Anthracycline Toxicity Research Articles

New model system for testing effects of flavonoids on doxorubicin-related formation of hydroxyl radicals

Doxorubicin belongs to anthracycline cytotoxic drugs and it is widely used as a major therapeutic agent in the treatment of various types of tumors. However,its therapeutic use is limited by the development of myelosuppression and cardiotoxicity after a specific cumulative dose is reached. The aim of this study was to investigate the effect of flavonoids, either natural or synthetic on doxorubicin-mediated formation of oxidative stress implicated in doxorubicin toxicity. Doxorubicin caused a concentration-dependent increase in the formation of hydroxyl radicals in minipig liver microsomes used as an in-vitro model system. When bacterial membranes heterologously expressing human NADPH cytochrome-P450 oxidoreductase were incubated with doxorubicin, formation of the superoxide radical under aerobic conditions and the doxorubicin–semiquinone radical under anaerobic conditions was detected. Forty different flavonoids were tested for their potency to prevent NADPH-induced or Fe2+-induced peroxidation of lipids in the microsomal system. According to the results, seven flavonoids were selected for evaluation of their potency to inhibit doxorubicin-dependent formation of hydroxyl radicals assessed by electron spin resonance. Myricetin, fisetin, and kaempferol were found to produce a significant protective effect against hydroxyl radicals in the minipig liver microsomal system. In conclusion, this study shows the use of a novel cost-effective in-vitro model system for preselection of antioxidants for testing of their protective effects against toxicity of anthracyclines and potentially other oxidative stress-inducing chemicals.

Report of a Phase II Study of Clofarabine and Cytarabine in De Novo and Relapsed and Refractory AML Patients and in Selected Elderly Patients at High Risk for Anthracycline Toxicity

To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara-C, 1,000 mg/m(2) per day i.v. over 2 hours. Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML.

Is Liposome Encapsulated Doxorubicin Able to Reduce the Cardiotoxicity of Doxorubicin In the Treatment of DLBCL? A Randomised Study by the Austrian Working Party of Medical Oncology (AGMT-study NHL-14)

AbstractAbstract 1766 Introduction:A combination of Rituximab with a chemotherapy regimen consisting of cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) is the current standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin is known to induce short-time and long-time cardiac toxicity. By encapsulating doxorubicin in liposomes the cardiac toxicity may be reduced. This is the 1st randomised study comparing doxorubicin and liposome encapsulated doxorubicin in the 1st line treatment of DLBCL. Patients and methods:Aim of the study was to reduce the cardiotoxicity of R-CHOP by substituting doxorubicin by liposome encapsulated doxorubicin. The primary endpoint was left ventricular ejection fraction (LVEF) measured by the Simpson method and NT-proBNP levels, respectively. Both parameters were measured before each treatment cycle and after the end of treatment. From December 2007 until July 2010 we performed a two arm prospective randomised study. In arm 1 patients were treated with rituximab 375 mg/m^2 iv day 1, cyclophosphamide 750 mg/m^2 iv day 1, liposome encapsulated doxorubicin (Myocet®) 50 mg/m^2 iv day 1, vincristine 2 mg iv day 1, and prednisolone 100 mg po day 1–5. In arm 2 the regimen was identical, but liposome doxorubicin was substituted by standard doxorubicin 50 mg/m^2 i.v. day 1. Treatment cycles were repeated every 2 to 3 weeks, due to the discretion of the treating physician. Six cycles were scheduled. This study was conducted in accordance with the “Good Clinical Practice” Guidelines and the Declaration of Helsinki and was reviewed by the independent ethics committees at the trial centres. All patients gave their written informed consent. Eighty-eight patients were registered, eight were excluded. In each arm 40 patients were eligible. Median age was 66 years (range 19–84 years), 64% of patients were older than 60 years. The two arms were balanced in respect to age, international prognostic index, smoking status, hypertension, NT-proBNP, and LVEF. At the time of the abstract submission 44 patients (24 and 20 in arm 1 and 2, respectively) had finished their treatment and were fully documented. The complete remission rate was 78.8% and 69.6% in arm 1 and 2, respectively. The two progressive lymphomas were in arm 2. We observed 26 and 32 serious adverse events in 19 and 24 patients in arm 1 and arm 2, respectively. Most of them had neutropenic fever. The mean relative difference in LVEF after the 6th cycle was 2.98 and -3.92 in arm 1 and arm 2, respectively. Two of 24 (8.3%) and 5/20 (25%) had a more than 20% decline of their LVEF during treatment in arm 1 and 2, respectively. However, this was not statistically significant. The difference in median NT-proBNP levels were significantly different 73.1 and 97.2 pg/ml in arm 1 and 2, respectively (P=.0235). Conclusion:In this 1st analyses we did not observe any safety concerns in the two arms. The remission rate was as expected. The substitution of doxorubicin by liposome encapsulated doxorubicin seemed not to alter the efficacy of the treatment. With the limited data available the cardiotoxicity may be lower in the arm with liposome encapsulated doxorubicin. However, the primary endpoint of the study was not met, respective to the attenuation of acute anthracycline cardiac toxicity. A possible attenuation of the frequency and severity of chronic heart failure will need a much longer follow up.The study was registered under the Eudract #: 2007–004970-24 Disclosures:Fridrik:Cephalon: Honoraria, Research Funding. Off Label Use: Liposome encapsulated doxorubicin in diffuse large B-cell lymphoma. Greil:Cephalon: Research Funding.

