Risk Of Anthracycline Cardiotoxicity Research Articles

The Spatial Ventricular Gradient Is an Independent Predictor of Anthracycline-Associated Cardiotoxicity

BackgroundAnthracyclines are effective chemotherapies that are limited by cardiotoxicity. The spatial ventricular gradient (SVG) is a marker of electrical heterogeneity linked to adverse cardiovascular outcomes, including sudden cardiac death and heart failure (HF). ObjectivesThe purpose of this study was to assess if SVG values before chemotherapy are associated with the risk of anthracycline-associated HF or cardiomyopathy (CM). MethodsWe analyzed 12-lead electrocardiograms obtained within 6 months before initiation of anthracyclines in a retrospective cohort treated for cancer between 1992 and 2019 at a single academic medical center. Incident HF and CM were defined by ICD-9/10 codes and confirmed by chart review. Vectorcardiograms were constructed from baseline electrocardiograms, and the SVG was calculated. The cumulative incidence of anthracycline-associated HF or CM was regressed on SVG vector orientation and magnitude with death as a competing risk. ResultsIn 889 patients (47% male; mean age 58 ± 16 years; 71% hematologic malignancies), larger SVG magnitude prechemotherapy was associated with decreased risk of HF or CM after multivariable adjustment, with a subhazard ratio of 0.76 per 1 SD increase (95% CI: 0.59-0.96; P = 0.024). SVG vector orientation, specifically a more leftward oriented VGx, was associated with decreased risk of HF or CM with a subhazard ratio of 0.77 per 1 SD increase (95% CI: 0.61-0.96; P = 0.023). ConclusionsLarger SVG magnitude and more leftward SVG orientation were associated with a decreased risk of anthracycline cardiotoxicity in a large retrospective cohort. Improved cardiac risk stratification algorithms incorporating the SVG could personalize both cancer and cardioprotective therapy.

Abstract 11622: A Case of Successful Malignant Lymphoma Treatment Following Transcatheter Aortic Valve Replacement

Doxorubicin, an anthracycline drug, is a key drug in the treatment for diffuse large B-cell lymphoma (DLBCL). It is contraindicated in patients with serious heart diseases due to the cardiotoxicity. Transcatheter aortic valve replacement (TAVR) has been an established treatment for patients with severe aortic stenosis (AS) at high or prohibitive risk for surgical aortic valve replacement (SAVR). A 67-year-old woman was referred to our department with severe AS. Two months ago, the patient presented with bilateral cervical and inguinal lymphadenopathy. A biopsy of the lymph nodes revealed the primary diffuse large B-cell lymphoma (DLBCL). The patient had been diagnosed with stage IVA non-Hodgkin lymphoma according to the Ann Arbor staging system. The echocardiogram demonstrated a left ventricular ejection fraction of 67% and severe bicuspid AS with a peak velocity of 4.1 m/sec, mean pressure gradient of 44.1 mmHg, and aortic valve area of 0.58 cm 2 . She was initially treated with chemotherapy without anthracycline due to the high risk of anthracycline cardiotoxicity. However, anthracyclines were thought to be essential for controlling DLBCL. She was referred to our department and evaluated from the heart-team, which considered the following characteristics: severe impairment of mobility and frailty with a Society of Thoracic Surgeons (STS) score of 5.99%. Due to the high surgical risk for SAVR, we decided to perform TAVR. The procedure was completed without complications during the perioperative period. Ten days after TAVR, the patient received the therapy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), which resulted in complete remission without cardiac symptoms. Before the advent of TAVR, it was difficult for patients with both severe AS and cancer to receive surgery and/or cardiotoxic treatment. In patients with cancer, AS may interfere with optimal antineoplastic therapy (ie, high-risk oncological surgery and/or cardiotoxic anticancer drugs). TAVR does not need cardiac arrest, extracorporeal circulation, and thoracotomy. TAVR could increase therapeutic options in cancer patients with severe AS who are at high surgical risk.

Prevention of chemotherapy-induced left ventricular dysfunction.

Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed, this complication threatens to limit the significant gain in cancer survival achieved to date. Oncology strategies with cumulative dose limitation, continuous infusion, dexrazoxane, and liposomal formulations have been shown to decrease the risk of anthracycline cardiotoxicity. The preventive use of ace inhibitors, sartans, and/or beta-blockers has not yet provided convincing evidence and the positive effect on left ventricular ejection fraction decline appears poor without a clear clinical relevance. Assessment of the cardiovascular risk profile is a key aspect of the baseline evaluation of any patient scheduled for cancer therapy. Control and/or correction of modifiable cardiovascular risk factors is the first form of primary prevention of cardiotoxicity. It will be necessary to select populations at higher risk of developing cardiac dysfunction, identify patients genetically predisposed to develop cardiotoxicity in order to build the most appropriate strategies to correctly and timely target cardioprotective therapies.

Intrauterine Growth Retardation is a Risk Factor for Anthracycline Toxicity

Background Anthracycline chemotherapy is used to treat a variety of cancers. However, late cardiac effects of anthracycline chemotherapy, such as subclinical left ventricular dilatation and/or dysfunction, have been observed in more than half of long-term survivors of childhood cancers. A major risk factor for anthracycline cardiotoxicity is intrauterine growth restriction (IUGR). We assessed the significance of IUGR as an important risk factor for late cardiotoxic effects of anthracycline therapy in asymptomatic long-term survivors of childhood cancers. Materials and methods The study included 61 survivors of childhood cancers. Cardiac functions were prospectively studied using both conventional and non-conventional echocardiographic methods (two-dimensional speckle tracking echocardiography) after completion of the treatment. The patients were divided into two groups based on their birth weights: Group 1 (patients with IUGR) and Group 2 (patients with normal birth weight). Results Conventional echocardiography revealed a similar and normal range of left ventricle systolic and diastolic functions in both groups. However, global longitudinal and circumferential strain values demonstrated subclinical left ventricular systolic dysfunction in both groups as compared with normal reference strain values. Furthermore, Group 1 patients had significantly lower global longitudinal and circumferential strain and strain rate values than those in Group 2 patients. Conclusion Asymptomatic long-term survivors of childhood cancers with a history of IUGR may have an increased risk of anthracycline cardiotoxicity due to the low content of mitochondrial DNA (mtDNA). IUGR is a risk factor for late anthracycline cardiotoxicity.

Association of genetic polymorphisms NCF4 rs1883112, CBR3 rs1056892, and ABCC1 rs3743527 with the cardiotoxic effects of doxorubicin in children with acute lymphoblastic leukemia.

Cardiotoxicity is a frequent complication secondary to the use of anthracyclines for cancer chemotherapy. Evidence suggests that certain polymorphic genetic variants modify the risk for anthracycline-related cardiotoxicity. Reports documenting the impact of genetic polymorphisms on anthracycline-cardiotoxicity risk in pediatric patients with cancers from Latin American countries are scarce. The objective of this study was to evaluate associations between NCF4 rs1883112, CBR3 rs1056892 and ABCC1 rs3743527 genotype status and echocardiographic parameters indicative of anthracycline-cardiotoxicity in a group of Mexican children with acute lymphoblastic leukemia (ALL). Sixty-seven children (2-18 years old) with ALL were treated at the State Cancer Center in Durango, Mexico. NCF4, CBR3, and ABCC1 genotypes were examined by real-time PCR. Left ventricular ejection fraction and diastolic filling ratio were examined as markers of systolic and diastolic anthracycline-toxicity. NCF4 rs1883112 genotype status was significantly associated with the risk of doxorubicin cardiotoxicity [odds ratio (OR) = 10.80, 95% confidence interval (CI) 1.69-68.98, P = 0.01]. There was a significant association between heterozygous CBR3 rs1056892 genotype status and anthracycline-cardiotoxicity risk (OR = 9.91, 95% CI 1.07-91.47, P = 0.04). Heterozygosis for the ABCC1 rs3743527 allele was associated with protection from anthracycline-cardiotoxicity (OR = 0.30, 95% CI 0.09-0.91, P = 0.03). This pilot study suggests that selected polymorphic variants may impact the risk for anthracycline-cardiotoxicity in pediatric patients with ALL treated with a contemporary chemotherapeutic regimen in Mexico.

