概述
儿童肿瘤主要分为血液肿瘤和实体肿瘤两大类。儿童血液系统恶性肿瘤是一类起源于造血系统的肿瘤性疾病,严重地威胁儿童及家庭的身心健康。《国家儿童肿瘤监测年报(2022)》显示:2019-2020我国儿童肿瘤平均发病率为125.72/百万,前三位疾病中两种为血液系统恶性肿瘤即白血病和淋巴瘤[1]。按照儿童肿瘤的年龄标化发病率:我国儿童白血病发病率为35.6/百万,淋巴瘤6.4/百万,尤以急性白血病更多见。儿童恶性实体肿瘤主要包括神经母细胞瘤、横纹肌肉瘤、骨肿瘤、肾母细胞瘤、肝母细胞瘤、颅外生殖细胞瘤、视网膜母细胞瘤以及脑肿瘤等。这些肿瘤通常具有生长迅速、侵袭性强和易转移等的特点,对儿童的健康和生命造成严重威胁。规范儿童肿瘤疾病诊治流程,进一步提高疗效,改善患儿生存质量,是关系到肿瘤患儿生存及生活质量的重大民生问题。
近年来,随着医学技术的不断进步,儿童肿瘤的诊断和治疗取得了长足进展。神经母细胞瘤作为婴儿最常见的肿瘤和儿童常见肿瘤,其治疗策略已经从传统的手术、化疗和放疗逐渐转向针对特定靶点和基因突变的免疫治疗和靶向治疗。同时,肾母细胞瘤、肝母细胞瘤、脑肿瘤等其他恶性实体瘤的诊断和治疗也取得了重要突破,使得患儿的生存率和生存质量得到了显著提高。国内多中心临床试验的开展和高水平研究结果的发表,也显著提高了我国儿童血液肿瘤疾病的诊疗水平。
在诊断与疾病分类方面,随着病理学、影像学和分子生物学技术的不断进步,儿童恶性肿瘤的病理分型和诊断准确性得到了显著提高。这为精准医疗的实施提供了有力支持,使得治疗方案更加个性化和精准化。
在全球范围内,针对儿童恶性肿瘤的研究持续深入,新靶点的发现和新药物的开发不断取得突破。这些进展为改善患儿的生存率和生存质量提供了更多可能性。但仍存在一系列亟待解决瓶颈问题,如区域诊疗水平尚存在很大差异,难治/复发肿瘤缺乏规范治疗方案,新药及新型免疫治疗应用的适应症及最佳时机等仍有待于进一步商拓。
本报告旨在概述儿童常见恶性肿瘤的病种、特性、治疗策略的演进以及未来的发展方向。通过深入总结这一领域的最新进展和挑战,为患儿提供更加有效的治疗方案和更好的生存机会。
5. 2024年中国儿童肿瘤学科十大前沿进展(新成果、新技术、大事记)
(1)全国儿童肿瘤发病情况监测报告
儿童恶性肿瘤已经成为除意外伤害外 造成儿童死亡的第二大原因。此前,我国儿童癌症登记处获得的儿童癌症发病率和相关卫生服务的可及性仍然未知。2023年9月23日,首都医科大学附属北京儿童医院倪鑫院长在顶刊《柳叶刀》[96]杂志上发表了首个针对我国儿童和青少年癌症发病率和卫生服务可及性现状的横断面研究,第一次发布了中国儿童青少年肿瘤发病情况,填补了中国儿童肿瘤发病国际数据库空白。该研究使用了来自国家儿童癌症监测中心、全国医院质量监测系统和公共数据库的数据,涵盖了中国大陆31个省、自治区和直辖市。通过分层比例估计了中国儿童(0-14岁)和青少年(15-19岁)的癌症发病率。该研究证实从2000年到2015年,中国儿童和青少年的癌症负担远高于之前全国报道的水平。作为健康的社会决定因素,卫生服务可及性的分布可能在中国儿童和青少年癌症发病率的社会经济不平等中发挥显著作用。在实现可持续发展目标方面,政策方针应优先考虑增加早期诊断保健服务的可及性,以改善结果并随后减轻疾病负担,并缩小儿童和青少年癌症的社会经济不平等。
(2)NTRK融合儿童肿瘤精准诊疗进展
