pirarubicin and Heart-Diseases

Pirarubicin (tetrahydropyranyl-adriamycin: THP) is a derivative of doxorubicin with reportedly less cardiotoxicity in adults. However no studies of cardiotoxicity in children treated with THP have been reported. This study was performed to assess the THP-induced cardiotoxicity for children with acute lymphoblastic leukemia (ALL).. This study comprised 61 asymptomatic patients aged from 7.6 to 25.7 years old. Median follow-up time after completion of anthracycline treatment was 8.1 years (range: 1.7-12.5). The cumulative dose of THP ranged from 120 to 740 mg/m(2) with a median of 180 mg/m(2) . Patients underwent electrocardiogram (ECG), echocardiography, the 6-min walk test (6MWT), and measurements of serum brain natriuretic peptide (BNP) before and after exercise.. All subjects showed normal left ventricular function assessed by echocardiography. Ventricular premature contraction in Holter ECG and reduced exercise tolerance in the 6MWT were detected in 2/46 (3.3%) and 5/41(12.2%), respectively. Abnormal BNP levels were detected in 6/60 (10%) both before and after exercise. The cumulative dose of THP was significantly correlated with BNP levels after exercise (r = 0.27, P = 0.03), but not with any other cardiac measurements. Further analysis revealed that subjects with a high cumulative dose ≧300 mg/m(2) had significantly higher BNP levels after exercise compared with subjects with a low cumulative dose <300 mg/m(2) (P = 0.04).. No significant cardiac dysfunction was detected in long-term survivors who received THP treatment. The use of post-exercise BNP level to indicate high cardiotoxicity risk should be verified by further study.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Agents; Child; Doxorubicin; Electrocardiography; Heart Diseases; Heart Function Tests; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Young Adult

Standard treatment for relapsed or refractory follicular lymphoma has not been established. Doxorubicin is often given during the initial treatment. The dosage or drugs chosen for salvage therapy are limited by doxorubicin-induced cardiomyopathy.. The R-EPOCT (rituximab with etoposide, vincristine, pirarubicine, cyclophosphamide, and prednisone) regimen, in which less cardiotoxic pirarubicine is used instead of doxorubicin, with granulocyte colony-stimulating factor (G-CSF) was administered to 20 patients with relapsed or refractory follicular lymphoma. The safety (especially cardiotoxicity) and efficacy of this regimen were studied. As markers of cardiotoxicity, serum troponin T and plasma B-type natriuretic peptide (BNP) levels were measured.. Adverse reactions occurred in 14 of the 20 patients and mainly consisted of grade 3/4 hematologic toxicity. In the evaluation of cardiotoxicity, the BNP level was slightly elevated before the treatment in two patients and the BNP level did not significantly increase after R-EPOCT treatment. The troponin T level was undetectable before and after the treatment in all patients. The response rate was 100%, with complete remission in 16 patients (80%). G-CSF administration increased both Fc gamma receptor type I expression on neutrophils and antibody-dependent cellular cytotoxicity activity. There were no significant differences in the levels of Fc gamma receptor type I expression nor antibody-dependent cellular cytotoxicity activity after three or five cycles of the treatment.. We conclude that the combination of R-EPOCT and G-CSF is well tolerated. This regimen was not cardiotoxic. We are planning a randomized trial to compare the efficacy between R-EPOCT and a combination of R-EPOCT with G-CSF.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Heart Diseases; Humans; Lymphoma, Follicular; Male; Middle Aged; Natriuretic Peptide, Brain; Neoplasm Recurrence, Local; Prednisone; Receptors, IgG; Remission Induction; Rituximab; Salvage Therapy; Troponin T; Vincristine