Early diagnosis of anthracycline toxicity in asymptomatic long-term survivors: dobutamine stress echocardiography and tissue Doppler velocities in normal and abnormal myocardial wall motion

Asymptomatic long-term cancer survivors treated with anthracycline were investigated for late anthracycline cardiotoxicity using dobutamine stress echocardiography (DSE) and tissue Doppler (TD) velocities. The study comprised 20 asymptomatic patient and 18 healthy children as the control group. Twenty patients were divided into two groups according to the myocardial wall motion during DSE: Group 1 (normal myocardial wall motion; six girls and five boys) and Group 2 (abnormal myocardial wall motion: nine boys). Intravenous dobutamine infusion was started at a dose of 5 µg/kg/min (D5) and gradually increased to 10 (D10), 15 (D15) and 20 µg/kg/min (D20). Echocardiographic assessment was performed at rest and after each dose of dobutamine infusion. Abnormal myocardial wall motion was observed at rest in 3 patients and during DSE in six patients. There were no significant differences between the patients and control groups at rest except the end systolic wall stress and mitral deceleration time measured by conventional methods; however, both patients group showed significant differences of systolic and diastolic functions at D20. In patients groups, systolic and diastolic functions of interventricular septum (IVS) and systolic function of left ventricle (LV) and right ventricle (RV) TD velocities showed significant changes compared with control group at rest. Significant differences of diastolic functions of IVS and RV were noted during dobutamine infusion in abnormal myocardial wall motion compared with other groups. LV, RV and IVS TD velocities systolic function at rest and during DSE can provide valuable information for early detection of subclinical cardiac toxicity. TD velocities of diastolic functions during DSE are a valuable parameter for assessment of subclinical cardiac toxicity in patient with abnormal wall motion.

Current management of pediatric dilated cardiomyopathy

American and European guidelines for treatment of adult heart failure have been recently revised. This review will reconcile those guidelines to recent studies and experience in the treatment of pediatric dilated cardiomyopathy. Therapy for pediatric dilated cardiomyopathy includes establishing a diagnosis for diagnostic-specific therapies as well as preventive strategies for anthracycline toxicity and muscular dystrophy. Pediatric studies demonstrate safety and efficacy for use of angiotensin-converting enzyme inhibition and beta-blockers in dilated cardiomyopathy. Cardiac resynchronization and mitral annuloplasty represent potential nonpharmacologic therapies. Implantable defibrillator therapy may be of less import in children as compared with adults. Ventricular assist devices (VADs) are now available for all ages, which can improve survival and potentially can lead to recovery. The robust development of new therapies for adult heart failure has been successfully applied to children with dilated cardiomyopathy. Therapies for severe, intractable heart failure have been more widely utilized than therapies for mild-to-moderate heart failure.

