Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review.

BACKGROUND: Anthracyclines are essential for the treatment of the children with cancer. We performed a systematic review to evaluate the existing evidence of the frequency and risk factors of anthracycline-induced clinical heart failure (A-CHF) in children. DESIGN: Medline was searched for articles reporting the frequency of A-CHF, published from 1966 to December 2000. Information about study features, risk factors and frequency were abstracted, and a validity score was given for each study. The potential predictive factors of A-CHF were analysed both within and across the studies. RESULTS: The frequency of A-CHF in children was estimated in 30 studies described in 25 articles. All studies have serious methodological limitations. The frequency varied between 0% and 16%. In the analysis across the studies the type of anthracyclines and the maximal dose in 1 week explain a considerable part of the variation of the frequency of A-CHF. CONCLUSIONS: Doxorubicin and a dose above 45 mg/m2 within 1 week seemed to increase the frequency of A-CHF. Well designed and executed studies are needed to accurately estimate the frequency of A-CHF and reliably assess the importance of potential risk factors.     

A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia

A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P  = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%; P  < 0.0001). Therefore complete remission rates were higher with idarubicin (62% v 53%; P  = 0.002). Among remitters, fewer of the patients allocated to idarubicin relapsed ( P  = 0.008) but slightly more died in remission, leading to a non-significant benefit ( P  = 0.07) in disease-free survival. Overall survival in these five trials was significantly better with idarubicin than with daunorubicin (13% v 9% alive at 5 years; P  = 0.03). There was a trend ( P  = 0.006 for remission rate) for the benefit of idarubicin over daunorubicin to decrease with increasing age. There were no significant differences in outcome in the small trial comparing idarubicin versus doxorubicin, or in the large trial comparing idarubicin versus zorubicin. The induction regimens based on idarubicin achieved, in the particular circumstances of the trials reviewed here, better remission rates and better overall survival than those based on daunorubicin.     

Monoclonal antibody–drug conjugates

This review covers cytotoxic antibody–drug conjugates for use in oncology. The focus is on drug conjugates of current interest, such as those of the taxanes, maytansines, CC-1065 and the duocarmycins, the calicheamicins and other enediynes, and the auristatins. A few classes of drug conjugates from earlier work are also mentioned, such as those of the antifolates, vinca alkaloids, and the anthracyclines. Also covered are some more recent linker systems that are useful for making antibody–drug conjugates. This review does not cover conjugates of plant toxins, other bioactive proteins, enzymes (i.e., antibody-directed enzyme prodrug therapy [ADEPT]), radioisotopes (photodynamic therapy), or conjugates made with secondary carriers for the cytotoxic agent, such as liposomes or polymers.     

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancer

Anthracyclines, including doxorubicin, are the mainstay of therapy for breast cancer. However, doxorubicin can cause dose-dependent cardiotoxicity, limiting the cumulative dose. Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues. Nonpegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity, with anti-tumor responses comparable to those of conventional doxorubicin. The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity, while allowing a higher cumulative dose. This allows patients who have already received the maximum cumulative dose of doxorubicin to receive further doxorubicin, as well as those with risk factors for anthracycline-induced cardiotoxicity. The favorable cardiac safety profile of NPLD may allow it to be combined with newer therapies, such as trastuzumab.     

NT-proBNP与CVP对蒽环类药物致心脏毒性的早期监测应用的临床意义

目的:探讨N末端原脑利钠肽前体（NT-proBNP）与中心静脉压（CVP）对蒽环类药物所致心脏毒性的早期监测及其临床意义。方法:对我院乳腺癌术后应用蒽环类化疗药物化疗的女性患者80例,在化疗前、第1、2、3个疗程结束及全程化疗结束后5个时间点,使用免疫荧光法定量测定患者血浆NT-proBNP浓度,同时对患者行深静脉穿刺置管CVP测定并记录结果。结果:NT-proBNP在第1、2、3个疗程结束及全程化疗结束时其水平与化疗前比较均有统计学意义（均P<0.05）,CVP在化疗结束时与化疗前比较有统计学意义（P<0.05）。结论:NT-proBNP联合CVP对在乳腺癌患者中应用蒽环类药物化疗致心脏毒性的早期监测有必要,加强其检测可对保护心脏功能以及判断预后有重要意义。     

Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia

AIMS

It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed ‘the inocculum effect’. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated.

