Higher Cumulative Anthracycline Dose Research Articles

Empagliflozin restores autophagy and ameliorates ponatinib-induced cardiomyocyte death

Abstract Background The tyrosine kinase inhibitor ponatinib has proven cardiovascular toxicity, for which no counteractive treatment is available at the moment. Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors are approved drugs treat patients with chronic heart failure of different aetiologies. They play direct anticancer activity in SGLT2-expressing cancer cells, independent of glucose metabolism and through inhibition of oxidative phosphorylation. Ongoing studies are now testing empagliflozin (EMPA) in the prevention of left ventricular dysfunction in patients receiving high cumulative doses of anthracyclines. Aims To determine the effect of EMPA on cardiomyocytes in an in vitro model of PON-induced cardiac toxicity, and to assess underlying cardioprotective mechanisms. Methods and Results We exposed cardiomyocytes to PON (1.7 nM) or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nM) for 24 hours. Compared with vehicle, incubations with PON significantly reduced cell viability at 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, decreased autophagic cells at immunofluorescence assay (1±0.5 vs 6±1 fluorescence intensity/total area, p=0.0006, Figure 1), and increased cell senescence (15±5 vs 4±2 β-gal positivity/tissue area, p<0.02), effects all reverted by EMPA (p<0.01). We observed no significant effects of PON or EMPA on formation of reactive oxygen species. Compared with vehicle, PON significantly reduced serum response factor (SRF)/serum response elements (SRE) binding activity (25±9 vs 218±15 SRE complex abundance, arbitrary units, p<0.001), in parallel with a reduction in cardiac actin expression (0.32±0.06 vs 0.98±0,12 cardiac actin/GAPDH ratio, arbitrary units, p=0.001), which was reversed by EMPA (p=0.001). Conclusion EMPA attenuates PON cardiotoxicity by reducing senescence and enhancing autophagy, apparently independent of antioxidant mechanisms. This study suggests the design of clinical studies aimed at assessing the effects of EMPA on PON-induced cardiotoxicity.Legend to Figure 1.CON, control (vehicle, DMSO); PON, ponatinib; EMPA 100, empagliflozin 100 nM; EMPA 500, empagliflozin 500 nM

Early surveillance of anthracycline induced cardiotoxicity in children using echocardiography and biomarkers: A prospective study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIHR Background Anthracyclines, which are commonly used in cancer treatment can induce myocardial damage, result in heart failure during treatment and have cardiac effects even decades after treatment. Monitoring of cardiotoxicity during treatment is largely based on the use of echocardiographic functional markers like ejection fraction and more recently myocardial strain imaging. Some studies have also looked at the utility of biomarkers like troponin and BNP. The utility of this surveillance strategy remains controversial as larger prospective studies are lacking. Purpose The aim of this study was to prospectively describe the impact of anthracycline treatment on echocardiographic functional parameters and cardiac biomarkers (high sensitivity troponin T and NT-Pro BNP) during the treatment period and twelve months after completion of treatment. In the current study we wanted to look at whether monitoring parameters during treatment were predictive of left ventricular function 12 months after treatment. Methods This was a prospective multi-centre nested case-control study of 256 children diagnosed with cancer requiring anthracycline therapy. Baseline functional echocardiographic parameters and cardiac biomarkers were obtained prior to starting anthracycline therapy, during the treatment protocol, and 12 months after treatment completion. Patients were assigned to one of two comparison groups based on the fractional shortening at the12-month echocardiogram: patients in group 1 had normal fractional shortening, (FS ³ 28%) while patients in group 2 had reduced fractional shortening (FS < 28%). Results A total of 917 echoes were performed, 376 of these occurred during the treatment period. FS was reduced in 27 (7%) of echoes obtained during the treatment period with 22 patients developing new onset dysfunction. Twelve months after treatment completion 232 patients had normal FS (Group 1), while 24 patients showed reduced FS (Group 2). Both groups had normal systolic function and cardiac biomarkers at baseline, however patients in group 2 were older at diagnosis (13.2 years (11.8-16) vs 6.5 years (3.4-13.2), p = 0.003) and received a higher cumulative anthracycline dose (200 mg/m2 (143-318) vs 125 mg/m2 (75-200), p= 0.005). One third (8/24) of patients in group 2 had at least 1 abnormal echo during the treatment period compared to 7% (16/232) in the normal group P < 0.001. The proportion of patients with at least one abnormal biomarker during this period however, was similar between groups. Conclusion(s) Patients receiving higher accumulative anthracycline doses and those with abnormal FS during the treatment period are at higher risk of having reduced cardiac function 12 months after treatment. High sensitivity troponin and NT-Pro BNP levels during the treatment period fail to discriminate patients at risk of developing early reduced systolic function. The relationship of these early results to long term cardiac function remains to be demonstrated.

