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Quintana, Raymundo A., Jose Banchs, Ridhi Gupta, et al. "Early Evidence of Cardiotoxicity and Tumor Response in Patients with Sarcomas after High Cumulative Dose Doxorubicin Given as a Continuous Infusion." Sarcoma 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/7495914.
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Background. Despite the dose-dependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. This study evaluates early evidence of cardiotoxicity in patients treated with high-dose doxorubicin given as a continuous infusion. Methods. Data was collected on patients who received 90 mg/m2 doxorubicin as a continuous infusion and 10 gm/m2 ifosfamide for up to 6 cycles as part of a phase II study. Cardiotoxicity was assessed with serial echocardiograms or multigated acquisition scans and serum brain natriuretic peptide and troponin levels. Tumor responses were determined by serial radiographic imaging per RECIST. Result. Out of the 48 patients enrolled, no patient developed heart failure symptoms; however, 4 out of the 38 (10%) patients with serial left ventricular ejection fraction assessments developed subclinical cardiotoxicity (asymptomatic drop in LVEF ≥ 10%). Twenty-three patients received all six 72-hour cycles of doxorubicin with a mean cumulative dose of 540 mg/m2. Among these patients, 4% (n=1) developed subclinical cardiotoxicity. In the advanced disease group (n=39), patients with a complete or partial response received a higher mean cumulative dose than those with stable disease (p<0.033). Conclusions. Doxorubicin cardiotoxicity can be limited by administering doxorubicin as a continuous infusion, allowing higher cumulative dosing to maximize efficacy.
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Zhong, Hua, Bhoomi Mehrotra, Kristine Bond, Sherly Jacob-Perez, Nathaniel Reichek, and Haoyi Zheng. "ABSOLUTE CUMULATIVE DOSE NOT CUMULATIVE DOSE INDEXED BY BSA PREDICTS DOXORUBICIN-INDUCED SUBCLINICAL CARDIOTOXICITY." Journal of the American College of Cardiology 77, no. 18 (2021): 3307. http://dx.doi.org/10.1016/s0735-1097(21)04661-1.
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Esteban, L. López, A. Liras Medina, R. Diez Fernández, and T. Molina García. "CP-179 Patients exceeding doxorubicin recommended cumulative dose." European Journal of Hospital Pharmacy 23, Suppl 1 (2016): A79.1—A79. http://dx.doi.org/10.1136/ejhpharm-2016-000875.179.
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Alhaja, Maher, Sherry Chen, Alan Chin, Brian Schulte, and Carlo S. Legasto. "Cardiac safety of pegylated liposomal doxorubicin after conventional doxorubicin exposure in patients with sarcoma and breast cancer." JCO Oncology Practice 19, no. 11_suppl (2023): 388. http://dx.doi.org/10.1200/op.2023.19.11_suppl.388.
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388 Background: Lifetime cumulative doses of conventional doxorubicin (>450 mg/m2) are associated with dose-dependent cardiotoxicity. In soft tissue sarcoma (STS) and breast cancer, conventional doxorubicin is often utilized in earlier lines of therapy, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is associated with less cardiotoxicity than conventional doxorubicin and high doses of PLD can be administered without increased risk of cardiotoxicity in patients without prior exposure to conventional doxorubicin. Limited data exists evaluating cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to evaluate the cardiac safety of PLD use in patients who had prior exposure to conventional doxorubicin. Methods: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with STS or breast cancer, who were exposed to conventional doxorubicin from an earlier line of treatment prior to PLD between January 2010 – May 2022. Patients participating in clinical trials were excluded. The primary outcome of the study was cardiac safety. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or new diagnosis of heart failure within 6 months after PLD cessation. Results: 494 patients were screened and 50 patients met inclusion criteria, 8 STS and 42 breast cancer patients. Median lifetime cumulative conventional doxorubicin dose in patients with STS was 450 mg/m2 with a max dose of 825 mg/m2, and 240 mg/m2 with a max dose of 300 mg/m2 in breast cancer patients. Median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the STS group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the STS group. 22 breast cancer patients had available LVEF data on PLD; 3 of these patients experienced ≥ 10% in LVEF drop and one of three patients was diagnosed heart failure. The average cumulative dose of PLD administered in patients with > 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Most of STS patients initiated PLD treatment within 2 years after conventional doxorubicin while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. Conclusions: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe with limited cardiotoxicity in patients with STS and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.
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Hequet, O., Q. H. Le, I. Moullet, et al. "Subclinical Late Cardiomyopathy After Doxorubicin Therapy for Lymphoma in Adults." Journal of Clinical Oncology 22, no. 10 (2004): 1864–71. http://dx.doi.org/10.1200/jco.2004.06.033.
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Purpose To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. Patients and Methods We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. Results Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m2), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P < .01), older age (P < .01), higher cumulative dose of doxorubicin or association with another anthracycline (P = .04), radiotherapy (P = .04), and being overweight (P = .04). Conclusion Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.
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Green, Daniel M., Yevgeny A. Grigoriev, Bin Nan, et al. "Congestive Heart Failure After Treatment for Wilms’ Tumor: A Report From the National Wilms’ Tumor Study Group." Journal of Clinical Oncology 19, no. 7 (2001): 1926–34. http://dx.doi.org/10.1200/jco.2001.19.7.1926.
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PURPOSE: We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms’ tumor that included doxorubicin. PATIENTS AND METHODS: Flow sheets and medical records were reviewed to identify cases of congestive heart failure in a cohort of patients treated on National Wilms’ Tumor Studies (NWTS)-1, -2, -3, and -4. The frequency of congestive heart failure was estimated using the Kaplan-Meier method. A case-control study was conducted to determine the relationship among cumulative doxorubicin dose, site(s), total dose of abdominal and thoracic irradiation, sex, and the frequency of congestive heart failure. RESULTS: The cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin and 17.4% at 20 years after diagnosis among those treated with doxorubicin for their first or subsequent relapse of Wilms’ tumor. The relative risk (RR) of congestive heart failure was increased in females (RR = 4.5; P = .004) and by cumulative doxorubicin dose (RR = 3.3/100 mg/m2; P < .001), lung irradiation (RR = 1.6/10 Gy; P = .037), and left abdominal irradiation (RR = 1.8/10 Gy; P = .013). CONCLUSION: We conclude that congestive heart failure is a risk of treatment with doxorubicin for Wilms’ tumor. Additional follow-up of those children treated on NWTS-4 will be necessary to determine if the decrease in dose to 150 mg/m2 significantly reduces this risk.
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Avalyan, A. A., E. V. Oshchepkova, M. A. Saidova, et al. "Evaluation of subclinical cardiotoxicity in patients with breast cancer and arterial hypertension in two regimens of anthracycline-containing chemotherapy." Systemic Hypertension 15, no. 4 (2018): 59–64. http://dx.doi.org/10.26442/2075082x.2018.4.000021.
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Objective. To study of subclinical cardiotoxicity of two anthracycline-containing chemotherapy regimens in breast cancer patients with normotension and arterial hypertension. Materials and methods. 119 women (mean age 48,8±10,9 years) with triple negative breast cancer were enrolled. They are received one of two chemotherapy options that differed in the intensity and duration of treatment, including the total dose of anthracyclines. Depending on the chemotherapy option, the patients were divided into two groups: group 1 (n=54) - treatment duration ≤8 weeks, cumulative dose of doxorubicin was 200 mg/m2, group 2 (n=65) - treatment duration ≤16 weeks, the cumulative dose of doxorubicin was 320 mg/m2. Before and after chemotherapy completion of all patients, the level of troponin T (h.s.) and NT-proBNP was determined, and heart ultrasound was performed, 2D and 3D speckle tracking imaging. Results. In patients who received a higher cumulative dose of doxorubicin (group 2), a statistically significant increase in biomarkers of myocardial damage was observed (h.s. troponin T before chemotherapy was 7.8±0.5 pg/ml, after chemotherapy - 55.0±7.0 pg/ml, p
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Perez, D. J., V. J. Harvey, B. A. Robinson, et al. "A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer." Journal of Clinical Oncology 9, no. 12 (1991): 2148–52. http://dx.doi.org/10.1200/jco.1991.9.12.2148.