Abstract 14410: A Machine Learning Approach to Predicting Risk of Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

Background: Despite known clinical and genetic risk factors, predicting anthracycline cardiotoxicity remains challenging. Objective: To develop a risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 cases with LV ejection fraction (LVEF) ≤55% despite low-dose doxorubicin (DOX) (≤250 mg/m2), and 106 controls with LVEF >55% despite DOX >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between cases and controls. The top-ranked genes were functionally evaluated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results: Thirty-one genes were differentially enriched for variants between cases and controls (p<0.001). Only 42.6% cases harbored a variant in these genes compared to 89.6% controls [Odds ratio (95% CI), 0.086 (0.043-0.171), p=3.98x10 -15 ] suggesting that absence of these variants may predispose to cardiotoxicity. A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical model. In vitro inhibition of gene-associated pathways ( PI3KR2, ZNF827 ) provided protection from cardiotoxicity in CMs. Conclusions: Our study identified variants that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and also provided new targets in autophagy genes for development of cardio-protective drugs.

Genetics of Anthracycline-Mediated Cardiotoxicity: Current Status and Challenges

Anthracyclines are potent and widely used anti-cancer compounds which carry a significant risk of cardiotoxicity. Genetic background is a key determinant of risk susceptibility and identifying causal genes and polymorphisms is an area of intense and growing interest. In this review, we provide an overview of the strategies employed to identify causal alleles and key findings stemming from recent studies. We describe candidate gene association studies and genome-wide association studies of anthracycline cardiotoxicity and summarize key findings. The importance of data robustness is discussed, as well as the largely untapped potential of stem cell–based strategies for both validation and discovery purposes. Multi-disciplinary and coordinated efforts will be vital to fully understand the link between genetic background and anthracycline cardiotoxicity risk. Doing so will enhance understanding of pathological mechanisms and enable more personalized and nuanced treatment strategies for patients undergoing anthracycline chemotherapy.

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy

BackgroundAnthracyclines are a mainstay of chemotherapy. However, a relatively frequent adverse outcome of anthracycline treatment is cardiomyopathy. Multiple genetic studies have begun to dissect the complex genetics underlying cardiac sensitivity to the anthracycline drug class. A number of single nucleotide polymorphisms (SNPs) have been identified to be in linkage disequilibrium with anthracycline induced cardiotoxicity in paediatric populations.MethodsHere we screened for the presence of SNPs resulting in a missense coding change in a cohort of children with early onset chemotherapy related cardiomyopathy. The SNP identity was evaluated by Sanger sequencing of PCR amplicons from genomic DNA of patients with anthracycline related cardiac dysfunction.ResultsAll of the published SNPs were observed within our patient group. There was no correlation between the number of missense variants an individual carried with severity of disease. Furthermore, the time to cardiac disease onset post-treatment was not greater in those individuals carrying a high load of SNPs resulting from missense variants.ConclusionsWe conclude that previously identified missense SNPs are present within a paediatric cohort with early onset heart damage induced by anthracyclines. However, these SNPs require further replication cohorts and functional validation before being deployed to assess anthracycline cardiotoxicity risk in the clinic.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen

Background: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or β-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. Methods: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. Results: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. Conclusions: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

1028P - L-arginine – targeted for the anthracycline cardiotoxicity prevention in patients with acute leukemia of high cardiological risk