Is There More for Us to Learn From Oncology?

Decades of basic and clinical research have improved the cure rates of many forms of cancer, particularly childhood malignancies. An unintended consequence of this success is the fact that cancer survivors are often left with increased risk of cardiovascular disease, particularly congestive heart failure, after the use of anthracycline antibiotic chemotherapeutics. Discovered >50 years ago, these agents have enjoyed widespread use in solid and hematologic malignancies for >30 years. The cardiac effects of these drugs remain a dose-limiting toxicity and can be neither predicted nor prevented. Oncology has adapted by reducing the total dose to limit exposure and developing cotreatments that reduce cardiac damage.1 This well-documented problem, which continues to induce cardiac dysfunction severe enough to warrant heart transplantation, is tolerated in part because of the efficacy of anthracyclines as important components of chemotherapy regimens. Studies examining possible mechanisms for anthracycline cardiac toxicity have been occurring for decades and have revealed many aspects of cardiac biology. Despite these efforts, there is no generally accepted mechanism for how these drugs cause heart failure.2 Article see p 675 A general construct for anthracycline-induced cardiac toxicity is that some form of cardiac injury occurs with every exposure. Compensatory changes at the cellular and subcellular levels allow recovery, permitting function to return to “normal” under resting conditions. Exercise stress–induced cardiac reserve is abnormal after anthracycline exposure, even when resting function appears normal.3 This conceptual view is further supported by the finding that persons at greatest risk are those with limited reserve such as patients with hypertension and old age.4 Thus, anthracycline exposure leads to a subclinical cardiomyopathy that manifests itself variably, depending on a number of factors, including total anthracycline dose and reserve. A puzzle from this perspective is why children, who perhaps have the greatest cardiac reserve, are also …

The development of congestive heart failure and ventricular tachycardia after first exposure to idarubicin in a patient with acute myeloid leukaemia

The development of congestive heart failure and ventricular tachycardia after first exposure to idarubicin in a patient with acute myeloid leukaemia

Transfusional Iron Overload: An Underappreciated Danger in AML Patients?

Abstract 4133The survival rate for childhood cancer has improved steadily over the last 3 decades creating an increasing population of survivors. Though this is one of the great successes in medicine, there is a growing awareness that survivors are at increased risk for late therapy related adverse effects including cardiovascular toxicity. The Childhood Cancer Survivor Study showed that the standardized mortality ratio for cardiac causes was > 8 times higher than expected and cumulative probability of cardiac death increased 15-25 years after cancer diagnosis.[i]The cardiotoxic effects of anthracyclines are well documented in the literature. They are an essential component of treatment for AML. However, their use is limited by dose-related cardiomyopathy. An important factor in anthracycline toxicity is iron's role in promoting the formation of toxic oxygen species. Cardiac tissue is recognized to be especially vulnerable to free radical damage. Anthracyclines cause altered expression of iron-regulated genes and change intracellular iron trafficking. It is known that, dexrazoxane-an iron chelator, is an effective cardioprotective agent against doxorubicin effects in animal models. The American Society of Clinical Oncology recommends its use in metastatic breast cancer patients receiving a doxorubicin dose of >300 mg/m2.[ii] Dexrazoxane was found to prevent or reduce cardiac injury associated with doxorubicin use in childhood ALL without compromising the anti-leukemic effect.[iii]We hypothesize that cardiomyocytes damaged by anthracyclines are more susceptible to iron accumulation, potentiating anthracycline toxicity in patients with a heavy transfusion burden.Consecutive adolescent patients with AML admitted to our institution were reviewed. These patients received a cumulative anthracycline dose of 200 to 300 mg/m2. Iron loading was estimated from the number of red cell units given. The iron content of a single red cell unit is approximately 200 mg. 10 AML patients received 24-59 units of blood (median 35) over a median of 222 days. This equates to 65-235 mg of iron/kg (median of 129 mg/kg).Iron loading was identified in AML patients due to transfusion. The iron load is less than seen in children with thalassemia but in AML patients, who are known to have increased adverse cardiac events, it is possible that anthracycline induced cardiomyopathy could have been exacerbated by transfused iron. To prove the hypothesis the next step is to investigate T2* MRI detectable myocardial iron deposition and cardiac dysfunction and markers of myocardial injury in AML patients. These observations may provide evidence for using iron chelation therapy in the treatment of AML.[i] Lipshultz S, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525-533[ii] Carver JR, Shapiro CL, Ng A, et al. ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cance survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991-4008[iii] Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145-53 Disclosures:No relevant conflicts of interest to declare.