神经营养酪氨酸受体激酶(neurotrophic receptor tyrosine kinase,NTRK)融合在儿童肿瘤的发生率显著高于成人,基因融合是许多儿童肿瘤的重要特征之一,NTRK融合基因作为“钻石靶点”,TRK抑制剂在儿童实体瘤患者中显示出快速、持久、安全、有效的特性。拉罗替尼及恩曲替尼均为一代口服TRK抑制剂,已在中国上市。研究数据显示。中国抗癌协会小儿肿瘤专业委员会于2023年出版《拉罗替尼治疗 TRK 融合儿童肿瘤中国专家共识》,旨在为中国儿科医师应用拉罗替尼提供规范指导,并为进一步开展相关临床研究提供思路[97]。中山大学肿瘤防治中心张翼鷟教授团队于2023年9月在国际顶尖肿瘤学期刊《肿瘤学年鉴》(Annals of Oncology)[98] 正式发表了关于儿童肿瘤患者对拉罗替尼的耐药机制的探索研究(影响因子为50.5)。本研究的创新性在于:1)儿童患者中首次发现off-target耐药;2)儿童患者中首次发现MAPK通路激活导致拉罗替尼耐药;3)首次发现拉罗替尼新的耐药机制的基因改变形式:EGFR扩增、BRAF新的变异形式:BRAF/CREB3L2重排、intergenic/BRAF重排、BRAF-exon9_exon18扩增。
(3)儿童急性早幼粒细胞白血病减化疗、去化疗新策略的建立和推广应用
为建立儿童急性早幼粒细胞白血病(APL)诊疗新策略、改善儿童APL预后及生活质量,通过前瞻性多中心研究(CCLG-APL2016方案),建立了儿童APL的精准、分层治疗临床路径,证实了新治疗策略的有效性,并填补了砷剂在儿童APL药代动力学方面的空白。此外,该研究简化了APL的治疗方法,开创了新型家庭治疗模式,节约了医疗资源及成本。研究成果得到了国际认可,并被发表在行业内高水平期刊《Journal of Clinical Oncology》杂志(IF:45.3)上。目前,该项目已在全国69家医院推广应用,使近600余例APL患儿受益,为中国儿童APL的总体治疗效果做出了贡献。
(4)急性T细胞淋巴细胞白血病克隆演化模式及耐药新机制
2024年中国医学科学院血液病医院儿童血液病诊疗中心竺晓凡教授团队利用单细胞多组学技术解析了儿童T细胞型急性淋巴细胞白血病(T-ALL)的白血病克隆演化存在2种类型的克隆演化模式:即主克隆发生改变的克隆“更替(Shift)”和同一主克隆持续存在但转录特征改变的克隆“漂移(Drift)”。揭示了克隆演化过程中RNA结合蛋白MSI2通过调控癌基因MYC表达诱导化疗耐药,MSI2高表达与化疗耐药及化疗后偏高水平的微小残留病密切相关。体外药理模型和小鼠体内实验表明,MSI2功能抑制剂(Ro 08-2750)与T-ALL诱导及巩固化疗中重要的细胞毒药物柔红霉素和阿糖胞苷具有显著的协同作用,Ro 08-2750联合化疗药物,能够延缓白血病细胞的体内扩增并显著延长白血病模型小鼠生存时间,该发现为儿童T-ALL靶向治疗联合化疗克服耐药及复发提供了新思路[99]。
(5)小儿实体肿瘤无血无瘤器官保存手术理论与技术创新及应用
儿童肿瘤主要是胚胎性肿瘤,发生于腹膜后和后纵隔,位置深入、多数发生中线区大血管的侵犯和包埋,对周围组织器官侵犯严重,就诊时往往肿瘤体积巨大,手术操作复杂、风险高,王焕民主任团队广泛借鉴成人和国外经验、深入钻研各种技术和设备、优化科学全面的术前评估和治疗方案,研究和总结出了以无血无瘤器官保存为基础的手术理论与技术;大大降低儿童肿瘤手术的风险、减少出血和死亡、更多地保留组织器官;更为重要的是,这项研究成果迅速在国内同行传播,大大推动了我国小儿肿瘤外科工作的普及和提高。本项目实施期间,10篇代表作总影响因子36.1、总他引次数112;发起或参与制订诊疗规范、指南或专家共识共16项;获得实用新型专利两项,其中微波手术刀头专利已成果转化并完成医疗器械注册,显著提高全国儿童肿瘤外科的诊疗技术水平,惠及全国各地肿瘤患儿。
(6)利用二代测序技术检测免疫球蛋白重链和轻链基因重排定量儿童B系急性淋巴细胞白血病微小残留病