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One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were randomly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks. These doses were selected to produce equivalent toxicities. All patients were assessed for toxicity, and 138 patients were assessable for response. After a median of five treatment cycles, 47% (32 of 68) of doxorubicin-treated patients achieved a partial or complete response. Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin, respectively. Noncardiac toxicities were similar for both drugs. Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessments, seven sustained a fall of 10% or more, and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2. Of 39 patients receiving epirubicin who had serial cardiac assessments, five sustained left ventricular ejection fraction falls of 10% or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2. These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates, response duration, or survival in advanced breast cancer.
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Swain, S. M., F. S. Whaley, M. C. Gerber, M. S. Ewer, J. R. Bianchine, and R. A. Gams. "Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy." Journal of Clinical Oncology 15, no. 4 (1997): 1333–40. http://dx.doi.org/10.1200/jco.1997.15.4.1333.
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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.
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Lipshultz, Steven E., Stuart R. Lipsitz, Stephen E. Sallan, et al. "Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia." Journal of Clinical Oncology 23, no. 12 (2005): 2629–36. http://dx.doi.org/10.1200/jco.2005.12.121.
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Purpose Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare. Methods Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (−) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively. Results Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to −2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later. Conclusion Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.
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Shapiro, C. L., T. Ervin, L. Welles, N. Azarnia, J. Keating, and Daniel F. Hayes. "Phase II Trial of High-Dose Liposome-Encapsulated Doxorubicin With Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer." Journal of Clinical Oncology 17, no. 5 (1999): 1435. http://dx.doi.org/10.1200/jco.1999.17.5.1435.
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PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (IV) bolus of TLC D-99 with 5 μg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days. RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value ≥ 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by IV bolus infusion does not warrant further investigation.
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Kremer, L. C. M., M. M. C. Tiel-van Buul, M. C. Ubbink, et al. "Indium-111–Antimyosin Scintigraphy in the Early Detection of Heart Damage After Anthracycline Therapy in Children." Journal of Clinical Oncology 17, no. 4 (1999): 1208. http://dx.doi.org/10.1200/jco.1999.17.4.1208.
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PURPOSE: To determine the value of indium-111–antimyosin (111In-AM) scintigraphy in the early detection of myocardial damage in children treated with doxorubicin. PATIENTS AND METHODS: Twelve planar scintigrams were made of eight patients (seven children and one young adult; mean age, 12 years). Three scans were obtained before doxorubicin therapy in three patients, and nine scans were obtained during doxorubicin therapy in seven patients. The heart-to-lung ratio (HLR) was calculated. Left ventricular function was assessed by echocardiography before and during therapy by measuring the fractional shortening (FS). RESULTS: The HLR of the three baseline scans was below 1.5, within the normal range for adults. Six of the seven patients whose scans were obtained during chemotherapy had abnormal HLR values (> 1.5). One patient had severe myocyte damage and showed an early increase in the HLR (2.3) after a cumulative doxorubicin dose of 150 mg/m2. The FS measured by echocardiography was normal throughout therapy, and the final cumulative dose of doxorubicin was 450 mg/m2. This patient developed fatal clinical heart failure 3 months after completion of chemotherapy. In one patient, who was pretreated with the cardioprotective agent dexrazoxane, the HLR remained within normal limits during therapy. CONCLUSION: 111In-AM scintigraphy seems to be suitable to detect early myocardial damage after a cumulative doxorubicin dose of 150 mg/m2 in children and may be useful for identifying children who are at increased risk of developing cardiac sequelae.
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Speyer, J. L., M. D. Green, A. Zeleniuch-Jacquotte, et al. "ICRF-187 permits longer treatment with doxorubicin in women with breast cancer." Journal of Clinical Oncology 10, no. 1 (1992): 117–27. http://dx.doi.org/10.1200/jco.1992.10.1.117.
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PURPOSE To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.
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Gergely, Szabolcs, Csaba Hegedűs, Petra Lakatos, et al. "High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/178513.
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Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge’s DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury.
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Shee, Kevin, Alan T. Kono, Susan P. D'Anna, et al. "Maximizing the Benefit-Cost Ratio of Anthracyclines in Metastatic Breast Cancer: Case Report of a Patient with a Complete Response to High-Dose Doxorubicin." Case Reports in Oncology 9, no. 3 (2016): 840–46. http://dx.doi.org/10.1159/000453608.
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Despite the clinical efficacy of anthracycline agents such as doxorubicin, dose-limiting cardiac toxicities significantly limit their long-term use. Here, we present the case of a 33-year-old female patient with extensive metastatic ER+/PR+/HER2– mucinous adenocarcinoma of the breast, who was started on doxorubicin/cyclophosphamide therapy after progressing on paclitaxel and ovarian suppressor goserelin with aromatase inhibitor exemestane. The patient was comanaged by cardiology, who carefully monitored measures of cardiac function, including EKGs, serial echocardiograms, and profiling of lipids, troponin, and pro-BNP every 2 months. The patient was treated with the cardioprotective agent dexrazoxane, and changes in cardiac markers [e.g. decreases in ejection fraction (EF)] were immediately addressed by therapeutic intervention with the ACE inhibitor lisinopril and beta-blocker metoprolol. The patient had a complete response to doxorubicin therapy, with a cumulative dose of 1,350 mg/m2, which is significantly above the recommended limits, and to our knowledge, the highest dose reported in literature. Two and a half years after the last doxorubicin cycle, the patient is asymptomatic with no cardiotoxicity and an excellent quality of life. This case highlights the importance of careful monitoring and management of doxorubicin-mediated cardiotoxicity, and that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit.
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Wang, Yuehan, Cécile M. Ronckers, Flora E. van Leeuwen, et al. "Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer." Nature Medicine 29, no. 9 (2023): 2268–77. http://dx.doi.org/10.1038/s41591-023-02514-1.
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AbstractAnthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m−2: 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m−2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m−2, HR: 2.33 for 300–399 mg m−2 and HR: 2.78 for ≥400 mg m−2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m−2 of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m−2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
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Asanov, M. A., A. O. Poddubnyak, R. A. Muhamadiyarov, A. V. Sinitskaya, M. V. Khutornaya, and M. Yu Sinitsky. "Comprehensive assessment of subchronic low-dose exposure to doxorubicin in the Wistar rat model." Siberian Journal of Clinical and Experimental Medicine 39, no. 4 (2024): 171–79. https://doi.org/10.29001/2073-8552-2024-39-4-171-179.
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Rationale. Doxorubicin is a chemotherapeutic antibiotic from the anthracycline class that has cumulative and dose-dependent cardiotoxic effects. The cardiotoxic properties of doxorubicin are manifested in characteristic pathologies of the heart and its microenvironment. Doxorubicin also exhibits genotoxic properties and is often used to model acute genotoxic effects in small laboratory animal models.Aim: To evaluate chronic low-dose exposure to doxorubicin in a Wistar rat model using cytogenetic methods and electron microscopy.Material and Methods. The study included two groups of 10 male Wistar rats: an experimental group (weekly doxorubicin in the tail vein 2 mg/kg for 4 weeks) and a control group (0.9% NaCl). A micronucleus test was used to evaluate genotoxic effects. Visualization of the myocardial structure was carried out using scanning electron microscopy in back-scattered electrons on an electron microscope.Results. The analysis showed a significant difference between the control (0.8%) and experimental groups (3.2%) in the level of polychrome erythrocytes with a micronucleus. It was found that rats from the experimental group were characterized by a significant decrease in the number of polychromatic red blood cells compared to the control group. In the experimental group, pronounced heterogeneity of the morphological structure of the myocardium was noted. Electron micrographs of hepatocytes from rats treated with doxorubicin showed degenerative changes in the structure of liver cells.Conclusion. The results of our study provide insight into the subacute effect of a small dose of doxorubicin on the heart, liver and hematopoietic system of normolipidemic Wistar rats. We have proposed mechanisms of interaction between important organs and systems of the body exposed to doxorubicin against the background of a general pathological condition. In the future, the nature of the toxic effects of lower and optimal doses of the mutagen in the context of subchronic cumulative exposure should be determined.