Current Possibilities of Early Detection of Cardiotoxicity of Cytostatic Treatment.

Due to growing long-term survival rate of oncologic patients, there is increased interest in cardiotoxicity of oncologic treatment among medical professionals. It is concerning both paediatric and adult patients. When prescribing oncologic treatment, there should be focus on the efficacy and safety of the used drugs. Nowadays, the main problem is early dia-gnosis of cardiotoxicity. In our work we wanted to investigate whether the increase in bio-markers after the cytostatic therapy with anthracyclines can predict further increase in the left ventricular volume and decrease of the left ventricular ejection fraction. We were monitoring 36 patients with the dia-gnosis of non-Hodgkins lymphoma who received therapy with anthracyclines. After the therapy we were measuring the cardiac bio-markers NT-proBNP and high-sensitivity troponin I and performed echocardiography. In our group of patients there is a statistically significant correlation between increased levels of troponin I, NT-proBNP and increment of the left ventricular volume measured before the treatment and 3 months after the treatment. There is also a significant inverse correlation between the left ventricular volume and left ventricular ejection fraction. There was no relationship between higher cumulative doses of anthracyclines and the increment of the left ventricular volume. There is a significant correlation between higher cumulative doses of anthracyclines and higher levels of troponin I. The measurement of bio-markers troponin I and NT-proBNP should be considered for an early dia-gnosis of cardiotoxicity in oncologic patients. Echocardiography is also beneficial for the dia-gnosis in these patients. All efforts after the dia-gnosis should be focused on the therapy with cardioprotective drugs, which can prevent the development of severe heart failure.

Critical Illness and Cardiac Dysfunction in Anthracycline-Exposed Pediatric Oncology Patients.

To determine if the presence of cardiac dysfunction in anthracycline-exposed pediatric oncology patients is associated with an increased frequency of PICU admission or mortality. Retrospective parallel cohort study. PICU at an academic freestanding children's hospital. Children with oncologic diagnoses who received anthracyclines between January 2006 and December 2014 and were admitted to the hospital within 1 year of completion of therapy. None. Charts of 734 patients were reviewed and 545 were included in analysis. Anthracycline-exposed pediatric oncology patients with cardiac dysfunction were more likely to be admitted to the PICU than those without cardiac dysfunction (87% vs 37% rate of PICU admission). PICU admission was also associated with identified infection and higher cumulative anthracycline dose. Once admitted to the PICU, those anthracycline-exposed patients with cardiac dysfunction had significantly higher mortality (26% vs 6%) and longer length of stay (7 vs 2 d) than children without cardiac dysfunction. Patients with cardiac dysfunction were more likely to require mechanical ventilation (59% vs 18%), required more vasoactive medications for longer, and were more likely to develop fluid overload. Death within 1 year of ICU admission was associated with higher cumulative anthracycline dose. Children with cancer who received anthracyclines, especially at higher doses, and who develop cardiac dysfunction are at higher risk of critical illness, have higher rates of multiple organ dysfunction and higher rates of mortality than anthracycline-exposed patients without cardiac dysfunction.

Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL

AbstractPediatric acute promyelocytic leukemia (APL) can be cured with all-trans retinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 109/L or ≥10 × 109/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m2 and 405 mg/m2, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients (P = .002 and P = .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov as EudractCT 2008-002311-40.

Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy - a retrospective study including 32 patients.

BackgroundAnthracyclines, as the most effective therapy, are the cornerstone of advanced stage sarcoma treatment. However, anthracyclines can also contribute to myocardial dysfunction and congestive heart failure, ultimately limiting the therapeutic potential of the drug. Coadministration of Dexrazoxane has been shown to effectively reduce cardiotoxicity, however primarily in patients suffering in diseases other than sarcoma.MethodsThe aim of this retrospective analysis was to evaluate safety and efficacy of chemotherapy with high cumulative doses of anthracyclines in combination with Dexrazoxane. The medical charts of 32 patients treated in four institutions were analyzed. Reasons for coadministration were rechallenge, reaching the cumulative anthracycline dose and preexisting heart failure.ResultsThe median age was 54 years [18–68 years]. The median cumulative anthracycline dose before adding DRZ was 450 mg/m2 and after administration of last anthracycline containing therapy 750 mg/m2. Either during treatment or follow up, 2/27 patients (7 %) without preexisting major cardiac findings developed anthracycline-induced cardiotoxicity. The median overall survival (OS) from start of the first anthracycline containing chemotherapy was 46 months and 17 months from the initial coadministration of DRZ. At rechallenge, the median progression free survival (PFS) with DRZ was 7 months. In continuous therapy, the median PFS was 13 months from beginning of chemotherapy and 9 months from the addition of DRZ.ConclusionChemotherapy with high cumulative doses of anthracyclines in addition with DRZ demonstrated a remarkable OS in these advanced disease patients. Cardiac side-effects due to high cumulative doses of anthracyclines requiring discontinuation of anthracycline treatment were rare. A PFS of 9 months from the beginning of the coadministration of DRZ indicates that continuing anthracycline therapy beyond established cumulative doses is a promising therapeutic option.

Alveolar rhabdomyosarcoma after treatment of osteosarcoma

Secondary rhabdomyosarcoma (RMS) after treatment of osteosarcoma (OS) is rare. Reported here is the case of a metachronous RMS in the nasal cavity, developing 12 years after successful treatment of non-metastatic OS. The patient was diagnosed as having OS of the femur at 2 years of age. Chemotherapy for OS included doxorubicin (cumulative dose, 488 mg/m(2) ). No radiotherapy was given. There was no family history suggestive of cancer predisposition syndrome. At 14 years of age, alveolar RMS was diagnosed on histopathology. PAX3-FKHR fusion transcripts were detected on reverse transcription-polymerase chain reaction. Germline TP53 mutation was not seen on standard DNA sequencing. The occurrence of secondary sarcomas, in the Children's Cancer Survivor study conducted in North America, has been associated with high cumulative doses of anthracyclines, which may also have played a role in the development of RMS in the present case. In the future, novel molecular technologies might uncover genetic cancer predisposition in patients with metachronous cancers.

Defining late onset occult asymptomatic cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy: a cardiac magnetic resonance imaging study

Background There are over 270,000 childhood cancer survivors in the US. Of these survivors, more than 50% have been treated with anthracyclines and are at risk of developing progressive cardiotoxicity. Novel cardiac magnetic resonance imaging (CMRI) techniques are now able to reliably detect diffuse myocardial fibrosis and changes in regional myocardial function. We hypothesized that these novel CMRI techniques will identify occult asymptomatic cardiotoxicity in a cohort of childhood cancer survivors with normal global systolic function. Methods Twenty seven long-term childhood cancer survivors between 11.8-28.8 years with a cumulative dose >240mg/ m2 (mean 363±89) and normal systolic function (SF>29%) were studied 2.4-24 years after exposure to anthracycline therapy. Patients underwent CMRI techniques to characterize changes in T1 relaxation time, left ventricular myocardial peak circumferential and longitudinal strain parameters and were analyzed using the 17-segment model. Extracellular volume (ECV) was measured in 13 subjects all of whom were late gadolinium enhancement (LGE) negative. We performed standard CMRI assessment and quantification of myocardial mass, end-systolic and end-diastolic volumes, ejection fraction, and end systolic fiber stress. Results Twenty seven of 60 planned subjects have been imaged. End systolic fiber stress was significantly increased with higher cumulative anthracycline dose (R2=0.18, p<0.03) and younger age at diagnosis (R2=0.20, p<0.02). Lower average circumferential strain magnitude (ecc) and regional changes in peak circumferential strain were seen in multiple segments despite n ormal values of global systolic function by echocardiography and CMRI (Figure1). T1 maps are depicted in Figure 1. The mean T1 values of the myocardium were not significantly different between patients and controls at 4 min (375±67ms vs.389±36, p<0.07) and 10 min (433±52 ms vs.435±36, p<0.39), but were significantly lower at 20 minutes (455±50ms vs. 487 ±44, p<0.003) (Figure 2). Low myocardial T1 at 20 minutes was significantly associated with increases in end systolic fiber stress (R2=0.7, p<0.002). Higher mean ECV was observed in patients with cumulative dose ≥400mg/m2 (0.27 vs. 0.21, p<0.05). Conclusions