Health Outcomes in Childhood Cancer Survivors: Screening for Anthracycline-Induced Cardiac Toxicity.

Abstract 70 Background:Cardiac toxicity secondary to anthracyclines is a significant problem in childhood cancer survivors, and the Children's Oncology Group (COG) has developed a recommended screening protocol for echocardiograms based on age at diagnosis, cumulative anthracycline dose, and chest radiation. The objective of this study was to assess the yield of screening and risk factors for cardiac toxicity in long-term survivors. Methods:A retrospective medical record review was performed for all patients seen in a single institution long-term survivor clinic from 2000 through 2007. Patients eligible for analysis included any patient previously treated with anthracyclines and/or chest radiation; patients with prior cardiac disease were excluded. Results:370 patients were eligible for analysis; 206 (56%) patients were male, 236 (64%) were white, and 197 (53%) were ≤5 years of age at diagnosis. The most common diagnoses included acute lymphoblastic anemia in 152 (41%) patients and Wilms' tumor in 44 (12%). 360 (97%) patients received anthracyclines, and the median dose received was 190 mg/m2. Fifty (14%) patients received radiation to the chest only while an additional 64 (17%) patients received total body irradiation. Overall, 308/370 (83%) patients had received at least one screening echocardiogram with a mean time from diagnosis to latest follow-up of 9.3 years. Younger patients at diagnosis were more likely to be screened during follow-up (p=0.007). All other measured factors were similar between those screened and not screened, including diagnosis, sex, BMI, anthracycline dose, and having received radiation. Of all patients receiving a screening echocardiogram, 24/308 (8%) patients had an abnormal echocardiogram defined as shortening fraction (SF) <28%. By the end of the study period, 9 patients had been placed on cardiac medications for the treatment of cardiac dysfunction identified through screening. Anthracycline dose was associated with a future abnormal echocardiogram; odds ratio (OR) of ever having SF<28% was 9.2 (95% CI: 3.1–27.6) for anthracycline dose ≥250 mg/m2. For all patients who had received an echocardiogram and received an anthracycline dose ≥250 mg/m2, 20/122 (16%) had a SF<28%; for patients who received an anthracycline dose <250 mg/m2, only 4/185 (2%) had a SF<28% (p<0.001). Further, only 1 patient who received a dose <175 mg/m2 had a SF<28%. Age, sex, chest radiation, type of anthracycline, history of relapse, and history of stem cell transplant were not associated with an abnormal echocardiogram in univariate analyses. Body mass index (BMI) was calculated from available weight and height data at latest follow-up visit. BMI category was significantly associated with having an abnormal echocardiogram, as currently underweight patients (BMI <5th%) were more likely to have a SF<28% than their heavier counterparts (p=0.001). For currently underweight patients, 4/12 (33%) had an abnormal echocardiogram with a SF<28%; for all patients in a non-underweight category, only 15/216 (7%) had a SF<28%. This result was significant with an OR of 6.7 (95% CI: 1.8–24.8). Conclusions:We found anthracycline toxicity to be dependent on dose although not on age, with a significantly increased risk with doses ≥250 mg/m2. We also describe a novel association between underweight status and anthracycline-induced cardiac toxicity. Eighty-three percent of patients at our institution are being screened by echocardiography. Our data support the current screening recommendations of the Children's Oncology Group (COG), as 24 patients were identified with decreased cardiac function. Echocardiography is a relatively inexpensive tool to identify patients with late-onset cardiac toxicity and may positively impact the medical care for the growing population of childhood cancer survivors. Disclosures:No relevant conflicts of interest to declare.