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NOUSIAINEN, Tapio, Esko VANNINEN, Esa JANTUNEN, et al. "Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients." Clinical Science 101, no. 6 (2001): 601–7. http://dx.doi.org/10.1042/cs1010601.
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Doxorubicin-induced cardiotoxicity was used as a model to prospectively investigate neuroendocrine changes during the development of left ventricular dysfunction. Radionuclide ventriculography, frequency domain analysis of heart rate variability (HRV), and plasma noradrenaline and natriuretic peptide measurements were performed in 27 adult lymphoma patients at baseline and after cumulative doxorubicin doses of 200, 400 and 500mg/m2. The left ventricular ejection fraction (LVEF) decreased from 58.1±1.4% to 50.3±1.1% (P < 0.001) and 49.3±1.7% (P < 0.001) after cumulative doxorubicin doses of 400 and 500mg/m2 respectively. With a doxorubicin dose of up to 400mg/m2 there was an increase in sympathetic tone, characterized by a decrease in the normalized high-frequency (HFnu) power (P = 0.011), and increases in the normalized low-frequency (LFnu) power (P = 0.011), the LF/HF ratio (P = 0.021) and the plasma noradrenaline concentration (P = 0.034). The decrease in LVEF was correlated with the changes in LFnu and HFnu power (r = 0.540, P =0.012) and LF/HF ratio (r =-0.452, P =0.04). However, after the cumulative doxorubicin dose of 500mg/m2 the changes in HRV components and plasma noradrenaline levels returned towards baseline. This was accompanied by increased concentrations of plasma atrial natriuretic peptide (P = 0.004) and brain natriuretic peptide (P = 0.021). Our findings suggest that doxorubicin-induced left ventricular dysfunction is associated with an early change in sympathovagal balance towards sympathetic predominance. Along with further progression of left ventricular dysfunction, there is an attenuation of sympathetic tone, which may be attributable to sympatho-adrenal inhibition by increased secretion of natriuretic peptides.
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Maravilla, Rachelle Diane Bautista, Paula Isabel Gimena Franco, Gale Rizzae Mercado Alcala, John Christopher Agsalud Pilapil, Agnes Evangelista Gorospe, and Anna Marie Mangune Pascual-Panganiban. "Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis." Journal of Clinical Oncology 42, no. 16_suppl (2024): e24004-e24004. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e24004.
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e24004 Background: The risk of anthracycline-related cardiotoxicity increases with cumulative dose, with most available literature based from studies on breast cancer patients. Although soft tissue sarcomas are heterogenous entities, anthracycline-based chemotherapy is considered the most active regimen. This study aims to clarify the incidence of cardiotoxicity among patients with advanced soft tissue sarcomas who receive a high cumulative dose of anthracyclines. Methods: We performed a systematic search across PubMed, Cochrane, Google Scholar, and ASCO and ESMO references. Studies were eligible if they (1) investigated soft tissue sarcoma patients, (2) receiving high cumulative doses of doxorubicin ( > 450mg/m2), lipodox ( > 550mg/m2) or epirubicin ( > 900mg/m2), and (3) reported the incidence of cardiotoxicity (clinical and subclinical). Three authors independently assessed validity of the articles using the Cochrane Tool for randomized trials and the Newcastle-Ottawa scale for cohorts. Pooled analysis was performed using MetaXL with the random effects model. Pooled incidence with 95% CI and heterogeneity (Cochran's Q) were determined. Results: For doxorubicin, 4 studies with 168 patients without pre-existing cardiomyopathy, and a mean age of 47 years were included. At a mean cumulative dose of 651.1mg/m2, clinical cardiotoxicity was seen in 2.6% (0.62–5.62%,Q3) while subclinical cardiotoxicity was seen in 23.8%(17.67%-30.53%,Q86). For epirubicin, we included 3 studies with 109 patients, without pre-existing cardiomyopathy, and mean age of 39 years. At a cumulative dose of 1128.33mg/m2, clinical cardiotoxicity was seen in 5.3% (1.74–10.38%,Q25), and subclinical cardiotoxicity was seen in 13.4% (7.62%-20.50%,Q37). Conclusions: The incidence of cardiotoxicity in patients with advanced soft tissue sarcomas receiving high cumulative dose of anthracyclines is comparable with existing data on breast, lymphoma and leukemia patients. Subclinical cardiotoxicity is more prominent. Majority of the patients received cardioprotective strategies during their treatment (dexrazoxane or continuous infusions of doxorubicin). Evidence with regard to lipodox is lacking.
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Herman, Eugene H., Jun Zhang, Steven E. Lipshultz, et al. "Correlation Between Serum Levels of Cardiac Troponin-T and the Severity of the Chronic Cardiomyopathy Induced by Doxorubicin." Journal of Clinical Oncology 17, no. 7 (1999): 2237. http://dx.doi.org/10.1200/jco.1999.17.7.2237.
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PURPOSE: To investigate, over a wide range of cumulative doxorubicin doses, the feasibility of using serum concentrations of cardiac troponin-T (cTnT) as a biomarker for doxorubicin-induced myocardial damage.MATERIALS AND METHODS: Groups of spontaneously hypertensive rats (SHR) were given 1 mg/kg doxorubicin weekly for 2 to 12 weeks. Cardiomyopathy scores were assessed according to the method of Billingham and serum levels of cTnT were quantified by a noncompetitive immunoassay. Myocardial localization of cTnT was studied by immunohistochemical staining and confocal microscopy.RESULTS: Increases in serum levels of cTnT (0.03 to 0.05 ng/mL) and myocardial lesions (cardiomyopathy scores of 1 or 1.5) were found in one out of five and two out of five SHR given 2 and 4 mg/kg doxorubicin, respectively. All animals given 6 mg/kg or more of doxorubicin had increases in serum cTnT and myocardial lesions. The average cTnT levels and the cardiomyopathy scores correlated with the cumulative dose of doxorubicin (0.13 v 0.4 ng/mL cTnT and scores of 1.4 v 3.0 in SHR given 6 and 12 mg/kg doxorubicin, respectively). Decreased staining for cTnT was observed in cardiac tissue from SHR receiving cumulative doses that caused only minimal histologic alterations (scores of 1 to 1.5). Staining for cTnT decreased simultaneously with increases in the severity of the cardiomyopathy scores.CONCLUSION: cTnT is released from doxorubicin-damaged myocytes. Measurements of serum levels of this protein seem to provide a sensitive means for assessing the early cardiotoxicity of doxorubicin.
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Podyacheva, E. Yu, T. V. Shmakova, D. D. Andreeva, et al. "MOLECULAR MARKERS PROFILE OF FIBROSIS IN RATS EXPOSED TO DIFFERENT DOSES OF DOXORUBICIN." Журнал эволюционной биохимии и физиологии 59, no. 2 (2023): 121–30. http://dx.doi.org/10.31857/s0044452923020043.
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Text of the abstract. The study is devoted to the investigate of the molecular markers profile of fibrosis when various doses of doxorubicin are administered to Wistar drain rats. The study was performed on 40 male Wistar rats weighing 260 ± 19 g. Animals were divided into 4 groups: control and three experimental groups with a certain frequency of administration (6 times in two days) and a certain dose of doxorubicin (5, 10, 15 mg/kg, intraperitoneally). At the end of the administration of the chemotherapy drug, the animals were observed for 2 months. To solve this aim, the hearts were taken from anesthetized animals for molecular and morphological studies. Histological, echocardiographic and molecular analyses revealed dose-dependent damaging changes in the left ventricular myocardium against the background of exposure to various doses of doxorubicin. The expression level of TGF-β did not differ from the control values 2 months after the end of administration of all cumulative doses of the chemotherapy drug. However, at this stage of the study, the preserved increased expression of type I, type II collagen, ET-1, FGF4 and TNF-α was characteristic of animals receiving the maximum cumulative dose of doxorubicin, which may reflect the incompleteness of the fibrous tissue formation process, as well as their active participation in the development of inflammatory processes with pronounced cardiotoxic damage against the background of exposure the chemotherapy drug. For animals receiving 10 mg/kg, there were no changes in these molecular markers of fibrosis compared to the control group, whereas in the group of animals with the minimum cumulative dose of the drug, a decrease in the expression of COL I, II type, ET-1, TNF-α and an increase in FGF4 levels were revealed.