Anthracycline Causes Impaired Vascular Endothelial Function and Aortic Stiffness in Long Term Survivors of Childhood Cancer

Vascular and endothelial functions were investigated in long term survivors of childhood cancer exposed to anthracycline treatment. We enrolled 96 long-term survivors (57 males and 39 females, mean age 14.9 ± 5.3 year) of different childhood cancers and 72 age-, sex-, bodyweight- and blood pressure matched controls (39 males and 33 females, mean age 13.7 ± 4.9 year). Aortic stiffness was characterized by echocardiography. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD%) and nitrate-mediated dilatation (NTG%). Results were compared between three subgroups: anthracycline treated, only chemotherapy treated and control subgroups. The cumulative anthracycline dose was less than 350 mg/m². The healthy control subgroup had a significantly greater FMD response (13.13 ± 2.40 %), and lower stiffness index (2.08 ± 0.6) than both the anthracycline (7.12 ± 6.28 % and 6.45 ± 3.25, respectively) and only chemotherapy treated (10.17 ± 4.23 % and 4.12 ± 2.32, respectively) subgroups. In the anthracycline treated subgroup a significantly (p < 0.01) lower FMD% response, and higher stiffness index were detected than in the only chemotherapy treated subgroup. Higher triglyceride level, higher cumulative anthracycline dose and lower age at the start of treatment were found to be associated independently with impairment of FMD% response and aortic stiffness. We found a significant negative correlation between FMD and aortic stiffness (p < 0.001) and a positive correlation between FMD and distensibility (p < 0.0001). Childhood cancer long term survivors exposed to anthracycline treatment exhibit a marked preclinical vasculopathy, characterized by endothelial dysfunction and increased arterial stiffness, contributing to a deteriorated cardiovascular function.

Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients

Anthracyclines play a major role in chemotherapeutic regimens for a variety of pediatric cancers, but produce undesirable dose-related cardiotoxicity. Dexrazoxane reduces early myocardial injury during anthracycline treatment, but data remain insufficient to fully understand its cardioprotective effectiveness in treating pediatric cancers and additional research is necessary to find efficient methods of dexrazoxane administration. Therefore, we retrospectively evaluated the cardioprotective effect of dexrazoxane against anthracyclines in 258 pediatric cancer patients who had received any anthracyclines from January 1997 to May 2005 at a tertiary teaching hospital in Korea. The results of this study suggest that the early use of dexrazoxane protects against the development of cardiotoxicity during anthracycline treatment in pediatric cancer patients. Further studies involving larger pediatric cancer patients are needed to evaluate the cardioprotective effect of dexrazoxane at higher cumulative doses of anthracyclines and on late-onset cardiotoxicity in long-term survivors.

Cardiotoxicity in childhood cancer survivors: strategies for prevention and management.

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.

