In addition, peak ejection rate ( p < 0.005) and peak filling rate ( p < 0.0005) increased significantly following short-term doxorubicin administration. There was no relationship between either the individual or cumulative dose of doxorubicin and the acute ejection fraction, peak ejection rate, or peak filling rate response. Our data suggest that doxorubicin acutely increases left ventricular systolic and diastolic function.

Long term doxorubicin cardiotoxicity in childhood: non-invasive evaluation of the contractile state and diastolic filling.

Cardiac performance was evaluated at least two years after doxorubicin treatment in childhood in 55 patients without overt congestive cardiomyopathy. None of the patients had received mediastinal irradiation. Computer-assisted analysis of digitised echocardiograms showed impaired rapid diastolic filling and an increased change of dimension between minimal cavity dimension and mitral valve opening. This impairment of diastolic function was related to the cumulative dose of doxorubicin. In contrast when angiotensin II was infused to increase the afterload the end systolic pressure-length and stress-shortening relation indicated normal left ventricular systolic function. But during baseline conditions the end systolic wall stress was significantly increased in patients in whom the cumulative dose of doxorubicin exceeded 360 mg/m2.

Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: Seven-year experience using serial radionuclide angiocardiography

To impact on the development of clinical congestive heart failure as a complication of doxorubicin therapy, left ventricular ejection fraction was monitored with serial resting radionuclide angiocardiography in 1,487 patients with cancer over a seven-year period in both university and community hospital environments. A high-risk subset of 282 patients was selected for retrospective analysis of their clinical outcome. High-risk patients were identified by one or two of the following three criteria: (1) decline of 10 percent or more in absolute left ventricular ejection fraction from a normal baseline to 50 percent or less; (2) high cumulative dose of doxorubicin (more than 450 mg/m 2); (3) abnormal baseline left ventricular ejection fraction (less than 50 percent). Clinical congestive heart failure occurred in 46 (16 percent) during the treatment period, and in an additional three patients (1.3 percent) at last follow-up examination 11.8 ± 14.2 months following discontinuation of doxorubicin. Total cumulative dosages of doxorubicin that precipitated congestive heart failure (75 to 1,095 mg/m 2) and those that did not (30 to 880 mg/m 2) varied widely. Decline of 10 percent or more in absolute left ventricular ejection fraction to a value of 50 percent or less preceded administration of the final dose of doxorubicin that precipitated clinical congestive heart failure in the majority of patients in whom congestive heart failure developed. Clinical congestive heart failure improved in 87 percent given routine therapy with digitalis, diuretics, and/or vasodilators. Criteria for monitoring left ventricular ejection fraction and discontinuing doxorubicin were formulated. The occurrence of clinical congestive heart failure was compared in those patients whose management was concordant with proposed criteria (Group A) and in those whose management was not (Group B). Group A had a lower incidence of congestive heart failure compared with Group B (2.9 percent versus 20.8 percent, p <0.001) and had only mild congestive heart failure that resolved with treatment (n = 2) and no deaths due to congestive heart failure. Multivariate analysis with proportional-hazards regression (Cox's model) demonstrated a fourfold reduction in the incidence of congestive heart failure independent of other clinical predictor variables in those patients whose management was concordant with proposed guideline criteria. The incidence, persistence, late development, predictability, and reversibility of clinical congestive heart failure were comparable in university and community hospital settings. It is concluded that in doxorubicin-treated patients at high risk for congestive heart failure, (1) monitoring resting left ventricular function with radionuclide angiocardiography is associated with a low incidence, benign course, and reversible degree of doxorubicin-induced congestive heart failure; (2) adherence to appropriate guidelines reduces the incidence and severity of clinical congestive heart failure; (3) serial resting radionuclide angiocardiography reliably monitors cardiotoxicity and identifies patients who safely tolerate high cumulative doses of doxorubicin.

Doxorubicin-induced congestive heart failure in adults.

The prognosis of doxorubicin-induced congestive heart failure (CHF) is reported to be poor. To define the clinical course of doxorubicin-induced CHF, the authors reviewed their experience with 43 patients with this diagnosis. The median age of the total group was 55 years (range, 23-69); the median cumulative dose of doxorubicin was 450 mg/m2 (range, 200 mg/m2-1150 mg/m2). A majority of the patients had a diagnosis of breast cancer. The median survival of the whole group estimated by means of a Kaplan-Meier plot was 112 weeks. Twelve of 43 patients (28%) died of CHF, 7 of them (16%) because of fulminant failure in less than 8 weeks and the remaining 5 because of a more protracted course with recurrent episodes of cardiac decompensation. Twenty-five of the 43 patients (58%) achieved complete control of CHF. In the remaining 6 patients (14%), CHF had improved but was not completely controlled at the time of death, which was secondary to progressive tumor. Treatment consisted of standard therapy with digitalis and diuretics. Survival was significantly shorter in patients who presented with class IV dyspnea and in those who developed CHF less than 4 weeks after administration of the last dose of doxorubicin. The authors conclude that in a majority of patients, doxorubicin-induced CHF is easily treatable and frequently controlled with digitalis and diuretics.