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Veleti, Kowmudi, Hemanth Kumar, Nazia Begum, Sharath Kondra, and Prashanth Nallavelli. "Protective Effect of Beta-Caryophyllene on Doxorubicin Induced Multiple Organ Toxicity in Rats." INTERNATIONAL JOURNAL OF APPLIED PHARMACEUTICAL SCIENCES AND RESEARCH 5, no. 02 (2020): 22–29. http://dx.doi.org/10.21477/ijapsr.5.2.1.
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The major limiting factor in doxorubicin’s long-term administration is the development of cumulative dosedependent cardiomyopathy and congestive heart failure. Also, doxorubicin causes deterioration in hepato-renal function. It significantly increases the levels of blood urea nitrogen, creatinine, alanine transaminase, and aspartate transaminase distortion in normal renal and hepatic histology. The present study was undertaken to find out the protective role of beta-caryophyllene (BCP), an anti-oxidant against doxorubicin-induced multiple organ toxicities in experimental animals. In this study, male Wistar rats were divided into four groups. The first group, control group, was administered with vehicle (2.5% tween 20); the second group received doxorubicin (15 mg/kg intraperitoneally at a single dose), third and fourth groups (treatment groups) received BCP plus doxorubicin (15 mg/kg) at doses of 100 mg/kg and 200 mg/kg respectively. BCP was given orally for 15 days and doxorubicin was given on 13th day of treatment. Cardiac function was assessed by measuring electrocardiogram changes and cardiac biomarkers—doxorubicin-induced significant lengthening of QT-interval and ST-elevation, which was completely prevented by BCP treatment. Doxorubicin caused oxidative stress as indicated by a significant decrease in reduced superoxide dismutase, glutathione level, and catalase activity with an increase in malondialdehyde compared to control. Doxorubicin and BCP significantly reversed these values compared to doxorubicin in heart, kidney, and liver. The histopathological examination has also shown signs of toxicity in doxorubicin treated groups, and healing effect was noticed in treatment groups.
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Krischke, Miriam, Alan V. Boddy, Georg Hempel, Swantje Völler, Nicolas André, and Mauricio D'Incalci. "EUROPEAN PAEDIATRIC ONCOLOGY OFF-PATENT MEDICINES CONSORTIUM (EPOC): A PHARMACOKINETIC STUDY OF DOXORUBICIN IN CHILDREN WITH CANCER." Archives of Disease in Childhood 101, no. 1 (2015): e1.6-e1. http://dx.doi.org/10.1136/archdischild-2015-310148.14.
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BackgroundDoxorubicin is a key component of a number of treatment regimens used in paediatric oncology. The pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multicentre, multinational pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after 2 administrations, with 5 samples collected in children 3 yrs. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. NT-proBNP and cardiac troponin T were measured to evaluate their role as early indicators of cardiotoxicity.Results101 children could be recruited including 27 patients less than 3 years and among those 5 infants younger than 1 year. Overall, the patient acceptance of the trial was very good.Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a lower clearance (21.1±5.8 l/h/m2) than older children (26.6±6.7 l/h/m2) (p=0.0004), after correcting for body weight. Pharmacogenetic variants, including those in transporters and drug metabolizing enzymes, had little influence on pharmacokinetic parameters.Natriuretic peptides plasma levels increased significantly shortly after doxorubicin administration, whereas cardiac troponin levels increased only with the administered cumulative anthracycline dose. Only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionThe paediatric need concerning missing PK-data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were found to be justified based on our PK analyses.
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Wnukowska, Magdalena, Slawomir Mandziuk, Agnieszka Korga, et al. "The effect of one-electron reduced drugs on hepatic aconitase activity and triglycerides level." Current Issues in Pharmacy and Medical Sciences 28, no. 1 (2015): 5–7. http://dx.doi.org/10.1515/cipms-2015-0031.
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Abstract The redox cycle triggered by one electron reduction of doxorubicin and tirapazamine - both anticancer agents - leads to superoxide production. This superoxide production itself removes one iron atom from the [4Fe-4S] cluster, being an active center of aconitase. In addition, the incurred changes in cell redox equilibrium may affect lipid metabolism. The aim of the study was to evaluate a concomitant effect of both drugs on hepatic aconitase activity and triglycerides level. In our study, doxorubicin (1.8 mg/kg b.w.) was administered intraperitoneal (i.p.) six times, once a week, within male Wistar rats, to achieve a cumulative dose of 10.8 mg/kg b.w. Two hours before every doxorubicin administration, tirapazamine in the dose of either 5 or 10 mg/kg b.w. was also i.p. injected. A week after withdrawing drug administration, the liver was taken for biochemical analysis. Therein, an increase in aconitase activity and a decrease in triglycerides level was seen in all groups exposed to doxorubicin. Our work demonstrated that tirapazamine administration had no influence on both tested parameters, but its higher dose rate normalized aconitase activity affected by doxorubicin.
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Chennuru, Anusha, and Mohamed T. S. Saleem. "Antioxidant, Lipid Lowering, and Membrane Stabilization Effect of Sesamol against Doxorubicin-Induced Cardiomyopathy in Experimental Rats." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/934239.
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The present study was designed to evaluate the cardioprotective effect of sesamol against doxorubicin-induced cardiomyopathy in rats. In this study, the cardioprotective effect of sesamol against doxorubicin induced cardiomyopathy in experimental rats was evaluated at the dosage of 50 mg/kg bw. Doxorubicin was administered to rats at a total cumulative dose of 15 mg/kg through intraperitoneal route for 2 weeks in six-divided dose on 8th, 10th, 14th, 16th, 18th, and 21st day. After the last dose administration, the endogenous antioxidants and lipid peroxidation were estimated in heart tissue homogenate. Cardiac biomarkers such as troponin T, LDH, CK, and AST and lipid profiles such as cholesterol, triglycerides, HDL, LDL, and VLDL were estimated in serum. Sesamol has cardioprotective activity through normalization of doxorubicin-induced-altered biochemical parameters. Biochemical study was further supported by histopathological study, which shows that sesamol offered myocardial protection from necrotic damage. From these findings, it has been concluded that the sesamol has significant cardioprotection against doxorubicin induced cardiomyopathy via amelioration of oxidative stress, lipid lowering, and membrane stabilization effect.
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Rahman, A., J. Treat, J. K. Roh, et al. "A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin." Journal of Clinical Oncology 8, no. 6 (1990): 1093–100. http://dx.doi.org/10.1200/jco.1990.8.6.1093.
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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.
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Abdikhalimovna, Amerova Dilafruz. "Cardiotoxicity of Doxorubicin in Acute Leukemia." International Journal for Research in Applied Science and Engineering Technology 12, no. 3 (2024): 83–85. http://dx.doi.org/10.22214/ijraset.2024.58775.
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Abstract: Doxorubicin, an anthracycline chemotherapeutic agent, is widely utilized in the treatment of acute leukemia due to its potent anti-neoplastic properties. However, its clinical utility is limited by the occurrence of dose-dependent cardiotoxicity, which may manifest as cardiomyopathy, heart failure, or arrhythmias. This review provides an overview of the mechanisms underlying doxorubicin-induced cardiotoxicity, including oxidative stress, mitochondrial dysfunction, and DNA damage. Additionally, it discusses risk factors predisposing patients to cardiotoxicity, such as cumulative dose, age, pre-existing cardiac conditions, and concomitant use of other cardiotoxic agents. Furthermore, this review highlights various strategies for the prevention and management of doxorubicin-induced cardiotoxicity, including the use of cardioprotective agents, cardiac monitoring protocols, and lifestyle modifications. Finally, future directions for research aimed at minimizing cardiotoxicity while preserving the antineoplastic efficacy of doxorubicin in acute leukemia treatment are discussed.