Background: The risk of anthracycline cardiotoxicity (AC) significantly increases in patients with comorbid ischemic heart disease (IHD), which requires monitoring and prevention during chemotherapy (CT) of acute leukemia (AL). In this study we aim to evaluate the effectiveness of L-arginine in AC prevention in AL patients with comorbid IHD during induction CT. Methods: A total 66 patients with newly diagnosed AL and comorbid IHD were included in the study, ECOG I-II. The cohort consisted of 34 (51.5%) males and 32 (48.5%) females, age 54-72 years. The IHD duration was 3–15 years. CT included doxorubicin. We determined the level of troponin I, nitrite anions [NO2]-, performed daily ECG-monitoring: at baseline and in achieving a cumulative dose of anthracyclines (CDA) from 100 to 200 mg/m2. Depending on AC prevention patients were divided into two groups: I (n = 36) – AL patients treated with CT; II (n = 30) – AL patients treated with CT and L-arginine. Results: Prior to CT, according to the daily ECG-monitoring in 47 (71.2%) patients’ periods of tachycardia were diagnosed, with single supraventricular extrasystoles (SEs) and ventricular extrasystoles (VEs) – in 35 (53%) and 17 (25.7%) pts, respectively. The decreased concentration of [NO2]- in blood serum in 1.5 times relative to normal values (p<0.05) was noticed. Troponin I in all patients of both groups was <0.5 ng/ml. Reaching low CDA in group I we recorded: periods of tachycardia in 36 (100%) pts, increasing number of single and paired SEs – in 24 (66.6%), VEs episodes – in 19 (52%), clinically significant ST-segment depression – in 29 (80.5%) and interval QT prolongation – in 14 (38.8%) pts. Troponin I was >0.5 ng/ml in 7 (19.4%) pts. Simultaneously, deepening of endothelial dysfunction (ED) was noted: [NO2]- was in 1.8 times lower vs norm. After 2 CT courses in 20 (66.6%) patients of group II on tachycardia background the single SEs were recorded and only in 1 (3.3%) patient troponin I level was >0.5 ng/ml. The ED leveled: [NO2]- didn’t significantly differ from the norm. Conclusions: Thus, L-arginine in AL patients with comorbid IHD during induction CT leads to reducing the risk of necrotic injury of cardiomyocytes and improves endothelial function that prevents early AC. Legal entity responsible for the study: Ukrainian Medical Stomatological Academy Funding: None Disclosure: All authors have declared no conflicts of interest.

Cardiovascular complications of antineoplastic therapy in children

The improvement of long-term survival in children with malignant tumors is noted in the last five decades. Serious late consequences of the applied therapy including early death, the second tumors, different organ dysfunctions (heart, gonads, liver, lungs) began to come to light with increase in number of cured and follow-up. The article discusses the emergence of cardiotoxicity in children treated with cytostatic and radiation therapy for malignant tumors. Particular attention is paid to the influence of anthracycline antibiotics on the state of the heart muscle. Anthracycline and similar medicines - doxorubicin, rubomycin, idarubicin, mitoxantrone - are an important component of most regimen of chemotherapy in children. Briefly describes the history of the application of this group of drugs in oncology and the study of their effects on heart function. The attention to the pathogenesis of anthracycline cardiotoxicity risk factors for its development, display options, how to identify and mitigate. We describe the clinical manifestations of early and late cardiotoxicity arising after the application of antitumor antibiotics anthracyclines. The article defines the role of chemotherapeutic agents other groups in the development and worsening cardiotoxicity. No less important role in the development of long-term effects of the heart and blood vessels plays radiotherapy. The paper paid attention to cardiovascular dysfunctions that arise in different periods of observation after irradiation of the mediastinum. Finally, recommendations for practitioners on screening, monitoring and treatment of identified diseases of the cardiovascular system in patients cured of childhood malignancies are presented.