Close cardiac surveillance of patients treated with anthracyclines, also necessary after chemotherapy?

In women, breast cancer is the second most common form of cancer and the leading cause of death caused by malignancy. Anthracyclines are well known chemotherapeutics for treatment of these tumors, other solid tumors and hematologic malignancies. As adjuvant treatment in breast cancer it improves survival and reduces recurrence [1]. Unfortunately, their clinical use is currently limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, which is usually refractory to conventional therapy [2]. Studies have reported that 10–26% of patients administered cumulative anthracycline doses above those, develop congestive heart failure, and that more than 50% of patients administered these doses will experience measurable functional impairment months to years after the end of therapy [3]. The pathophysiology of this cardiomyopathy is incompletely understood. Anthracyclines decrease b-andrenoceptor density in the cell membrane, increase the permeability of myocytes and alter the ultrastructure of myofibrils and actin networks [4]. Risk factors for anthracycline-induced cardiotoxicity include high cumulative anthracycline doses, high anthracycline dose intensity, and radiotherapy. Radiotherapy in patients with cancer treated with anthracyclines can exacerbate cardiac tissue damage. Cardiovascular complications of treatment may be observed during administration of the drugs, days to months following administration, or years to decades following exposure. Several strategies have been developed to decrease the risk of cardiotoxicity while maintaining efficacy. These strategies include altered schedules of drug administration and adjunctive treatment with dexrazoxane. Unfortunately, none of these approaches have been successful, and patients remain at risk for the development of anthracycline cardiomyopathy, particularly with higher cumulative doses. Therefore careful serial monitoring is required for optimal medical management. Cardiomyopathy disease progression can be delayed in adults by using carvedilol or angiotensin-converting enzyme inhibitors [5, 6]. The permanent risk of cardiomyopathy by anthracyclines has made monitoring for the earliest evidence of cardiotoxicity necessary. In clinical practice monitoring is mostly performed using echocardiography or radionuclide angiography. The study of Appel et al. in the current issue of the International Journal of Cardiac Imaging shows that development of anthracycline toxicity is difficult to predict [7]. Although all patient in this study had a normal left ventricular function before receiving chemotherapy, 33% of the patients developed heart failure within a time period Editorial comment on the article of Appel et al. (doi:10.1007/ s10554-009-9518-2).

Effect of selenium on anthracycline induced cardiotoxicity in children that treated for cancer: Correlation with pro-brain natriuretic peptide levels