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Yakunina, M. N., A. Yu Fadeev, M. S. Kalishjan, et al. "EFFICACY OF AN TRANSARTERIAL CHEMOEMBOLIZATION (TACE) WITH MICROSPHERES FROM POLY(VINYL ALCOHOL) LOADED OF DOXORUBICIN AGAINST ANAPLASTIC CARCINOMA VX2 IN RABBITS." Russian Journal of Oncology 22, no. 2 (2017): 89–92. http://dx.doi.org/10.18821/1028-9984-2017-22-2-89-92.
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The research is devoted to the study of the efficacy of new Russian microspheres loaded by (MC/DOX) of 0.4-0.6 mm diameter on a basis of cryogel with poly(vinyl alcohol) intended for a transarterial chemoembolization (TACE). MC/DOX in dose of of 0.5-1.0 ml contained Doxorubicin of 16 mg or 32 mg were transarterially injected in a single dose to rabbits (n = 24) with the VX2 anaplastic carcinoma of the moderate volume of 3-5 cm2 which developed in femur muscles (the pool of a femoral artery). The time of complete released of DOX was 16 days up to dose (a cumulative dose) 16 and 32 mg, respectively. The efficacy was controlled with the decrease of the tumor growth rate and significant inhibition through embolization of turnpike blood of a tumor zone under radiological monitoring. MC/DOX were shown both to give rise in the regression of tumor nodes and reduce the growth rate by 2.0-2.5 times in dependence on the dose value. The reliable therapeutic prize of MC/DOX against embolization effect of 0.5 ml MC that achieved at the maximal DOX cumulative dose of 32 mg consists in the achievement of regression of VX2 up to 50% at 5 of 6 rabbits with the development of the cure pathomorphological effect of III degree which is characterized by the gain in the area of a necrosis by 1.5-3.0 times. The maximal efficient cumulative dose of 32 mg Doxorubicin exceeds value of Maximum Planned Dose (MPD) of Doxorubicin by 6 times for systemic injection to rabbits. The embolizing effect of MC/DOX in the form of blocking of shallow arterioles at preservation of turnpike blood supply did not depend on the size of the applied dose. The reliable antineoplastic effect revealed on this model allows good out perspective for a transarterial chemoembolization of a tumor with MC/DOX.
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Efentakis, Panagiotis, Aimilia Varela, Evangelia Chavdoula, et al. "Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy." Cardiovascular Research 116, no. 3 (2019): 576–91. http://dx.doi.org/10.1093/cvr/cvz163.
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Abstract Aims Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. Methods and results Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload. Conclusion Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
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Busse, A., G. Huetter, J. M. Siehl, A. Schmittel, and U. Keilholz. "A phase I/IIa clinical trial of CLAOP21 and CLAOP14 in patients with high grade non-Hodgkins lymphoma and cardiac risk factors." Journal of Clinical Oncology 24, no. 18_suppl (2006): 17548. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17548.
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17548 Background: CHOP combination chemotherapy is the most effective and least toxic regimen for high-grade Non-Hodgkin’s-lymphoma (NHL). Doxorubicin, however, presents a problem in patients at risk for cardiotoxicity. Pegliposomal doxorubicin is a liposomal preparation of doxorubicin with minimal cardiotoxicity. In the CLAOP regimen reported here, we substituted conventional doxorubicin in the CHOP regimen by pegliposomal doxorubicin. Methods: An open-label phase I/IIa study was performed evaluating CLAOP21/20 with 20 mg/m2 of pegliposomal doxorubicin every 21 days, and a dose-dense CLAOP14 regimen supported by G-CSF or pegylated G-CSF every 14 days with escalating doses of pegliposomal doxorubicin in elderly high-grade lymphoma patients. Results: A total of 12 patients were enrolled for CLAOP 21/20, and 24 patients for CLAOP 14/20. CLAOP21/20 was well tolerated with a degree of hematotoxicity similar to that reported with regular CHOP. In the CLAOP14 cohort, a trend towards cumulative hematotoxicity. Palmar plantar erythema (PPE) exceeding grade II and other non-hematological toxicities exceeding grade I, except of alopecia, were not observed. A pegliposomal doxorubicin dose of 25 mg/m2 (CLAOP14/25) was associated with dose-limiting haematotoxicity, febrile episodes, and PPE. Both, the 3-weekly and the 2-weekly regimens were active with an overall response rate of 60% and 77%, respectively. Cardiotoxicity attributable to doxorubicin was not observed in any patient. Conclusions: The recommended dose of pegliposomal doxorubicin in the biweekly CLAOP regimen for Phase II/III testing is 20 mg/m2, a regimen that can safely be administered to old patients without apparent cardiotoxicity. [Table: see text]
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Frolova, Mona, Marina Skrypnikova, Ekaterina Ignatova, et al. "Neoadjuvant chemotherapy with metronomic doxorubicin, cyclophosphamide, and capecitabine in patients with locally advanced (LA) triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 31, no. 15_suppl (2013): e12027-e12027. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e12027.
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e12027 Background: TNBC is associated with aggressive behavior and poor prognosis. It has been shown that patients (pts) with TNBC with pathological complete regression (pCR) after neoadjuvant chemotherapy have a higher survival. Rates of pCR with standard antracycline- and taxanebased chemotherapy regimens don’t exceed 20-27%. Dose-dense and metronomic schedules may be more effective in these highly proliferative tumors. We performed a prospective pilot trial to evaluate efficacy of metronomic schedule of doxorubicin, cyclophosphamide and capecitabine in pts with LA TNBC. Methods: Pts with LA TNBC (cT2-4N1-3M0) were treated with doxorubicin 25 mg/m2 iv weekly, cyclophosphamide 50 mg po daily and capecitabine 1500 mg po daily for planned 16-19 weeks followed by surgery. Pathological response was evaluated according to the Chevallier classification. Results: Twenty pts was included in the study in 2009-2010. Median agewas 47 years (33-70), 63% of pts had tumor grade 3, Ki67 was >20% in all cases. Nineteen pts completed chemotherapy (median treatment duration 17.1 weeks) and underwent surgery. One pt had a disease progression during chemotherapy and was switched to 2nd-line chemotherapy. Seven pts (36,8%) achieved a pCR (6 pts class 1 and 1 pt class 2). With median follow-up of 33 months, 3-year DFS and OS were 60%. All but one pt with pCR, who developed brain mts shortly after surgery, are currently alive without relapse. In contrast 50% of pts with residual tumor relapsed. Pts with pCR had significantly higher median cumulative dose of doxorubicin (420 mg/m2) than pts with residual disease (300 mg/m2, p=0.046). The dose-limiting toxicities were hand-foot syndrome (26.3% grade 3), mucositis (31.6% grade 3), and neutropenia (31.6% grade 3-4), which resulted in permanent discontinuation of doxorubicin in 4 pts. Conclusions: Despiterelatively hightoxicity metronomic doxorubicin, cyclophosphamide and capecitabine regimen shows promising activity as neoadjuvant treatment of LA TNBC. Achievement of pCR and higher cumulative dose of doxorubicin were strongly associated with improvement of survival.
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Lo, Andrea C., Amy Liu, Qi Liu, et al. "Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children." JAMA Network Open 7, no. 1 (2024): e2351062. http://dx.doi.org/10.1001/jamanetworkopen.2023.51062.
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ImportanceContemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain.ObjectiveTo estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials.Design, Setting, and ParticipantsFor this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children’s Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023.ExposuresAll patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane.Main Outcomes and MeasuresEstimated 30-year cumulative incidence of grade 3 to 5 cardiac disease.ResultsThe study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines.Conclusions and RelevanceIn this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.
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Lo, Andrea C., Amy Liu, Qi Liu, et al. "The Evolution of Children's Oncology Group Hodgkin Lymphoma Trials: Predicted Impact on Late Cardiac Toxicity." Blood 138, Supplement 1 (2021): 881. http://dx.doi.org/10.1182/blood-2021-147678.
