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American Society of Clinical Oncology... 2017The combination of cisplatin, doxorubicin, and methotrexate was established as the standard backbone of contemporary osteosarcoma therapy in 1986. Since then, however,...
The combination of cisplatin, doxorubicin, and methotrexate was established as the standard backbone of contemporary osteosarcoma therapy in 1986. Since then, however, further improving the survival of patients with osteosarcoma has been challenging-30% to 40% of patients with osteosarcoma still die of this disease. In addition, these patients often experience loss of fertility at a young age, short- and long-term treatment-related cardiotoxicity, and adverse orthopedic effects from surgical resection of the tumor or endoprosthetic reconstructions. Cancer treatment often markedly increases the risk of infertility later in life, causing many patients substantial distress and regret. Sperm banking and oocyte cryopreservation are standard of care and should be available to all at-risk patients. Newer techniques, such as autologous gonadal tissue transplant for prepubertal children, are being developed, and newer systemic agents have infertility risk profiles that remain undefined and warrant further study. Cost and access remain barriers to these options. The late effects of anthracycline-induced cardiotoxicity are also increasingly a problem for these patients. These effects are often progressive and can be disabling. Adding dexrazoxane to doxorubicin therapy significantly reduces the risk for most adverse cardiac outcomes without compromising the efficacy of induction chemotherapy. Limb salvage surgery remains the standard of care for treatment in the majority of patients with extremity sarcomas. Modular metal prostheses and allograft reconstructions comprised the majority of surgical procedures for limb salvage surgery. The most common mechanism of failure of these implants is infection and mechanical failure of the implant.
Topics: Adolescent; Adult; Bone Neoplasms; Cancer Survivors; Cardiotoxicity; Child; Cisplatin; Dexrazoxane; Doxorubicin; Female; Humans; Infertility; Male; Methotrexate; Osteosarcoma
PubMed: 28561655
DOI: 10.1200/EDBK_174708 -
Annals of Oncology : Official Journal... 2003
Review
Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Dimethyl Sulfoxide; Doxorubicin; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Injections, Intravenous; Mitomycin; Necrosis; Razoxane; Skin Ulcer
PubMed: 12821535
DOI: 10.1093/annonc/mdg744 -
Future Cardiology Jul 2012Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in... (Review)
Review
Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.
Topics: Adiponectin; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Carbazoles; Cardiolipins; Cardiotonic Agents; Carvedilol; Doxorubicin; Erythropoietin; Heart; Heart Diseases; Humans; Lipid Peroxidation; Liposomes; Neoplasms; Piperazines; Propanolamines; Purines; Razoxane; Risk Factors; Sildenafil Citrate; Sulfones; Survivors; Ventricular Dysfunction, Left
PubMed: 22871201
DOI: 10.2217/fca.12.44 -
Cancer Research and Treatment Jan 2019Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary...
PURPOSE
Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients.
MATERIALS AND METHODS
Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected.
RESULTS
Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis.
CONCLUSION
Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.
Topics: Adolescent; Adult; Anthracyclines; Cardiotonic Agents; Cardiotoxicity; Child; Child, Preschool; Dexrazoxane; Factor Analysis, Statistical; Female; Humans; Incidence; Infant; Infant, Newborn; Male; Multivariate Analysis; Neoplasms; Neoplasms, Second Primary; Republic of Korea; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome; Young Adult
PubMed: 29764117
DOI: 10.4143/crt.2017.457 -
Journal of Clinical Oncology : Official... Jul 2020To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk...
PURPOSE
To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.
PATIENTS AND METHODS
This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.
RESULTS
A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).
CONCLUSION
Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
Topics: Cardiotonic Agents; Child; Child, Preschool; Dexrazoxane; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Treatment Outcome; Ventricular Function, Left
PubMed: 32343641
DOI: 10.1200/JCO.19.02856 -
Mutation Research. Genetic Toxicology... Jan 2020Bioflavonoids have a similar chemical structure to etoposide, the well-characterized topoisomerase II (Top2) poison, and evidence shows that they also induce DNA...
Bioflavonoids have a similar chemical structure to etoposide, the well-characterized topoisomerase II (Top2) poison, and evidence shows that they also induce DNA double-strand breaks (DSBs) and promote genome rearrangements. The purpose of this study was to determine the kinetics of bioflavonoid-induced DSB appearance and repair, and their dependence on Top2. Cells were exposed to bioflavonoids individually or in combination in the presence or absence of the Top2 catalytic inhibitor dexrazoxane. The kinetics of appearance and repair of γH2AX foci were measured. In addition, the frequency of resultant MLL-AF9 breakpoint cluster region translocations was determined. Bioflavonoids readily induced the appearance of γH2AX foci, but bioflavonoid combinations did not act additively or synergistically to promote DSBs. Myricetin-induced DSBs were mostly reduced by dexrazoxane, while genistein and quercetin-induced DSBs were only partially, but significantly, reduced. By contrast, luteolin and kaempferol-induced DSBs increased with dexrazoxane pre-treatment. Sensitivity to Top2 inhibition correlated with a significant reduction of bioflavonoid-induced MLL-AF9 translocations. These data demonstrate that myricetin, genistein, and quercetin act most similar to etoposide although with varying Top2-dependence. By contrast, luteolin and kaempferol have distinct kinetics that are mostly Top2-independent. These findings have implications for understanding the mechanisms of bioflavonoid activity and the potential of individual bioflavonoids to promote chromosomal translocations. Further, they provide direct evidence that specific Top2 inhibitors or targeted drugs could be developed that possess less leukemic potential or suppress chromosomal translocations associated with therapy-related and infant leukemias.