Selenium in the Prevention of Anthracycline-Induced Cardiac Toxicity in Children with Cancer

High cumulative doses of anthracyclines (300–500 mg/m2) used in the treatment of children with cancer may result in cardiotoxicity, a major long-term adverse effect that limits clinical usefulness of this class of chemotherapeutic agents. We assessed anthracycline-induced cardiotoxicity by measuring Pro-BNP levels and echocardiographic (ECHO) findings and investigated potential protective effect of selenium (Se) supplementation in a group of pediatric cancer patients. Plasma level of Pro-BNP was measured, and ECHO was performed in 67 patients (45 boys, 22 girls; ages 2–18 years; median age 12 years) after they completed anthracycline-containing chemotherapy. Serum Se level was measured in 37 patients. Eleven patients had high Pro-BNP levels and/or cardiac failure with Pro-BNP levels of 10–8,022 pg/mL (median 226.3 pg/mL; laboratory normal level is less than 120 pg/mL). Serum Se levels were low (20–129 mcg/L, median 62 mcg/L) in ten of these eleven patients. Eight of 10 patients with low Se and high Pro-BNP levels were supplemented with Se 100 mcg/day for a period of 4–33 months (median 6 months) which resulted in improvement in Pro-BNP and/or ECHO findings. These results suggest that Se supplementation may have a role in protection against anthracycline-induced cardiac toxicity.

Abnormal cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation

Clinical cardiac complications in oncologic patients may develop from subclinical myocardial damage. Biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T (cTnT) have been hypothesized to reflect preclinical cardiotoxicity earlier than echocardiography. The aim of this study was to assess prospectively the serial values of these cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-one patients who were treated with allogeneic HSCT for acute leukemia at mean age of 32.8 years (range: 19-58) were studied. The conditioning regimen included high-dose cyclophosphamide in combination with total body irradiation (TBI) or busulphan. All patients were treated with anthracyclines earlier (median cumulative dose 250 mg/m, range: 150-580). Cardiomarkers were measured before the preparative regimen (PR) and on days 1, 14 and 30 after HSCT. Their cardiac systolic function was assessed before PR, and 1-2 months after HSCT by echocardiography. The differences in NT-proBNP before PR and after HSCT were statistically significant (p<0.001). The values of cTnT before and after HSCT were also significantly different (p=0.005). Persistent abnormalities (30 days after HSCT) of NT-proBNP levels were found in 19/21 patients (90.5 %) and of cTnT levels in 10/21 patients (47.6 %). The median cTnT concentrations were higher in patients treated with TBI than in patients without TBI (p=0.013). The median NT-proBNP values were higher in patients pretreated with higher cumulative doses of anthracyclines (>250 mg/m vs ≤250 mg/m) Cardiac symptoms developed in 3/21 (14.3 %) patients (Tab. 1, Fig. 3, Ref. 36).

Body mass index and annual increase of body mass index in long-term childhood cancer survivors; relationship to treatment

PurposeEvaluation of body mass index (BMI) at final height (FH) and annual BMI increase in adult childhood cancer survivors (CCS) after treatment with anthracyclines, platinum, and/or radiotherapy.MethodsBMI (weight/height²) was calculated retrospectively from diagnosis until FH. The prevalence of underweight (BMI < 18.5 kg/m2) and overweight (BMI ≥ 25 kg/m2)/obesity (BMI ≥ 30 kg/m2) at FH was compared with age-matched controls. The association between underweight/overweight at FH and treatment was assessed by multivariate logistic regression. Annual BMI increase after treatment was assessed by multilevel analysis. Analyses were adjusted for age and underweight/overweight at diagnosis, and age at FH.ResultsAt FH the prevalence of overweight had not increased, while CCS experienced more underweight as compared to controls (14% vs. 4%, P < 0.001). Overweight at FH was associated with cranial/craniospinal radiotherapy (CRT; OR, 2.23; 95% CI, 1.17–4.26) and underweight at FH with anthracyclines > 300 mg/m2 (OR, 2.84; 95% CI, 1.33–6.06). Annual BMI increase was +0.47 (0.34–0.60) kg/m2/year. In CCS, the annual BMI increase was greater in those with CRT ≥ 30 Gy as compared with those with less or no CRT (+0.15 kg/m2/year [0.04–0.25 kg/m2/year], P = 0.008) and smaller in those with a higher cumulative anthracycline dose (−0.03 kg/m2/year [−0.05 to −0.0005 kg/m2/year] per 100 mg/m2, P = 0.046).ConclusionsAfter treatment with anthracyclines, platinum, and/or radiotherapy, CRT-treated survivors have more overweight at FH, and a greater annual BMI increase, while anthracycline-treated survivors have more underweight at FH and a lower annual BMI increase.

