cardiovascular-agents and Sarcoma

The aim of this article is to review (based on the literature data) the mechanism of chemotherapy- and radiation-induced cardiac toxicity, diagnostic procedures and methods of reducing this toxicity. Cardiac toxicity associated with chemotherapy and radiotherapy may be life threatening, can limit the dose and duration of the treatment and certainly adversely affect short-term and long-term quality of life. A development of new strategies for reduction and prophylaxis of cardiac toxicity has great clinical impact. Chemotherapeutic agents may cause acute myocardial injury or chronic complications (e.g. congestive heart failure). Among cardiotoxic agents anthracyclines cause most serious cumulative, dose-limiting and dose-related cardiomyopathy. Most of them are subclinical changes, however studies demonstrate that symptomatic congestive heart failure in 6-10% of adults who received a cumulative, bolus doses of 550 mg/m2. The frequency of cardiomyopathy may be reduced by modifying the schedule of administration, patients selection considering risk factors, careful cardiac monitoring during chemotherapy, using less toxic doxorubicin analogues and liposomal formulation. The use of pharmacological protection with dexrazoxane remains controversial. A substantial risk of cardiotoxicity may be associated with radiotherapy of the chest and mediastinum. Moreover, radiotherapy may have an additive affect to chemotherapy-induced toxicity. However, with the use of modern treatment techniques radiation cardiomyopathy is uncommon. A group of patients at risk of cardiac complication are patients with breast cancer, Hodgkin's and non-Hodgkin's lymphomas and soft tissue sarcomas.

Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Cardiomyopathy, Dilated; Cardiovascular Agents; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Neoplasms; Radiotherapy, Adjuvant; Razoxane; Risk Factors; Sarcoma

Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion.. Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 microg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 microl(-1). Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations.. Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (<500 microl(-1)) was nine and of platelet count <20,000 microl(-1) was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM.. These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.

Topics: Adult; Antibiotics, Antineoplastic; Cardiovascular Agents; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Heart Failure; Humans; Infusions, Intravenous; Levofloxacin; Male; Middle Aged; Neoplasms; Neutropenia; Ofloxacin; Razoxane; Sarcoma; Sepsis; Treatment Outcome

We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity.. Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies.. In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004).. DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Cardiovascular Agents; Drug Monitoring; Epirubicin; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Radionuclide Imaging; Razoxane; Sarcoma; Ventricular Function, Left

We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients.. Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities.. Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity.. ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Cardiovascular Agents; Child; Doxorubicin; Female; Heart; Humans; Injections, Intravenous; Male; Neuroectodermal Tumors, Primitive, Peripheral; Razoxane; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Stroke Volume; Survival Rate; Transaminases

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents.

Topics: Animals; Antibiotics, Antineoplastic; Cardiovascular Agents; Cells, Cultured; Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Drug Delivery Systems; Drug Synergism; Drug Therapy, Combination; Endothelium, Vascular; Hindlimb; Histamine; Humans; Male; Rats; Rats, Inbred BN; Sarcoma; Umbilical Veins