Topics: Animals; Cell Line; Chromosome Breakpoints; Chromosomes, Mammalian; DNA; DNA Breaks, Double-Stranded; DNA Repair; DNA Topoisomerases, Type II; Dexrazoxane; Etoposide; Flavonoids; Genistein; Histones; Kaempferols; Luteolin; Mice; Mouse Embryonic Stem Cells; Quercetin; Topoisomerase II Inhibitors; Translocation, Genetic
PubMed: 32087851
DOI: 10.1016/j.mrgentox.2020.503144 -
Archives of Disease in Childhood Nov 1994
Review
Topics: Antibiotics, Antineoplastic; Child; Child, Preschool; Drug Administration Schedule; Heart; Humans; Neoplasms; Razoxane; Risk Factors
PubMed: 7826122
DOI: 10.1136/adc.71.5.457 -
The Journal of Clinical Investigation Feb 2014Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS...
Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.
Topics: ATP-Binding Cassette Transporters; Animals; Antineoplastic Agents; Cardiotonic Agents; Crosses, Genetic; DNA Topoisomerases, Type II; DNA-Binding Proteins; Deferoxamine; Dexrazoxane; Dose-Response Relationship, Drug; Doxorubicin; Echocardiography; Heart; Hemodynamics; Humans; Iron; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Myocytes, Cardiac; RNA, Small Interfering; Reactive Oxygen Species; Topoisomerase II Inhibitors
PubMed: 24382354
DOI: 10.1172/JCI72931 -
Biology of Reproduction Mar 2015Preservation of ovarian function following chemotherapy for nonovarian cancers is a formidable challenge. For prepubescent girls, the only option to prevent chemotherapy...
Preservation of ovarian function following chemotherapy for nonovarian cancers is a formidable challenge. For prepubescent girls, the only option to prevent chemotherapy damage to the ovary is ovarian tissue cryopreservation, an experimental procedure requiring invasive surgeries to harvest and reimplant tissue, which carries the risk of cancer reintroduction. Drugs that block the primary mechanism of chemotherapy insult, such as dexrazoxane (Dexra) in the context of anthracycline chemotherapy, provide a novel approach for ovarian protection and have the potential to overcome current limitations to oncofertility treatment. Dexra is a catalytic topoisomerase 2 inhibitor that protects the mouse ovary from acute doxorubicin (DXR) chemotherapy toxicity in vitro by preventing DXR-induced DNA damage and subsequent gammaH2AX activation. To translate acute DXR ovarian insult and Dexra protection from mouse to nonhuman primate, freshly obtained marmoset ovarian tissue was cultured in vitro and treated with vehicle or 20 μM Dexra 1 h prior to 50 nM DXR. Cultured ovarian tissue was harvested at 2, 4, or 24 h post-DXR treatment. Dexra prevented DXR-induced DNA double-strand breaks as quantified by the neutral comet assay. DXR treatment for 24 h increased gammaH2AX phosphorylation, specifically increasing the number of foci-positive granulosa cells in antral follicles, while Dexra pretreatment inhibited DXR-induced gammaH2AX phosphorylation foci formation. Additionally, Dexra pretreatment trended toward attenuating DXR-induced AKT1 phosphorylation and caspase-9 activation as assayed by Western blots of ovarian tissue lysates. The combined findings suggest Dexra prevents primary DXR-induced DNA damage, the subsequent cellular response to DNA damage, and may diminish early apoptotic signaling in marmoset ovarian tissue. This study provides initial translation of Dexra protection against acute ovarian DXR toxicity from mice to marmoset monkey tissue.
Topics: Animals; Antineoplastic Agents; Apoptosis; Callithrix; Caspase 9; DNA Damage; Dexrazoxane; Doxorubicin; Female; In Vitro Techniques; Models, Animal; Ovary; Phosphorylation; Proto-Oncogene Proteins c-akt; Tissue Culture Techniques; Topoisomerase II Inhibitors
PubMed: 25609833
DOI: 10.1095/biolreprod.114.119495 -
Journal of Korean Medical Science Sep 2010This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The...
This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8+/-83.4 mg/m(2) in the dexrazoxane group and 266.1+/-75.0 mg/m(2) in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.
Topics: Adolescent; Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular Agents; Child; Child, Preschool; Cohort Studies; Disease-Free Survival; Doxorubicin; Echocardiography; Female; Follow-Up Studies; Heart Failure; Humans; Infant; Male; Neoplasms; Razoxane; Ventricular Function, Left
PubMed: 20808678
DOI: 10.3346/jkms.2010.25.9.1336