University of Miami, Leonard M Miller School of Medicine, Miami, FL, USA.
Lancet Oncol. 2010 Oct;11(10):950-61. doi: 10.1016/S1470-2045(10)70204-7. Epub 2010 Sep 16.
Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment.
Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087.
100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99).
Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys.
US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
多柔比星化疗会导致心肌病。在接受急性淋巴细胞白血病（ALL）治疗的儿童中，地拉佐辛可减少多柔比星治疗期间的心脏损伤。我们旨在确定地拉佐辛在多柔比星治疗结束后 5 年对高危 ALL 儿童幸存者心脏健康亚临床状态的长期影响。
1996 年 1 月至 2000 年 9 月，美国、加拿大和波多黎各的 9 个中心招募了高危 ALL 患儿。患儿按区组随机分配接受 10 剂 30mg/m² 多柔比星单独治疗或相同剂量的多柔比星加 300mg/m² 地拉佐辛。通过致电中央登记处获得治疗分配，以掩盖分配情况。调查人员对治疗分配情况不知情，但治疗医生和患者知情；然而，调查人员、医生和患者对研究血清心肌肌钙蛋白 T 浓度和超声心动图测量结果不知情。主要终点是通过超声心动图评估的晚期左心室结构和功能异常；分析包括所有治疗完成后有数据的患者。该试验已经完成，并在 ClinicalTrials.gov 上注册，编号为 NCT00165087。
100 例患儿被分配至多柔比星组（66 例可分析），105 例患儿被分配至多柔比星加地拉佐辛组（68 例可分析）。多柔比星化疗完成后 5 年，与仅接受多柔比星治疗的患儿相比，左心室短轴缩短分数和收缩末期内径 Z 评分明显更差（左心室短轴缩短分数：-0.82，95%CI -1.31 至 -0.33；收缩末期内径：0.57，0.21-0.93），但与同时接受地拉佐辛治疗的患儿相比并无差异（左心室短轴缩短分数：-0.41，-0.88 至 0.06；0.15，-0.20 至 0.51）。与仅接受多柔比星治疗相比，地拉佐辛对左心室壁厚度（组间差异：0.47，0.46-0.48）和厚度与内径比（0.66，0.64-0.68）的保护作用在 5 年后具有统计学意义。亚组分析显示，在女孩中，地拉佐辛在 5 年时具有保护左心室短轴缩短分数的作用（1.17，0.24-2.11），但在男孩中没有（-0.10，-0.87 至 0.68）。同样，亚组分析显示，在女孩中，地拉佐辛在 5 年时具有保护左心室厚度与内径比的作用（1.15，0.44-1.85），但在男孩中没有（0.19，-0.42 至 0.81）。中位随访时间为复发和死亡的 8.7 年（范围 1.3-12.1），多柔比星组患儿的无事件生存率为 77%（95%CI 67-84），多柔比星加地拉佐辛组患儿的无事件生存率为 76%（67-84）（p=0.99）。
地拉佐辛在不影响高危 ALL 患儿肿瘤疗效的情况下，提供了长期的心脏保护作用。地拉佐辛对女孩的长期心脏保护作用大于男孩。
美国国立卫生研究院、儿童心肌病基金会、迈阿密大学妇女癌症协会、兰斯阿姆斯特朗基金会、罗氏诊断公司、辉瑞公司和诺华公司。