Usefulness of NT-Probnp Levels and Fresco Cardiovascular Risk Scale for Prediction of Myocardiotoxicity Induced By Anthracyclines in Patients with Diffuse Large B-Cell Lymphoma

Introduction: Anthracyclines are cytotoxic antibiotics used in the treatment of lymphomas. Myocardiopathy is a well-known toxicity of anthracyclines, and both acute/subacute and late-onset presentations have been described. Early detection of asymptomatic cardiac dysfunction and identification of biomarkers for anthracycline cardiotoxicity risk may be important to prevent irreversible heart damage.Objective: To prospectively evaluate the incidence, time of appearance and clinico-biological variables associated with the development of myocardiotoxicity in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP/R-CHOP-like regimens.Patients and Methods: one hundred and sixty six patients with DLBCL from 05/2004 to 05/2014. Excluded: HIV infection (10), treatment without anthracyclines (21) and other causes (5) (Table 1). Left ventricular ejection fraction (LVEF) determined by high resolution echocardiography and the N-terminal brain natriuretic peptide (NT-proBNP) fragment were done prior initiation of treatment, at the end and every 6-12 months thereafter. Myocardiotoxicity was defined as: LVEF <55% or decrease >15% if prior LVEF <55% and/or clinical manifestations of heart failure (CHF). The FRESCO scale that accurately estimates 10-year cardiovascular risk in the adult European population was used to estimate cardiovascular risk. The C statistic for NT-proBNP and FRESCO scale was determined and competitive risk analysis was performed in the evaluation of myocardiotoxicity.Results: median age 68 years (IQR: 54-75), 51% male, median NT-proBNP 251.8 pg/mL (IQR: 76.2-560.1), median LVEF 64% (IQR: 60-69%) and median FRESCO scale 4.5 (IQR 2.1-7.2). NT-proBNP was correlated with FRESCO scale, but not with LVEF. With a median follow-up of 64.7 months (95% CI 56.4-73.6) 24 cardiac events were observed (5 clinical CHF + normal LVEF, 7 clinical CHF + LVEF low and 12 low LVEF without clinical CHF). Cumulative incidence of myocardiotoxicity was 8.8% at 6 months (95% CI 5.0 to 15.3), 12.3% at 12 months (95% CI 7.6 to 19.6), 14.2% at 24 months (95% CI 9.1 to 21.9) and 17.6% at 5 years (95% CI 11.6 to 26.1). C statistic for myocardiotoxicity was: FRESCO scale 0.7192 (95%CI: 0.6284- 0.8099) and FRESCO scale+NT-proBNP 0.807 (95%CI: 0.7309-0.8832). Competing risks analysis showed a significantly increased cumulative incidence of myocardiotoxicity in patients with NT-proBNP >600 +/- FRESCO >4.5 (Figure 1). Finally, we performed a computational modeling using 12 Bayesian networks to analyze the connections between demographic characteristics, cardiovascular risk factors, treatment, occurrence of cardiotoxicity and death (Figure 2 illustrates one of the networks).Conclusions: myocardiotoxicity induced by anthracyclines remains an important problem in the daily practice. The FRESCO cardiovascular risk function is useful for predictingmyocardiotoxicity and levels of NT-proBNP improved accuracy myocardiotoxicity risk. We propose that patients with NT-proBNP >600 pg/mL or FRESCO > 4.5 should have a specific cardiologic surveillance and follow-up in cardio-oncology units from the start of their anthracyclin-containing chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Pediatric quality of life in long-term survivors of childhood cancer treated with anthracyclines.

Anthracyclines are a common class of drugs used to treat pediatric cancer. While much attention is given to their cardiotoxicity, little is known about the relationship between the use of anthracyclines and health-related quality-of-life (HRQoL) outcomes. This study examines the association of anthracycline cardiotoxicity risk status and Pediatric Quality-of-Life (PedsQL) InventoryTM scores in childhood cancer METHODS: Pediatric cancer survivors aged 8-21 who were at least 5 years posttreatment were recruited from a Cancer Survivor Clinic. Participants completed the PedsQL 4.0 Generic Core Scales and a health behavior survey. Linear regression was used to evaluate the association between PedsQL scores and anthracycline cardiotoxicity risk status and to assess whether self-reported physical activity modified the association. Eighty survivors participated and were characterized by cardiotoxicity risk status (high: 12; moderate: 23, low: 24, no risk: 21) as defined by the Children's Oncology Group (COG). Measures in all PedsQL domains tended to be slightly lower for survivors exposed to anthracyclines as compared to the unexposed. The largest difference in unadjusted mean scores was for social functioning (96.0% for unexposed vs. 91.3% for exposed, P = 0.0068). There was also an inverse dose-response relation between adjusted PedsQL scores and increasing anthracycline cardiotoxicity risk; this association was not modified by physical activity level. These data indicate that regular psychosocial assessments, such as those currently recommended by the COG, may be especially important for survivors treated with anthracyclines.