10061 Background: High cumulative doses of an anthracyclin (300–500 mg/m2) are used in the several treatment protocols of children with Cancer. Probrain natriuretic peptit (Pro-BNP), is relased by cardiac cells and elevated even before overt cardiac distress symptoms. Selenium, is an antioxidant which its’ absence cause cardiomyopathy in people living in the poor selenium soil area. Aim 1: Assesment of anthracycline-induced cardiotoxicity with Pro-BNP levels, correlated with echo-cardiographic (ECHO) findings. Aim 2: Determine possible effects of selenium levels and supplemantation on cardiac toxicity. Methods: Plasma levels of Pro-BNP have been measured in 58 pediatric cancer patients (leukemias, lymphomas,solid tumors; 38 boys, 20 girls; between 2–18 years, median:12) after completed their anthracycline containing regimens. Serum selenium levels examined in 12 patients (six patients were with high and other six with normal pro-BNP levels). Three of four Patients with low level of selenium showed cardiac failure according to ECHO and supplemanted with selenium besides digoxine, ACE inhibitors. Results: Eleven patients have found with high pro-BNP levels (120–8022 pg/ml; normal: lower than 120 pg/ml).Six of these patients (with 170–8022 pg/ml, median:798pg/ml pro-BNP) and other six patients with normal levels of pro-BNP (10–74pg/ml, median: 67pg/ml) examined for their serum selenium levels. All patients with normal pro-BNP levels have found in normal levels of selenium levels (71–150 μg/L,median:125 μg/L). Four patients in high pro-BNP group showed low levels of selenium (52–129 μg/L; median:67.5 μg/L). Since three of that four patients have cardiac failure, treated accordingly and supplemented with 100 μg/day selenium to maintain normal levels. During follow-up periods of 27; 8 and 2 months, all 3 patients are doing well with normal ECHO finding. Two patients reached normal Pro-BNP levels while one of them has 80 % decrease. Conclusions: Serum Pro-BNP levels can be used as a marker for anthracycline toxicity and as follow-up marker for protective agents. Selenium suplemantation may have a potential role to protect and/or overcome the difficulties related anthracyclin-induced toxicities. No significant financial relationships to disclose.

Cardiopathie aux anthracyclines

Anthracycline-based antineoplastic therapy is the standard of care for various cancers today and represents a breakthrough in this area. The cardiac toxicity of anthracyclines is well established. The acute form is often reversible and has no predictive value for the future. This early form does not prevent continuation of chemotherapy. Late cardiac toxicity due to anthracycline is the leading limiting factor in its use. In adults, this resembles dilated cardiomyopathy, while in children it may be expressed as restrictive cardiomyopathy. The discovery of modifiable risk factors has made it possible to identify patients at high risk of developing late cardiac toxicity and heart failure. Because left ventricular dysfunction and heart failure may develop long after anthracycline treatment ends, prolonged close follow-up is mandatory in asymptomatic subjects. Follow-up of asymptomatic patients requires serial echocardiography (M-mode, 2D echo, Doppler, tissue Doppler, speckle tracking, etc.). Anthracycline-induced cardiomyopathy must be treated according to the standard guidelines for chronic heart failure with left ventricular dysfunction, by angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Lifestyle changes may reduce the long-term risk. Close collaboration between cardiologists and oncologists is highly desirable for optimizing management of these patients.

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m(2) doxorubicin-equivalent) were given i.v., together with 123I-labelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

Novel anti-tubulin cytotoxic agents for breast cancer

Regardless of stage of disease, cytotoxic chemotherapy remains an important part of the treatment paradigm for breast cancer. Anthracyclines and taxanes are the most active agents; however, limitations with their use exist. These include a maximum lifetime dose and tumor resistance with anthracycline, hypersensitivity reactions and cumulative toxicity with taxanes. Therefore, to meet these challenges, the development of new cytotoxics and novel taxane formulations is an important area of active research. Several recent advances have been made. Epothilones represent a novel group of cytotoxic agents, with proven activity in breast cancer. Nanoparticle drug delivery systems have led to the development of ABI-007, which has demonstrated superior response rates than 3-weekly paclitaxel, with a lower risk of hypersensitivity reactions. To circumvent the problem of taxane resistance, larotaxel, a semisynthetic taxoid, and vinflunine, a synthetic vinca alkaloid, have been developed with encouraging clinical results to date. Eribulin, a synthetic derivative of halichondrin has recently entered Phase III trials based on encouraging activity in heavily pretreated patients. A further novel approach is the conjugation of cytotoxic agents to targeted agents, such as with trastuzumab–MCC-DM1. Elucidating the relative importance of these agents and incorporating them into existing treatment paradigms is a significant challenge for the future.

Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone.