Possible enhancement of the cardiotoxicity of doxorubicin when combined with mitomycin C.

Forty-six patients with recurrent metastatic breast cancer were treated with a combination chemotherapy including doxorubicin and mitomycin C. Myocardial contractility was monitored by means of echocardiography. During therapy there was a progressive deterioration of myocardial function, and this phenomenon was found to be linearly correlated to the cumulative dose of doxorubicin. Six patients (13.8%) developed congestive heart failure during therapy; it occurred after the median cumulative dose of 322 mg/m2 (range 135-472). Possible risk factors of cardiomyopathy could be identified in only two patients. These results suggest that mitomycin C could enhance the cardiotoxicity of doxorubicin.

Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast

In order to test the possible cardiac-sparing effect of doxorubicin admininstered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall In resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m 2 was 0.06 (p <0.005); at 301 to 449 mg/m 2 it was 0.09 (p <0.0005); and at 450 mg/m 2 or greater it was 0.15 (p <0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the “normal range” (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 n M. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus Infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should Include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to Include deteriorations In function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.

Phase I trial of an implanted battery-powered, programmable drug delivery system for continuous doxorubicin administration.

A second generation, implantable drug administration device (DAD, Medtronic, Inc, Minneapolis) which contains a 20-mL drug reservoir, a lithium-thionyl-chloride battery, a peristaltic roller pump, a microprocessor circuit, and an acoustic transducer has entered clinical trials. After surgical placement, drug is entered into and removed from the DAD percutaneously through a Silastic "fill port" using a standard gauge needle and syringe. The pump is noninvasively programmed using a hand-held telemetry wand to administer the drug in a continuous infusion, bolus, or bolus-delay mode. Because of the apparent improved therapeutic index of continuous-infusion doxorubicin (CID), a phase I trial of the Medtronic DAD with CID was begun. Thirteen pumps in 13 patients have functioned for a median of 153 days (range, 11 to 395 days) with one pump still functioning. Four pumps ceased function at 170, 278, 331, and 370 days, respectively; there was a catheter-tip clot on one of the pumps that later malfunctioned. All other pumps functioned until the death of the respective patients. In 84 pump refills, without drug extravasation, the median drug delivery error (actual residual volume--calculated residual volume/calculated residual volume X 100%) was 14%. Doxorubicin was compatible with all components of the drug pathway and did not significantly decompose during two weeks in the drug reservoir. The starting dose of CID was 2.0 mg/m2/d and the maximum tolerated dose was 4.1 mg/m2/d (range, 3.5 to 5.5). A median cumulative doxorubicin dose of 244 mg/m2 per patient (range, 10 to 583 mg/m2) has been infused.(ABSTRACT TRUNCATED AT 250 WORDS)

24-Hour mean pulse: Simple predictor of doxorubicin-induced cardiac damage

Nineteen adult patients with cancer received six to 10 monthly treatments of doxorubicin and cisplatin. Recumbent pulse was measured for 24 to 30 hours before each treatment. Treatment was stopped for disease progression or when a total doxorubicin dose of 550 mg/m 2 was reached. Rising serial 24-hour pulse averages predicted congestive heart failure reliably. No patient had congestive heart failure during therapy, but three patients had congestive heart failure two to four months after receiving 540, 525, and 530 mg/m 2 of doxorubicin. In these, two to six months before completion of therapy, the 24-hour rhythm-qualified mean (mesor) of pulse showed a positive slope by linear regression analysis (p <0.05) that was apparent at cumulative doxorubicin doses of 300, 420, and 240 mg/m 2. All 19 patients received similar total doses of doxorubicin and were followed to death or 12 months after the last doxorubicin dose. In addition, a progressive rise in the 24-hour mean pulse coincided with histologically documented doxorubicin-induced lethal congestive heart failure in Wistar-Kyoto rats of both sexes.

Dose-response relationships of chronic adriamycin toxicity in rabbits

Doxorubicin was administered chronically to 55 female New Zealand White rabbits in order to determine a chronic dose-response relationship for doxorubicin-induced cardiomyopathy, skeletal myopathy and nephropathy. Systolic time interval recording as a measure of cardiac function in doxorubicin-induced cardiomyopathy in the rabbit is compared to histologic grading of the cardiomyopathy. Histologic evidence of cardiomyopathy was not seen at cumulative doses less than 100 mg/m 2 but incidence and severity of cardiomyopathy increased with increasing doxorubicin dosage. The most severe lesions were seen at cumulative doses in excess of 400 mg/m 2. The dose-response of skeletal myopathy paralleled that of cardiomyopathy but the severity of histologic abnormalities and the incidence of skeletal myopathy was less than half that of cardiomyopathy at all dose levels. Nephropathy was a consistent finding at cumulative doses of doxorubicin in excess of 100 mg/m 2.