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Abstract Introduction: Sequential Hodgkin lymphoma (HL) trials of the Children's Oncology Group (COG) have tested treatment strategies intended to reduce late toxicity while maintaining high rates of cure. However, the long latency of the relevant late effects makes it impossible to observe in a timely way the degree to which modifications to protocol-directed treatment will achieve this goal. The purpose of this study was to estimate late cardiac disease risk associated with sequential COG trial protocols using established risk models. Methods: We estimated the late severe or fatal cardiac toxicity associated with three consecutive completed COG trials enrolling intermediate- and high-risk classical HL patients: AHOD0031 (2002-2009), AHOD0831 (2009-2012), and AHOD1331 (2015-2019). Patients were less than 22 years old at the time of trial enrollment. In addition, we applied the model to the ongoing S1826 trial protocol for patients ≥12 to &lt;22 years of age. Eligible disease stages were IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease and IA or IIA with bulk disease for AHOD0031; IIIB and IVB for AHOD0831; IIB with bulk, IIB, IVA and IVB for AHOD1331; and III and IV for S1826. When radiotherapy (RT) was indicated, prescribed RT was 21Gy involved-field radiotherapy (IFRT) in AHOD0031, 21Gy IFRT in AHOD0831, 21-30Gy involved-site radiotherapy (ISRT) in AHOD1331, and 30-36Gy ISRT in S1826. Cardiac toxicity included coronary artery disease, heart failure, valvular disease, pericardial disease and arrhythmias. Statistical models quantifying the association between age, sex, doxorubicin dose, alkylating agent exposure and cardiac radiation dose and late cardiac risk were derived from HL survivors in the Childhood Cancer Survivor Study (CCSS) (Bates 2019 J Clin Oncol 1;37(13):1090-1101 & Shrestha 2021 Radiother Oncol, in press). These demographic and dose-risk relationships were then applied to the delivered COG trial protocol exposures to predict the 30-year cumulative incidence (CI) of cardiac disease for trial patients. To estimate the average cardiac risk, we accounted for the chance of receiving mediastinal RT, mean cardiac radiation dose among those receiving mediastinal RT, and cumulative doxorubicin dose, according to respective trial data. Results: Based on the median age of enrolled patients, results are reported for modeled age 15 years at treatment. The cumulative planned doxorubicin dose was 200mg/m 2 on AHOD0031 and AHOD0831, and increased to 250mg/m 2 on AHOD1331 to improve progression-free survival compared to the prior trials for select groups of higher risk patients. Doxorubicin dose was 300mg/m 2 on S1826 to limit RT use to selected patients with persistent disease on positron emission tomography (PET) at the end of systemic therapy. Mediastinal RT was given to 62% of patients on AHOD0031 (mean heart dose 13.2Gy), 58% on AHOD0831 (mean heart dose 13.6Gy), and 53% on AHOD1331 (mean heart dose 10Gy). For S1826, we assumed a 5% rate of mediastinal RT use, mean heart dose of 10Gy, and no long term cardiac risk associated with nivolumab or brentuximab. For the average 15-year old patient, the predicted 30-year cumulative incidence of any cardiac disease was 8.8% in AHOD0031, 8.7% in AHOD0831, and 8.5% in AHOD1331 (Figure 1). Despite the increase in doxorubicin dose, the anticipated reduction in the utilization of mediastinal RT in S1826 is predicted to reduce the 30-year risk of cardiac disease to 7.8%. The predicted 30-year cumulative incidence of any cardiac disease, for the average 12-, 15-, and 18-year old males and females are shown in Table 1. Conclusions: From 2002 - 2019, reductions in the proportion of patients receiving mediastinal RT and smaller target volumes with ISRT produce lower cardiac radiation dose, which is predicted to offset increase in doxorubicin dose and produce a small reduction in late cardiac disease. Limiting RT use based on end of chemotherapy PET on S1826 is predicted to further reduce late cardiac disease among children with HL risk despite higher doxorubicin dose in this protocol. Increasing use of dexrazoxane may further mitigate risk for cardiac toxicity in more contemporary cohorts. Clarification of the impact of nivolumab, brentuximab and relapse therapy would allow for a more complete prediction of cardiac disease risk. Figure 1 Figure 1. Disclosures Herrera: Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Tubulis: Consultancy; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy. Friedberg: Acerta: Other: DSMC ; Bayer: Other: DSMC ; Novartis: Other: DSMC .
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Chawla, Sant P., Victoria S. Chua, Andrew Hendifar, et al. "Phase Ib/II study of INNO-206 (EMCH-doxorubicin) in patients with soft tissue sarcoma." Journal of Clinical Oncology 30, no. 15_suppl (2012): 10036. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10036.
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10036 Background: The safety and preliminary tumor response of a doxorubicin conjugate, INNO-206, was evaluated primarily in patients with metastatic STS who progressed on prior chemotherpy. INNO-206 consists of doxorubicin attached to an acid-sensitive linker that binds covalently to cysteine-34 in circulating albumin. Methods: INNO-206 was administered IV at doses of either 230, 350 and 450 mg/m2 (165, 260 and 325 mg/m2 dox. eq.) every 21 days for up to 8 consecutive cycles. Subsequent dose levels were administered if < 2/5 or 4/8 patients experienced a non-hematological dose-limiting toxicity during Cycle 1. Tumor response was monitored every other month and treatment continued until tumor progression or unacceptable toxicity. Standard safety monitoring was performed and cardiac function was followed periodically using MUGA or cardiac ultrasound. Results: As of January 11, 2012, 25 patients were entered in the study. 21/25 patients had STS of various types. Of the 5 patients treated at 230 mg/m2 INNO-206, 1 subject had grade 3 fatigue and acid reflux. Of the initial 5 patients entered at the 350 mg/m2 dose, no individuals experienced a grade 3 or 4 non-hematological toxicity during cycle 1. 2 patients treated at the 450 mg/m2 dose developed grade 3 oral mucositis during cycle 1. No patient exhibited cardiotoxicity as determined by MUGA or cardiac ultrasound. The MTD was determined to be 350 mg/m2 INNO-206 (260 mg/m2 dox.eq.). 15 more patients were entered at this dose (total of 20 patients). Of the 16 patients with STS, 3 objective partial responses (one of whom received prior doxorubicin) are ongoing as well as 10 patients with stable disease (range 2-7 months). 1 patient had progressive disease at the first evaluation. 2 patients died within the first cycle, one due to progressive disease and the other due to sepsis. Conclusions: INNO-206 is an active drug for the treatment of patients with advanced STS who have failed prior chemotherapy. Cumulative doses of 2000 mg/m2 of doxorubicin equivalents have been achieved, which is over 3 1/2 x the peak cumulative dose of standard doxorubicin. Adverse events are primarily hematological and no cardiotoxicity has been observed.
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Scher, H. I., N. L. Geller, T. Curley, and Y. Tao. "Effect of relative cumulative dose-intensity on survival of patients with urothelial cancer treated with M-VAC." Journal of Clinical Oncology 11, no. 3 (1993): 400–407. http://dx.doi.org/10.1200/jco.1993.11.3.400.
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PURPOSE To evaluate the received dose-intensity in a mature data set of patients with advanced urothelial cancer who received at least one cycle of the methotrexate (M), vinblastine (V), Adriamycin ([A], doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (C) regimen (M-VAC). PATIENTS AND METHODS Received dose-intensity was evaluated over time by summing doses over cycles for each patient, cumulating treatment times, and assuming four cycles of chemotherapy were planned. Relative cumulative dose-intensity was then calculated for individual patients at the end of each cycle. To assess a relationship with survival, relative cumulative dose-intensity was then used as a time-dependent covariate in Cox regression. RESULTS The median follow-up was 6 years and median survival 13.3 months, with 20 patients alive at the time of analysis. Out of a maximum of 1.0, the median relative dose-intensity for the M-VAC combination decreased from .69 to .59 from cycle 1 to cycle 4. Similarly, a decrease from .68 to .62 and from .80 to .72 was observed for A and C, respectively. The median received dose-intensity for A was 6.0 mg/m2/wk, and for C 14 mg/m2/wk. Neither the four-cycle relative cumulative dose-intensity for the M-VAC combination, nor the relative cumulative dose-intensities for A or C were found to be significant prognostic factors. CONCLUSION The absence of an effect for received dose-intensity on survival may reflect the low dose-intensities of the components of the regimen actually delivered in this study. The results question whether the individual agents can be escalated sufficiently, with growth factor support, to improve significantly complete response proportions, a prerequisite for increasing the proportion of long-term survivors.