2023年,浙江大学医学院附属儿童院血液肿瘤科徐晓军教授团队在国际高水平期刊 Nature Communications发表了研究论文 “Minimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL”[95]。该论文基于国内最大的利用二代测序(NGS)技术监测B系急性淋巴细胞白血病(B-ALL)微小残留病(MRD)的临床队列,确定了B-ALL化疗的不同阶段NGS-MRD危险度分层的不同阈值,显示了该方法能筛选出82%的极低危B-ALL患儿,3年无事件生存率高达96.4%;明确了该方法能发现一部分流式细胞术MRD阴性而NGS-MRD阳性的相对高危的患儿。并在国际上率先明确提出重链IGH是具有较好的预后意义,而轻链(IGK/IGL)预后价值有限的结论,对于NGS-MRD的合理应用具有重要指导意义。
(7)儿童急性早幼粒细胞白血病治疗达世界领先
中山大学附属第一医院儿科血液专科罗学群教授团队一项针对华南儿童急性早幼粒细胞白血病(APL)的多中心随机对照研究(SCCLG-APL),随访中位时间长达6年,结果显示5年无事件生存率(EFS)为97.6%,为目前国际报道中随访时间最长和EFS最高;证实口服中成药复方黄黛片(RIF)在儿童APL的疗效与静脉As2O3相当,且缩短住院时间、减少感染和心脏毒性;砷不会在儿童体内长期潴留;提示低血砷浓度使复发率增加。此结果发表在Blood Cancer Journal,影响因子12.8[100]。此外,通过一系列实验和临床研究证明:明确了RIF治疗儿童APL的合适剂量不同于成人;发现砷+ATRA使FLT3-ITD突变不是APL高危因素的机制。另一协作组CCLG-APL的研究提示诱导期加用低剂量维奈托克可减少APL的早期并发症和死亡率。这些结果为今后探索和明确儿童非高危APL无化疗方案的疗效和安全性、维奈托克的作用、血砷浓度与复发的关系以及复发的治疗等提供依据。
(8)缓解诱导第19天MRD可以改善儿童急性淋巴细胞白血病(ALL)患者的个体化治疗和结果
中国临床试验注册(ChiCTR-IPR-14005706)研究:该项研究评估了儿童急性淋巴细胞白血病(ALL)患者缓解诱导期间可测量残留病(MRD)的预后和治疗意义。在CCCG-ALL-2015方案中,7640名患者根据临床和遗传特征被分为低、中、高风险组。最终风险分级由缓解诱导第19天和第46天流式细胞术评估的MRD确定,第19天的额外强化化疗MRD≥1%。在第19天或第46天,MRD为阴性(<0.01%)的B-ALL患者的5年无事件生存期(EFS)明显优于MRD为0.01-0.99%的患者,而MRD≥1%的患者的EFS又明显优于MRD≥1%的患者。第19天MRD≥1%,但第46天MRD为阴性的临时低危患者,重新归类为中危,其5年EFS与第19天MRD为0.3-0.99%的低危患者和第46天MRD为阴性的低危患者(82.5% vs. 83.0%)相当,并且在这两天的EFS均优于临时低危MRD患者(83.0% vs. 72.6%, P<0.001)。同样,第19天MRD≥1%但第46天MRD为阴性的临时中危险B-ALL患者接受额外治疗后,与第19天MRD在0.3-0.99%之间的患者相比,其5年EFS更好(70.7%对53.0%,P<0.001)。在第46天MRD阴性的低风险患者中,第19天MRD阴性的患者比第19天MRD阳性的患者有更好的EFS(91.7%比86.1%,P<0.001)。研究结果发表于2024年《Blood》doi: 10.1182/blood.2024026381. Online ahead of print。
(9)在传统化疗基础上联合利妥昔单抗(抗CD20单克隆抗体)可以明显提高成熟B细胞非霍奇金淋巴瘤晚期病例生存率,第一次将中国儿童淋巴瘤的临床研究推向了国际舞台。