The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS). The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation. SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU. This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

Predicting and preventing the cardiotoxicity of cancer therapy

For the past 40 years, cardiovascular disease and malignant neoplasms have been the leading causes of death in the USA. As treatments for cancer, cardiovascular disease, diabetes and other chronic illnesses improve, we are seeing more complicated patients in our clinics. Cancer therapies such as anthracyclines and radiation therapy continue to pose a risk for delayed-onset cardiovascular disease, in spite of decades of research. It has been reported that the risk of congestive heart failure is the second most common, late, long-term disabling health condition among cancer survivors. Improved understanding of an individual’s risk for cardiovascular complications of these therapies and earlier intervention for selected patients may help to improve the overall outcome for patients requiring these therapies. New therapies targeting oncogenes and the process of angiogenesis have ‘off-target’ effects regarding the cardiovascular system that remain poorly understood. Our knowledge and experience in the cardiovascular care of patients with cancer must continue to grow if we are to assure the best possible outcome for these people. The aim of this review is to highlight the risk of chemotherapy-induced cardiotoxicity among several of the most commonly used cancer therapies, various ways to screen for patients at highest risk of cardiotoxicity and management of cardiac complications of cancer therapy. We spend a disproportionate amount of space and time on the subject of anthracycline toxicity due to its often devastating nature, and its persistence as a clinical problem despite decades of use and research.

Anthracycline associated cardiotoxicity in survivors of childhood cancer

The development of effective antineoplastic therapies for childhood cancer is a great success in modern medicine. Five year survival rates of children diagnosed with cancer in the USA and Western...

Left Ventricular Ejection Fraction and Cardiotoxicity: Is Our Ear Really to the Ground?

Left Ventricular Ejection Fraction and Cardiotoxicity: Is Our Ear Really to the Ground?

ANTHRACYCLINE CARDIOTOXICITY IN CHILDHOOD

Over the last 40 years, a significant advance has been made in the treatment of childhood and adult cancers. However, the increase of the survival rate points out medium-and long-term adverse effects that constitute a serious limitation for the quality of life in adults survived from a childhood cancer. Cardiovascular disease is an important cause of morbidity and mortality in adults treated with chemo-and radiotherapy for childhood cancers. Although some antitumor treatments are potentially cardiotoxic, anthracycline therapy and radiotherapy are mostly responsable for long-term cardiac damage. Anthracycline toxicity is generally limited to the myocardium, while radiation can cause injury to all components of the heart. The purpose of this review is to discuss the mechanisms of action of anthracyclines, their cardiotoxicity, the feasibility of screening, and the prevention of cardiac damage after treatment in childhood.

New-Onset Heart Failure Due to Heart Muscle Disease in Childhood

We undertook the first prospective, national, multicenter study to describe the incidence and outcome of heart muscle disease-induced heart failure in children. Data were collected on patients admitted to a hospital through 2003 with a first episode of heart failure in the absence of congenital heart disease. All 17 pediatric cardiac centers in the United Kingdom and Ireland participated. Follow-up data were obtained to a minimum of 1 year. The incidence was 0.87/100,000 population <16 years (n=104; 53 girls; 95% confidence interval 0.71 to 1.05 per 100,000). Median age at presentation was 1 year, with 82% in New York Heart Association class III to IV. Causes of heart failure included dilated cardiomyopathy (50 idiopathic, 8 familial), probable myocarditis (23), occult arrhythmia (7), anthracycline toxicity (5), metabolic disease (4), left ventricular noncompaction (3), and other (4). Overall 1-year survival was 82%, and event (death or transplantation)-free survival was 66%. Regression analysis showed older age and reduced systolic function on admission echocardiogram increased the event risk. Only 8% of event-free survivors (n=69) remained in New York Heart Association class III to IV, but 35 required readmission during the study period, and all but 8 remained on medication. This first national prospective study of new-onset heart failure in children has shown an incidence of 0.87/100,000. Multivariable analysis of survival data indicates a better outcome for younger children and for those with better systolic function at presentation, but overall, one third of children die or require transplantation within 1 year of presentation.