Active Sperm Production after Cancer Chemotherapy with Doxorubicin

The sperm production of 14 cancer patients who received doxorubicin was examined after cessation of therapy. Doxorubicin was used in several multiple-drug protocols for the treatment of various malignancies. Seven patients also received radiotherapy to different sites. Total cumulative doses of doxorubicin ranged from 145 to 625mg./m.2. Sperm concentration, motility, morphology and the frequency of quinacrine-stained sperm with 2 fluorescent bodies (2F sperm) were measured 7 to 79 months after discontinuation of doxorubicin. Of the patients 6 remained azoospermic, 3 were oligospermic and 5 were normospermic. Sperm motility among the 8 patients with sperm ranged from 20 to 80 per cent. Morphology and 2F sperm distributions were not significantly different from controls. We conclude that, in contrast with the mechlorethamine, vincristine, procarbazine and prednisone protocol, active sperm production within relatively short recovery times is possible after treatment with protocols that include doxorubicin.

Doxorubicin-Vincristine Therapy for Wilms’ Tumor: A Pilot Study

Doxorubicin plus vincristine chemotherapy was given to 31 children following nephrectomy for Wilms' tumor. Radiation therapy was used as indicated. Disease-free survival by stage is: eight of nine patients (stage I), eight of nine (stage II), nine of ten (stage III), and two of three (stage IV). Median follow-up of survivors is 28 months (range, 2-67); for all but four patients, follow-up is greater than 12 months. Two of the three stage I-III failures occurred in children with unfavorable histologies; the third failure was due to fatal anthracycline cardiomyopathy. Lowering the maximal cumulative doxorubicin dose from 450 to 240 mg/m2 did not increase failures. Doxorubicin-vincristine appears to be effective chemotherapy for Wilms' tumor.

Evaluation of the cardiac effects of doxorubicin by serial echocardiography.

Serial echocardiographic studies were performed on 48 children who received chemotherapy with doxorubicin hydrochloride (Adriamycin). For the group as a whole, no correlation could be made between the cumulative dose of doxorubicin administered and left ventricular systolic function as measured by the fractional shortening of the left ventricle (delta s). Two asymptomatic patients, however, demonstrated depressed delta s and abnormal results from radionuclide studies at cumulative doxorubicin doses of less than 430 mg/sq m. Differentiation of the echoderived curve of left ventricular minor axis dimension indicated that these two patients had abnormalities in both diastolic and systolic function. Good correlation was demonstrated between echocardiographic and radionuclide studies in eight patients, including the two with depressed function. Inherent variability limits the sensitivity of echocardiographic functional studies, but serial studies are helpful in the evaluation of cardiac function in children who receive doxorubicin.

Doxorubicin Cardiotoxicity: Assessment of Late Left Ventricular Dysfunction By Radionuclide Cineangiography

Radionuclide cineangiography was used to evaluate 32 patients who sustained long-term remission of soft tissue sarcoma after adjuvant therapy with a cumulative doxorubicin dose from 480 to 550 mg/m body surface area. Left ventricular ejection fraction at rest was below normal (less than 45%) in eight of 32 patients. The abnormal response of ejection fraction to exercise identified an additional 12 patients with diminished left ventricular functional reserve. Ejection fraction determined at rest or during exercise did not differ 1 to 9 months) and those studied 30 months (range, 21 to 43 months) after completing doxorubicin treatment. Sequential studies in 13 patients, done 6 to 15 months after initial post-doxorubicin evaluation also showed persistent depression of average ejection fraction at rest and with exercise, with the continued deterioration of left ventricular function in six patients. Left ventricular dysfunction, evident in over half of asymptomatic patients even long after "acceptable" cumulative doses of doxorubicin, may persist for years.

Time- and dose-dependent changes in ejection fraction after anthracycline therapy.

Cardiac toxicity due to anthracycline therapy is dose related, and congestive failure is a major limiting factor to therapy. Radionuclide cardiac evaluation provides a sensitive noninvasive method for detecting changes in cardiac function. Fifteen patients receiving either doxorubicin or daunomycin were evaluated with radionuclide ejection fractions (EFrn). The data indicate that the EFrn can detect an acute depressant cardiac action of these drugs as early as 24 hr after drug administration. In addition, a cumulative or chronic cardiac depression was noted; cumulative dosage of doxorubicin or daunomycin correlated with a reduced EFrn (p less than 0.001). We conclude that (1) the EFrn can noninvasively detect significant changes in cardiac function at low cumulative doses of doxorubicin or daunomycin and (2) the EFrn may be useful in evaluating cardiac function in patients during doxorubicin or daunomycin therapy.