Risk factors for anthracycline-associated cardiotoxicity.

Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults. We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated. We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556). This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.

Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

Choosing First-Line Therapy for Follicular Lymphoma (FL): A Decision Analysis

Introduction: There is no standard of care for first-line therapy of low-grade FL. In US practice, the most common strategy is rituximab with combination chemotherapy. However, the optimal choice of regimen remains controversial; options include RCVP, RCHOP and R-Fludarabine-based chemotherapy (RFlu). Because data from randomized clinical trials are not available and unlikely to be generated in the future, we performed a decision analysis comparing RCVP, RCHOP, and RFlu as first-line therapy for FL.Methods: We constructed a Markov model of sequential first- and second-line therapy based on prescribing patterns in the US. The endpoint of the model was quality-adjusted time to tertiary referral for therapy such as RIT or autologous transplant (≥3rd line). A literature review was performed of the Medline database and international meeting abstracts. Clinical trials of both untreated and previously treated patients were systematically evaluated using explicit eligibility criteria. Data were extracted regarding response rates, treatment-related mortality, and progression-free survival (PFS). Weighted estimates were obtained using a fixed effects meta-analysis. The model also incorporated published data on heath state utilities, risk of anthracycline cardiotoxicity and fludarabine-related delayed cytopenias. Primary and sensitivity analyses were performed using TreeAge software.Results: The optimal treatment strategy consisted of RCHOP in first-line followed by RFlu in second-line (9.0 quality-adjusted life years; QALYs). Strategies containing RCVP in either first- or second-line were inferior (6.2–7.7 QALYs). The model was sensitive to first-line PFS of RCHOP and RFlu when these were varied over the range of estimates obtained from individual published trials. The model was robust in sensitivity analysis of most other parameters, including rate of delayed cytopenias after RFlu, anthracycline cardiotoxicity, and quality of life adjustments.Conclusions: Using decision analysis, the optimal first-line therapy for low-grade FL is RCHOP, followed by RFlu in second-line. This strategy maximizes quality-adjusted time to tertiary therapy. Use of RCVP does not improve overall quality-adjusted time relative to more intensive therapies.

Effect of dexrazoxane on doxorubicin pharmacokinetics in young and old rats.

Although dexrazoxane (ICRF-187) is used clinically to protect against doxorubicin cardiotoxicity, the age-related effect of dexrazoxane on doxorubicin pharmacokinetics has not been well studied. We therefore examined the effect of pretreatment with dexrazoxane (50 mg kg(-1) i.p. 1 h prior to administration of doxorubicin 2 mg kg(-1) i.v. bolus) on doxorubicin and doxorubicinol pharmacokinetics in Fischer 344 rats at 5 months of age (young adult) and 22 months of age (old). Dexrazoxane had no major effects on doxorubicin or doxorubicinol pharmacokinetics in plasma or heart in either young or old rats. However, age had significant effects on anthracycline pharmacokinetics. Early plasma concentrations were increased and systemic clearance of doxorubicin was decreased in old compared with young rats. Cardiac concentrations of doxorubicin (AUC) were significantly increased in old rats. In addition cardiac doxorubicinol concentrations (AUC 0-72 h) were increased by over 80% in old compared to young rats. The results suggest that dexrazoxane does not alter doxorubicin pharmacokinetics. In contrast, aging in the rat model is associated with altered doxorubicin and doxorubicinol pharmacokinetics, in particular in the heart. These changes could increase the risk of anthracycline cardiotoxicity with age.

Identifying patients at high risk of anthracycline cardiotoxicity

Identifying patients at high risk of anthracycline cardiotoxicity