A phase I-II study of weekly low-dose pirarubicin was performed in 19 patients with advanced breast cancer. The goal was to establish the optimal dose intensity, i.e., the maximal dose applicable at tolerable toxicity within the intended schedule. Each of the four different dose groups used (20, 24, 25, and 27 mg/m2) comprised 4-5 patients. In over 47% of patients, objective remissions were obtained (confidence interval 26%; 71%) including one complete and eight partial remissions; the median duration of remission was 41 weeks (range 16-72), and the median time to reach remission was 12 weeks (range 6-36). Efficacy of treatment was more dependent on prior chemotherapy than on pirarubicin dosage. The weekly i.v. push injection of the drug was easily applicable at an outpatient clinic and well tolerated. WHO grade 3 was the highest toxicity observed for leukopenia (3/19), leukopenia associated with infection (1/19), nausea/vomiting (2/19) and alopecia (6/19). More severe myelosuppression was avoided by interrupting the weekly application until recovery of leukocytes to greater than or equal to 3.5 x 10(3)/mm3. No clinical signs of cardiotoxicity were observed. Generally, mild to moderate signs of cardiac dysfunction acquired during therapy were detected by special cardiac monitoring. Only in 3 of 19 patients was a cumulative dose of more than 550 mg/m2 surpassed. This was accepted as the upper limit for conventional anthracycline therapy. The median cumulative dose applied was 325 mg/m2/week (range 58.2-800.0). Because of maldistribution of prognostic factors, no dose-response relationship could be established. With respect to the total time for which each patient was studied, the dose group of 27 mg/m2 achieved the highest dose intensity with a median of 17.4 mg/m2/week (range 13.5-22.4). Therefore, the dosage of 27 mg/m2/week is recommended to be used in further phase II-III trials of weekly applied pirarubicin.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Heart Diseases; Hematologic Diseases; Humans; Kidney Diseases; Middle Aged; Remission Induction

The authors have examined the cardiotoxic actions of pirarubicin (THP), compared with epirubicin (EPI) and doxorubicin (DXR), on the electrocardiogram (ECG) and myocardial structure in rats. The rats were treated once a week for four weeks with DXR (total dose 10 mg/kg), and then further treated (post-treated) once a week for four weeks with THP, EPI or DXR (total dose 5 and 10 mg/kg). In the ECG study, a prolongation of QaT interval (interval from the upstroke of R wave to the apex of T wave) and a flattening of T wave were observed more severely in the rats post-treated with EPI and DXR than in those treated with THP. Also, a prolongation of QRS duration was observed more prominently in those treated with DXR than with THP and EPI. Histopathologically, a vacuolization and swelling of myocardial cells and an infiltration of mononuclear cells were observed more severely in the rats post-treated with EPI and DXR than in those treated with THP. Furthermore, a meandering of myofibril was observed in those treated with EPI and DXR, but not with THP. These results suggest that the cardiotoxic actions of THP are weaker than those of EPI and DXR and that the replacement of DXR with THP leads to more successful cancer chemotherapy with less cardiotoxicity.

Topics: Animals; Doxorubicin; Electrocardiography; Epirubicin; Female; Heart Diseases; Myocardium; Myofibrils; Rats; Rats, Sprague-Dawley

Topics: Animals; Doxorubicin; Epirubicin; Heart; Heart Diseases; Male; Mice; Microscopy, Electron; Myocardium

Pirarubicin is an anthracycline with broad antitumor activity, and without significant cardiotoxicity in preclinical and early clinical trials. We treated 40 evaluable patients with metastatic breast cancer and no prior exposure to chemotherapy with 5-fluorouracil, pirarubicin, and cyclophosphamide at 21-day intervals until reaching cumulative doses of 800 mg/m2 of pirarubicin, or the development of progressive disease. The median age was 56 years and the median performance status, 1. Seventeen patients had prior hormone therapy and 12 had prior radiotherapy. The median number of metastatic sites was three, with 11 patients having less than three sites. Twelve patients were premenopausal. The median disease-free interval was 6 months. Four patients achieved a complete remission and 21 a partial remission, for an overall response rate of 63%. The median response duration was 8 months and the median time to progression for all patients was 9 months. The median survival has not been reached, but will exceed 13 months. Gastrointestinal toxicity was minimal to moderate, whereas myelosuppression was severe. Complete hair loss was observed by only 58% of patients. There were two episodes of mild congestive heart failure at high cumulative doses of pirarubicin; both were controlled with medical treatment. This three-drug combination containing pirarubicin is effective in treating metastatic breast cancer, with less severe toxicity than other anthracycline-containing combinations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Heart Diseases; Hematologic Diseases; Humans; Middle Aged; Remission Induction

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

Topics: Adult; Aged; Blood Cell Count; Breast Neoplasms; Doxorubicin; Drug Evaluation; Female; Heart Diseases; Humans; Middle Aged; Neoplasm Metastasis