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.

Cardiac Function in 5-Year Survivors of Childhood Cancer

Childhood cancer survivors (CCSs) have an increased risk of morbidity and mortality. We evaluated the prevalence and determinants of left ventricular (LV) dysfunction in a large cohort of long-term CCSs treated with different potentially cardiotoxic therapies. The study cohort consisted of all adult 5-year CCSs who were treated with potentially cardiotoxic therapies and who visited our late effects outpatient clinic. Echocardiography was performed in patients who had received anthracyclines, cardiac irradiation, high-dose cyclophosphamide, or high-dose ifosfamide. Detailed treatment data were registered. Both multivariate linear and logistic regression analyses were performed. Of 601 eligible CCSs, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the LV shortening fraction (LVSF). The median overall LVSF in the whole group of CCSs was 33.1% (range, 13.0%-56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF. Vincristine sulfate was associated with a nonsignificant decrease of cardiac function (P = .07). Epirubicin hydrochloride was as cardiotoxic as doxorubicin when corrected for tumor efficacy, and daunorubicin hydrochloride seemed less cardiotoxic. A high percentage (27%) of young adult CCSs have an abnormal cardiac function. The strongest predictors of subclinical cardiac dysfunction are anthracycline dose, cardiac irradiation, and younger age at diagnosis. There is a suggestion that daunorubicin is less cardiotoxic than other anthracyclines.

Impact of treatment characteristics on response of different breast cancer subtypes: Pooled multilayer analysis of the German neoadjuvant chemotherapy trials.

501 Background: Eight German neoadjuvant chemotherapy trials including 6,625 patients with uniform protocol and outcome definitions were conducted between 1998 and 2006 with pathological complete response (pCR) as primary endpoint. Methods: We used a more sophisticated multilevel model with random effects at the level of trials and regimens to pooled individual patient data. The model fully accounted for heterogeneity between trials in pCR. The analysis was restricted to a data set of 3,332 patients from 7 trials and 12 treatment arms with complete baseline parameters and no confounding by treatment indication based on interim response. Results: pCR was associated with an increase in cycle numbers (odds ratio [OR ] 1.2 with every two additional cycles; p = 0.009), with regimens using higher cumulative anthracycline doses (≥ 300 mg/m2 doxorubicin or ≥ 450 mg/m2 epirubicin; OR 1.6; p = 0.002), regimens with higher cumulative taxane doses (≥ 400 mg/m2 docetaxel or ≥ 700 mg/m2 paclitaxel; OR 1.6; p = 0.009), and with capecitabine containing regimens (OR 1.62; p = 0.022). Concurrent trastuzumab in patients with HER2-positive tumors increased the odds of pCR 3.2fold (p < 0.001). The association of pCR with increase in cycle numbers was more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; p for interaction = 0.046). The anthracycline dose effect was pronounced in HER2-negative tumors (OR 1.61), as compared with HER2-positive tumors (OR 0.83; p for interaction p = 0.14). There was no evidence that the effect of taxane dose (p for interaction ≥ 0.64) and the effect of capecitabine (p for interaction ≥ 0.57) varied between subtypes. PCR was not different after 4, 8 or 12 trastuzumab cycles (OR per 4 cycles increase 0.97, p = 0.87) overall or in subgroups. Conclusions: We postulate that HR-positive tumors benefit more from longer neoadjuvant treatments, HER2-negative tumors more from higher anthracycline doses, triple negative tumors from short-term higher dose taxane and anthracycline based treatment, HER2-positive tumors already from a limited number of 4 trastuzumab cycles, and all subtypes from the addition of capecitabine. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Novartis, Roche, sanofi-aventis Amgen, AstraZeneca, Novartis, Roche, sanofi-aventis AstraZeneca, Roche

Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses

Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m(2)) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 +/- 4% and event-free survival (pEFS) was 73 +/- 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 +/- 8%, 98: 85 +/- 7% and 2004: 94 +/- 8%, P((logrank)) = 0.63). Seventy-five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long-term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long-term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that - combined with ATRA - a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long-term sequelae, such as cardiotoxicity in APL patients.

