Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial.
Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial.
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DOI：
10.1158/1078-0432.ccr-20-4592
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Tap WD
中科院分区：
文献类型：
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作者：
Jones RL;Wagner AJ;Kawai A;Tamura K;Shahir A;Van Tine BA;Martín-Broto J;Peterson PM;Wright J;Tap WD
很少有前瞻性研究评估肉瘤患者蒽环类药物相关的心脏毒性。我们在3期ANNOUNCE试验（NCT02451943）中评估了给予阿霉素的软组织肉瘤患者的心脏毒性。患者为anthracycline-naïve患有局部晚期或转移性疾病且左室射血分数(LVEF)≥50%的成年人。患者可接受8个周期75 mg/m2的阿霉素治疗。心脏保护剂右拉唑烷可由研究者自行决定。使用MedDRA记录症状性心脏不良事件（ae），并使用CTCAE 4.0分级。通过超声心动图或多路采集扫描测量LVEF恶化，定义为下降到<50%，或从基线值下降10%。504例患者接受了≥1个周期的阿霉素治疗（中位累积剂量，450.3 mg/m2[范围，72.3-634.0]）。心脏ae的中位随访时间为28周。接受较高阿霉素累积剂量的患者更频繁地联合使用右razoxane(38.6%接受<450 mg/m2, 88.5%接受450 - <600 mg/m2, 90%接受≥600 mg/m2)，且不影响治疗效果。累积剂量<450 mg/m2的患者有62/153（40.5%）出现LVEF恶化，450 - <600 mg/m2的患者有82/159(51.6%)，≥600 mg/m2的患者有50/89（56.2%）。≥3级心功能障碍发生率在<450 mg/m2组为2%，450 - <600 mg/m2组为3%，≥600 mg/m2组为1.1%。在所有剂量范围内，与治疗相关的心脏不良事件的发生率都很低。虽然随访时间较短，但这些结果表明，在与右唑嗪共给药的情况下，阿霉素可以以高累积剂量（450mg /m2）施用，心脏毒性发生率低。
Few prospective studies have assessed anthracycline-associated cardiotoxicity in sarcoma patients. We evaluated cardiotoxicity in patients with soft tissue sarcomas administered doxorubicin in the Phase 3 ANNOUNCE trial (NCT02451943). Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive 8 cycles of doxorubicin at 75 mg/m2. The cardioprotectant dexrazoxane was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using MedDRA and graded using CTCAE 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%. 504 patients received ≥1 cycles of doxorubicin (median cumulative dose, 450.3 mg/m2 [range, 72.3–634.0]). Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was co-administered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450 – <600 mg/m2, 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62/153 (40.5%) who received a cumulative dose <450 mg/m2, 82/159 (51.6%) who received 450 – <600 mg/m2, and 50/89 (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m2, 3% at 450 – <600 mg/m2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs were low across all dose ranges. Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane co-administration.