淋巴瘤是儿童时期第3位最常见肿瘤。其中又以成熟B细胞非霍奇金淋巴瘤(B-cell non-Hodgkin lymphoma, B-NHL)最常见。上海儿童医学中心牵头的CCCG-BNHL-2015方案是CCCG淋巴瘤研究小组也是国内第一个原创前瞻性多中心临床研究。该研究同样证实在传统化疗基础上联合利妥昔单抗(抗CD20单克隆抗体)可以明显提高晚期病例生存率。同时,也证明利妥昔单抗会增加化疗毒副作用并致低丙种球蛋白血症时间延长,但是通过良好的支持治疗措施,但并未增加治疗相关死亡率。不仅如此,此研究还对利妥昔单抗不良反应、儿童成熟B淋巴瘤预后不良因素以及伯基特淋巴瘤/白血病的分子生物学、临床特征及精准治疗做了多方面的研究报道,第一次将中国儿童淋巴瘤的临床研究推向了国际舞台。基于自身临床研究数据,研究小组还更新了国内儿童侵袭性[119-122]。
(10)儿童视网膜母细胞瘤研究进展
视网膜母细胞瘤(retinoblastoma)是儿童最常见的眼内恶性肿瘤,发病与双等位抑制基因Rb1突变、缺失相关,又被双等位遗传性肿瘤。虽然过去的一个世纪,Rb的生存率已经有很大的进步,但是眼球摘除率、视力丧失仍然是占非常大的比例,转移期的RB病死率高达近60%。首都医科大学附属北京同仁医院牵头成立中国抗癌协会儿童血液肿瘤分会儿童视网膜母细胞瘤(RB)协作组,针对RB开展系统的研究。研究成果《儿童视网膜母细胞瘤临床资料库建立及晚期RB诊疗体系研究》获第十二届宋庆龄儿科医学奖。自2017年参与全球视网膜母细胞瘤现况调查,就不发达国家、地区的RB发病现况和预后开展多中心研究、随访。研究成果分别发表于2020年《JMAM Oncolgy》[50]和2022年《Lancet Global Health》[49]。
【主编】
王焕民 首都医科大学附属北京儿童医院
竺晓凡 中国医学科学院血液病医院
高怡瑾 上海交通大学医学院附属上海儿童医学中心
汤永民 浙江大学医学院附属儿童医院
赵 强 天津医科大学肿瘤医院
张翼鷟 中山大学肿瘤防治中心
【副主编】
徐晓军 浙江大学医学院附属儿童医院
黎 阳 中山大学孙逸仙纪念医院
金润铭 华中科技大学同济医学院附属协和医院
高 亚 西安交通大学第二附属医院
闫 杰 天津医科大学肿瘤医院
秦 红 首都医科大学附属北京儿童医院
王 珊 重庆医科大学附属儿童医院
黄东生 首都医科大学北京同仁医院
【编委】(按姓氏拼音排序)
杨文钰 中国医学科学院血液病医院
徐 敏 上海交通大学医学院附属上海儿童医学中心
李 杰 天津医科大学肿瘤医院
成海燕 首都医科大学附属北京儿童医院
李璋琳 天津医科大学肿瘤医院
苏 雁 首都医科大学附属北京儿童医院
施诚仁 上海交通大学医学院附属新华医院
汤静燕 上海交通大学医学院附属上海儿童医学中心
殷敏智 上海交通大学医学院附属上海儿童医学中心
陈 静 上海交通大学医学院附属上海儿童医学中心
姜大朋 上海交通大学医学院附属上海儿童医学中心
吕志宝 上海交通大学医学院附属上海市儿童医院
蒋莎义 上海交通大学医学院附属上海市儿童医院
蔡娇阳 上海交通大学医学院附属上海儿童医学中心
张安安 上海交通大学医学院附属上海儿童医学中心
钟玉敏 上海交通大学医学院附属上海儿童医学中心
汪 健 苏州大学附属儿童医院
胡邵燕 苏州大学附属儿童医院
王金湖 浙江大学医学院附属儿童医院
杨 超 重庆医科大学附属儿童医院
王珍妮 重庆医科大学附属儿童医院
张 谊 首都医科大学北京同仁医院
蒋马伟 上海交通大学医学院附属新华医院
袁晓军 上海交通大学医学院附属新华医院
杨 深 首都医科大学附属北京儿童医院
郑胡镛 首都医科大学附属北京儿童医院
彭晓敏 中山大学孙逸仙纪念医院
熊稀霖 中山大学孙逸仙纪念医院
周 芬 华中科技大学同济医学院附属协和医院
段 超 首都医科大学附属北京儿童医院
阙 旖 中山大学肿瘤防治中心
朱富艺 首都医科大学附属北京儿童医院
万 扬 中国医学科学院血液病医院
靳 燕 天津医科大学肿瘤医院
沈树红 上海交通大学医学院附属上海儿童医学中心
★
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