Exercise echocardiography in asymptomatic survivors of childhood cancer treated with anthracyclines: A prospective follow‐up study

Exercise echocardiography reveals abnormalities in asymptomatic childhood cancer survivors who previously have been treated with anthracyclines. We determined the added value of monitoring childhood cancer survivors with exercise echocardiography compared to monitoring with resting echocardiography alone to predict anthracycline-induced cardiotoxicity. Secondary aims were to evaluate change in resting cardiac function over 10 years and to determine risk factors for late cardiotoxicity. We invited a cohort of 110 originally asymptomatic anthracycline-treated childhood cancer survivors, who had undergone cardiac tests including exercise echocardiography 10.5 years earlier, for new cardiac evaluation. Each subject underwent a resting echocardiogram at both evaluations. At first evaluation a repeat echocardiogram was performed following peak exercise. Resting echocardiographic parameters were converted to z-character. Ninety-two of 110 survivors (mean anthracycline dose 307 mg/m(2), mean follow-up time from start of treatment 8.2 years at first and 18.8 years at second evaluation) were evaluated prospectively. Mean resting fractional shortening z-character (RFSz) decreased from -0.18 to -0.93. Higher cumulative anthracycline dose was a risk factor for a lower RFSz at late follow-up (P = 0.0002). Adding exercise fractional shortening (XFS) to a model containing RFSz did not improve prediction of abnormal RFSz at late follow-up. Monitoring with exercise echocardiography has no added value to monitoring with resting echocardiography alone in predicting late anthracycline-induced cardiotoxicity in childhood cancer survivors. RFSz deteriorates over time, even in originally asymptomatic patients. Previous treatment with higher cumulative anthracycline dose is the main risk factor for a lower RFSz at late follow-up.

Efficacy of Primary Systemic Chemotherapy Regimen Containing Anthracyclines with/without Taxanes in Comparison to CMF in Women with Early Breast Cancer

Neoadjuvant chemotherapy is the treatment of choice for locally-advanced breast cancer and leads to down staging and improved breast-conserving therapy (BCT) rates. While its efficacy is well established, considerably less is known about the most effective regimen.We have performed a retrospective analysis of 132 breast cancer patients who had undergone neoadjuvant chemotherapy at our institution. Patients had either received a) anthracyclines (“A”, n=35), b) anthracyclines and taxanes (“AT”, n=55), or c) neither of the two compounds (“NoA/T”, n=42). Clinical response, pathological response and survival were evaluated in each arm.While all three regimens resulted in significant tumor regression, AT was most effective with a mean tumor shrinkage of 39% (ultrasound) and 41% (mammography) (Kruskal-Wallis, p=0.004, and p=0.027). Breast conservation was achieved in 75% by AT, in 49% by A, and in 19% by NoA/T (Kruskal-Wallis, p<0.001). The treatment groups did not differ in respect to pathological complete response (pCR) (χ2-test, p=0.068), although higher cumulative anthracycline doses were predictive of pCR in multivariate analyses (p=0.022). While the mammographic but not the ultrasound-determined tumor diameter determined whether a woman underwent BCT, only an ultrasound-determined size reduction was predictive for disease-free survival (DFS) and overall survival (OS) (log rank, p=0.0093, and p=0.044, respectively). Other parameters that affected BCT rates were age (p=0.003), year of diagnosis (p=<0.001), presence of multifocal disease (p= 0.032) and the cumulative anthracycline dose (p= <0.001).While the combination of anthracyclines and taxanes is most effective in achieving clinical remission and BCT, the cumulative anthracycline dose appears most important for achieving pCR.