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Sturgeon, Kathleen, Keri Schadler, Geetha Muthukumaran, et al. "Concomitant low-dose doxorubicin treatment and exercise." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 307, no. 6 (2014): R685—R692. http://dx.doi.org/10.1152/ajpregu.00082.2014.
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Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 105) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice ( n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, β-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.
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Biganzoli, L., T. Cufer, P. Bruning, et al. "Doxorubicin and Paclitaxel Versus Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial." Journal of Clinical Oncology 20, no. 14 (2002): 3114–21. http://dx.doi.org/10.1200/jco.2002.11.005.
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PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m2 as an intravenous bolus plus paclitaxel 175 mg/m2 as a 3-hour infusion) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m2) and cyclophosphamide (750 mg/m2) dose escalation was planned at cycle 2 if no grade ≥ 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen
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Feijen, Elizabeth A. M., Wendy M. Leisenring, Kayla L. Stratton, et al. "Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer." Journal of Clinical Oncology 33, no. 32 (2015): 3774–80. http://dx.doi.org/10.1200/jco.2015.61.5187.
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Purpose Cumulative anthracycline dose is one of the strongest predictors of heart failure (HF) after cancer treatment. However, the differential risk for cardiotoxicity between daunorubicin and doxorubicin has not been rigorously evaluated among survivors of childhood cancer. These risks, which are based on hematologic toxicity, are currently assumed to be approximately equivalent. Patients and Methods Data from 15,815 survivors of childhood cancer who survived at least 5 years were used. Survivors were from the Emma Children's Hospital/Academic Medical Center (n = 1,349), the National Wilms Tumor Study (n = 364), the St Jude Lifetime Cohort Study (n = 1,695), and the Childhood Cancer Survivor Study (n = 12,407). The hazard ratio (HR) for clinical HF through age 40 years for doses of daunorubicin and doxorubicin (per 100-mg/m2 increments) was estimated by using Cox regression adjusted for sex, age at diagnosis, treatment with other anthracycline agents and chest radiation, and cohort membership. Results In total, 5,144 (32.5%) patients received doxorubicin as part of their cancer treatment, whereas 2,243 (14.7%) received daunorubicin. On the basis of 271 occurrences of HF during a median follow-up time after cohort entry of 17.3 years (range, 0.0 to 35.0 years), the cumulative incidence of HF at age 40 years was 3.2% (95% CI, 2.8% to 3.7%). The average ratio of HRs for daunorubicin to doxorubicin was 0.45 (95% CI, 0.23 to 0.73). A similar ratio was obtained by using a linear dose-response model, which yielded an HR of 0.49 (95% CI, 0.28 to 0.70). Conclusion Compared with doxorubicin, daunorubicin was less cardiotoxic among survivors of childhood cancer than most current guidelines suggest. This may have implications for follow-up guidelines. The feasibility of substitution of doxorubicin with daunorubicin in childhood cancer treatment protocols to reduce cardiotoxicity should be additionally investigated.
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Ferreira, W. L., R. C. A. Sousa, and A. A. Camacho. "High-resolution electrocardiography in dogs under doxorubicin-induced cardiomyopathy." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 60, no. 5 (2008): 1118–22. http://dx.doi.org/10.1590/s0102-09352008000500012.
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The occurrence of late potentials in dogs under doxorubicin-induced cardiomyopathy and their relationship with the development of ventricular arrhythmias or sudden death were studied. Seven adult mongrel dogs of both sexes were used. Cardiomyopathy was induced by slow intravenous infusion of doxorubicin (30mg/m²) at 21-day intervals, until a total cumulative dose of 240mg/m² was reached. Animals were monitored by echocardiography. After the induction of cardiomyopathy, high-resolution electrocardiography was recorded. Late potentials were observed in two animals that suddenly died a few days later.
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Estorch, M., I. Carrió, D. Martínez-Duncker, et al. "Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies." Journal of Clinical Oncology 11, no. 7 (1993): 1264–68. http://dx.doi.org/10.1200/jco.1993.11.7.1264.
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PURPOSE To compare myocyte cell damage induced by doxorubicin or mitoxantrone, we performed left ventricular ejection fraction (LVEF) measurements and indium 111 antimyosin antibody studies in a group of patients with advanced breast cancer who had been treated with these anthracycline derivatives. PATIENTS AND METHODS We studied 35 patients eligible to receive chemotherapy including the anthracyclines: doxorubicin or mitoxantrone (cumulative dose of doxorubicin, 500 mg/m2; or mitoxantrone, 120 mg/m2). LVEF was measured before and after 10 cycles of chemotherapy. Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR). RESULTS Patients treated with doxorubicin presented with a significant decrease in LVEF after chemotherapy (before, 60.4% +/- 8.92%; after, 49.8% +/- 9.71%; P = .001). Antimyosin uptake was observed in all patients with a HLR of 2.03 +/- 0.25. Seven of eight patients with a HLR greater than 2.03 had a greater than 10% decrease in LVEF. Patients treated with mitoxantrone did not present with a decrease in LVEF after chemotherapy (before, 55.4% +/- 6.25%; after, 55.8% +/- 7.25%; not significant). Antimyosin uptake was observed in 14 of 17 patients with a HLR of 1.77 +/- 0.18 (P < .05). CONCLUSION 111In antimyosin monoclonal antibodies defect myocardial cell damage produced by doxorubicin and mitoxantrone. In patients with advanced breast cancer, cumulative doses of 120 mg/m2 of mitoxantrone produce less myocardial cell damage than cumulative doses of 500 mg/m2 of doxorubicin. 111In antimyosin uptake without decrease in LVEF after treatment with mitoxantrone indicates the presence of myocyte cell damage, but not to the extent necessary to deteriorate function. These results indicate that 111In antimyosin antibody studies are useful in the noninvasive comparative assessment of cardiotoxicity produced by different anthracycline derivatives.
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Ono, Masaya, Saho Mochizuki, Kanako Tsuchitani, et al. "BOT-5 Chrysanthemum morifolium extract improves doxorubicin-induced cardiomyopathy by suppressing apoptosis in mouse heart." Neuro-Oncology Advances 3, Supplement_6 (2021): vi9. http://dx.doi.org/10.1093/noajnl/vdab159.032.
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Abstract Background: Doxorubicin is widely used for the treatment of various malignant tumors. However, doxorubicin causes cumulative and dose-dependent cardiotoxicity, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive heart failure. Since this problem affects the QOL and survival of cancer patients, solutions for this problem are urgently needed. Recently, it has been reported that Chrysanthemum morifolium extracts (CME) have antioxidant and anti-inflammatory activities. The purpose of this study is to clarify whether CME decreases doxorubicin-induced cardiotoxicity and prevents the development of heart failure. Methods and Results: H9C2 cardiomyoblast cells were treated with CME (0.3, 1 mg/mL) for 2 hours and then stimulated with doxorubicin. After 24 hours incubation, surviving cells were evaluated by MTT assay. CME dose-dependently decreased doxorubicin-induced cardiotoxicity in H9C2 cells. Western blotting showed that CME significantly suppressed doxorubicin-induced increases in four markers of apoptosis: p53, phosphorylated p53, and cleaved caspase-9 and -3. Next, to investigate the effects of CME on doxorubicin-induced cardiomyopathy in vivo, C57BL6 mice were orally administered with CME (400 mg/kg/day) or vehicle daily from 2 days before doxorubicin treatment and then treated once intraperitoneally with doxorubicin (20 mg/kg). The survival ratio of the CME-treated group was significantly higher than that of the vehicle-treated group. Echocardiographic analysis at 7 days after doxorubicin stimulation revealed that CME had significantly improved doxorubicin-induced left ventricular systolic dysfunction. Apoptotic cells in mouse heart tissue were detected by TUNEL assay, which showed that CME significantly suppressed doxorubicin-induced apoptosis. Discussion: These results indicate that CME decreases doxorubicin-induced cardiotoxicity both in vitro and in vivo, suggesting that CME might possess the therapeutic potency to reduce doxorubicin-induced cardiotoxicity in cancer patients. Further studies are required to assess the effectiveness of CME for preventing doxorubicin-induced heart failure in clinical settings.