METHODS

Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR.

RESULTS

A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r² = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect.

CONCLUSION

This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.     

右丙亚胺治疗蒽环类药物外渗2例疗效观察

蒽环类药物（Anthracyclines）由于其抗肿瘤谱广,疗效好,是乳腺癌、白血病、淋巴瘤、子宫癌、卵巢癌等多种恶性肿瘤的一线或基本用药,而乳腺癌大多数方案均以蒽环类药物为基础。既往化疗均为外周静脉化疗,而经外周静脉置入中心静脉导管术（ peripherally inserted central venous catheters, PICC）的开展,将很多患者从外周静脉化疗的痛苦中解脱出来,但仍然有部分病人因为经济原因、PICC 穿刺禁忌或维护不便等原因,选择外周静脉化疗。而蒽环类药物外渗一直是令医护人员倍感棘手的问题,目前还没有有效的方法解救其可能造成的毁灭性后果。欧盟及美国 FDA 分别于2006年和2007年批准右丙亚胺用于治疗葸环类药物外渗的适应症［1,2］,而国内仅见1例报道［3］。我科使用右丙亚胺治疗2例蒽环类药物外渗患者,对其疗效及安全性进行观察,报道如下。     

蒽环类药物对肿瘤患者心脏Tei指数影响的临床研究

目的探讨利用心肌做功指数(MPI,Tei指数)早期检测和评估蒽环类药物(ATC)对肿瘤患者心脏毒性的临床价值。方法用多普勒法测定46例恶性肿瘤患者ATC化疗前和化疗后3~6个月左心Tei指数,常规超声心动图EF、FS和E/A指标。结果与化疗前比较,Tei指数相关参数中ATC化疗后左心室等容舒张时间(IRT)延长,等容舒张指数(IRT/ET)增大,E/A指标降低(P<0.05)。左心室等容收缩时间(ICT),等容收缩指数(ICT/ET),EF和FS指标较化疗前无显著性差异。结论在早期评价ATC对肿瘤患者心脏功能损害方面,Tei指数、等容舒张指数是敏感的指标,E/A指标虽然在应用上有局限性,但也有一定参考意义。     

Risk Factors of Daunorubicine Induced Early Cardiotoxicity in Childhood Acute Lymphoblastic Leukemia: A Retrospective Study

Background: Daunorubicine, a type of anthracycline, is a drug commonly used in cancer chemotherapy that increases survival rate but consequently compromises with cardiovascular outcomes in some patients. Thus, preventing the early progression of cardiotoxicity is important to improve the treatment outcome in childhood acute lymhoblastic leukemia (ALL). Objective: The present study aimed to identify the risk factors in anthracycline-induced early cardiotoxicity in childhood ALL. Methods: This retrospective study was conducted by observing ALL-diagnosed children from 2014 to 2019 in Dr. Soetomo General Hospital. There were 49 patients who met the inclusion criteria and were treated with chemotherapy using Indonesian Childhood ALL Protocol 2013. Echocardiography was performed by pediatric cardiologists to compare before and at any given time after anthracycline therapy. Early cardiotoxicity was defined as a decline of left ventricle ejection fraction (LVEF) greater than 10% with a final LVEF < 53% during the first year of anthracycline administration.  Risk factors such as sex, age, risk stratification group, and cumulative dose were identified by using multiple logistic regression. Diagnostic performance of cumulative anthracycline dose was evaluated by receiver operating characteristic (ROC) curve. Results: Early anthracycline-induced cardiotoxicity was observed in 5 out of 49 patients. The median cumulative dose of anthracycline was 143.69±72.68 mg/m2. Thirty-three patients experienced a decreasing LVEF. The factors associated with early cardiomyopathy were age of ≥ 4 years (PR= 1.128; 95% CI: 1.015-1.254; p= 0.001), high risk group (PR= 1.135; 95% CI: 1.016-1.269; p= 0.001), and cumulative dose of ≥120 mg / m2 (CI= 1.161; 95% CI:1.019-1.332). Conclusion: Age of ≥ 4 years, risk group, and cumulative dose of ≥120 mg/m2 are significant risk factors for early cardiomyopathy in childhood ALL.