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Alshabanah, Othman A., Mohamed M. Hafez, Mohamed M. Al-Harbi, et al. "Doxorubicin Toxicity can be Ameliorated during Antioxidant L-Carnitine Supplementation." Oxidative Medicine and Cellular Longevity 3, no. 6 (2010): 428–33. http://dx.doi.org/10.4161/oxim.3.6.14416.
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Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 was intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12 and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increases the biochemical levels of alanine transaminase, alkaline phosphatase, total bilirubin, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH ), superoxide dismutase (SOD), glutathione peroxidase (GSHP x), glutathione-s-transferase (GST), glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reversed the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.
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D'Adamo, David R., Sibyl E. Anderson, Karen Albritton, et al. "Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas." Journal of Clinical Oncology 23, no. 28 (2005): 7135–42. http://dx.doi.org/10.1200/jco.2005.16.139.
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Purpose To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). Patients and Methods Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. Results A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. Conclusion The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.
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Valero, Vicente, Aman U. Buzdar, Richard L. Theriault, et al. "Phase II Trial of Liposome-Encapsulated Doxorubicin, Cyclophosphamide, and Fluorouracil as First-Line Therapy in Patients With Metastatic Breast Cancer." Journal of Clinical Oncology 17, no. 5 (1999): 1425. http://dx.doi.org/10.1200/jco.1999.17.5.1425.
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PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to ≤ 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.
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Radeva-Ilieva, Maya P., Kaloyan D. Georgiev, Nadezhda R. Hvarchanova, et al. "Protective Effect of Methylxanthine Fractions Isolated from Bancha Tea Leaves against Doxorubicin-Induced Cardio- and Nephrotoxicities in Rats." BioMed Research International 2020 (August 11, 2020): 1–9. http://dx.doi.org/10.1155/2020/4018412.
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Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin-induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na+, K+, and Cl-), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin.
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Abbott, Beverly D., and Cindy M. Ippoliti. "Dexrazoxane: A New Cardioprotective Agent." Journal of Pharmacy Technology 14, no. 5 (1998): 182–90. http://dx.doi.org/10.1177/875512259801400505.
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Objective: To review the literature discussing the use of dexrazoxane (e.g., Zinecard, ICRF-187) to prevent doxorubicin-induced cardiotoxicity. Data Sources: Pertinent English-language reports of studies in humans were retrieved from a MEDLINE search (January 1980-January 1997); search terms included chelating agents, razoxane, dexrazoxane, Zinecard, ICRF-187, ADR-529, and ICRF-159. Study Selection: Representative articles discussing the chemistry, pharmacology, pharmacokinetics, dosing, and administration of dexrazoxane and those discussing clinical trials were selected. Data Extraction: Data were extracted and analyzed if the information was relevant and consistent. Studies were selected for review in the text on the basis of study design and clinical end points. Data Synthesis: Dexrazoxane is a chemoprotective agent developed to prevent cardiac tissue toxicity. Dexrazoxane exerts a cardioprotective effect with some clinically significant toxicities; it may also interfere with the antitumor activity of doxorubicin. Until there are sufficient data to support its use in first-line supportive care therapy, dexrazoxane should be reserved for use in patients responding to doxorubicin-based chemotherapy but who have risk factors for cardiac toxicity or have received a cumulative doxorubicin bolus dose of 300 mg/m2. Conclusions: The management of doxorubicin-induced cardiotoxicity has led to the development of supportive care drugs that specifically counteract the dose-limiting toxicities. Dexrazoxane may not completely eliminate the concern about doxorubicin-induced cardiotoxicity, but it may open new avenues for continuing doxorubicin-based chemotherapy.
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Hochster, H. S., M. D. Green, J. Speyer, E. Fazzini, R. Blum, and F. M. Muggia. "4'Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma." Journal of Clinical Oncology 3, no. 11 (1985): 1535–40. http://dx.doi.org/10.1200/jco.1985.3.11.1535.
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Doxorubicin provides the most consistent response rate in hepatocellular carcinoma. We therefore initiated a trial with its analog 4'epidoxorubicin. Eighteen patients, all without prior treatment, were given the drug as a single agent every 3 weeks with dose escalation whenever possible. Five patients were treated by six-hour infusion and 13 by intravenous (IV) bolus injection, with the median dose being 90 mg/m2. The patients were of diverse ethnic background and included some with underlying cirrhosis and hepatitis B surface antigenemia. Three patients had partial remissions (6, 12, 48 weeks) for a response rate of 17%. Four patients also had prolonged stable disease (14, 26, 27, 38 weeks). Toxicity was mild, although cardiac toxicity developed in three patients at 685, 825, and 1,460 mg/m2 cumulative dose. The response to 4'epidoxorubicin in this study appears to be equivalent to the reported response rates for doxorubicin, with decreased toxicity.
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Smith, Malcolm A., Lawrence Rubinstein, James R. Anderson, et al. "Secondary Leukemia or Myelodysplastic Syndrome After Treatment With Epipodophyllotoxins." Journal of Clinical Oncology 17, no. 2 (1999): 569. http://dx.doi.org/10.1200/jco.1999.17.2.569.
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PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (< 1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (≥ 3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.
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Sakr, Bachir J., and Don S. Dizon. "Treating Endometrial Adenocarcinoma—Do Data Support the Use of Pegylated Liposomal Doxorubicin?" Oncology & Hematology Review (US) 07, no. 01 (2011): 58. http://dx.doi.org/10.17925/ohr.2011.07.1.58.
Full textAbstract:
Most women who are diagnosed with endometrial carcinoma present at an early stage and are usually cured of their disease by surgery with or without adjuvant radiation therapy and/or chemotherapy. For those patients who present with advanced disease or develop recurrent disease, survival is greatly diminished. Chemotherapy plays an important role in the management of these patients. Doxorubicin is one of the most active chemotherapy drugs in the advanced or recurrent setting, with response rates in the order of 25%. The use of doxorubicin is limited by its cumulative dose-dependent cardiotoxicity. Pegylated liposomal doxorubicin is a newer formulation of conventional doxorubicin. Its altered pharmacokinetics result in a longer half-life, decreased exposure in healthy tissues, and enhanced delivery of the active drug to the tumor bed. Pegylated liposomal doxorubicin has a relatively milder toxicity profile and a lower incidence of cardiac adverse events. In this article the data on the use of pegylated liposomal doxorubicin in advanced or recurrent endometrial cancer, including the serous papillary histologic variant, are reviewed.
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Shapiro, Ron, Daphna Barsuk, Lior Segev, et al. "Pre-operative cardiac workup after anthracycline-based neoadjuvant chemotherapy. Is it really necessary?" Annals of The Royal College of Surgeons of England 93, no. 2 (2011): 127–29. http://dx.doi.org/10.1308/003588411x12851639107836.
Full textAbstract:
INTRODUCTION In patients receiving pre-operative anthracyclines for locally advanced breast cancer, early cardiotoxicity is a well-recognised complication that may interfere with surgery. The aim of this study was to assess the safety of breast surgery after neoadjuvant treatment with Doxorubicin. PATIENTS AND METHODS A retrospective study of breast cancer patients treated with Doxorubicin as part of their neoadjuvant protocol. All patients were subsequently operated in our institution. Intra-operative and postoperative haemodynamic, cardiac or respiratory events were collected. RESULTS A total of 83 patients were included. All patients had a normal left ventricular ejection fraction before starting on chemotherapy. Doxorubicin was given in conjunction with Cyclophosphamide and Paclitaxel. The cumulative dose of Doxorubicin was 240 mg/m2. All patients completed their chemotherapy less than a year before surgery and were clinically asymptomatic. Of the patients, 2.3% displayed a significant reduction in cardiac function to meet cardiotoxicity criteria, although not clinically apparent. No complications occurred intra-operatively or postoperatively. CONCLUSIONS Breast surgery can be safely performed after breast neoadjuvant chemotherapy with Doxorubicin. The risk of early cardiotoxicity does not mandate a cardiac function assessment after completion of treatment. Work-up should be individualised according to the anthracycline regimen, patient's cardiac risk factors and functional status before surgery.