New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.
New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.
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DOI：
10.1186/s13054-017-1678-1
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发表时间：
2017-04-14
期刊：
影响因子：
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通讯作者：
Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group
中科院分区：
文献类型：
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作者：
Kroschinsky F;Stölzel F;von Bonin S;Beutel G;Kochanek M;Kiehl M;Schellongowski P;Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group
癌症的药理学和细胞治疗正在发生巨大变化，不仅对患者的结局和舒适度有利，而且还具有新的毒性特征。大多数不良事件可归类为轻度或中度，但也会发生需要ICU入院的严重和危及生命的并发症。本综述将根据现有文献重点介绍这些事件的病理生理学、症状和管理。虽然标准的抗病毒治疗与免疫抑制和感染有关，但最近的一些方法会诱导压倒性的炎症和自身免疫。细胞因子释放综合征（CRS）描述了一种复杂的症状，包括发热、低血压、皮肤反应以及实验室异常。CRS可在输注靶向免疫效应物和肿瘤细胞的单克隆或双特异性抗体（MAB、BAB）后发生，并且也是嵌合抗原受体（CAR）修饰的T淋巴细胞的接受者的主要问题。BAB和CAR T细胞治疗也可能受到中枢神经系统（CNS）毒性的影响，如脑病、小脑改变、意识障碍或癫痫发作。虽然已知CRS由极高水平的炎性细胞因子诱导，但CNS事件的病理生理学仍不清楚。用抗体治疗抑制免疫检查点可导致免疫相关不良事件（IRAE）;结肠炎，腹泻和内分泌失调通常是ICU入院的原因。呼吸窘迫是癌症患者ICU治疗的主要原因，在大多数情况下可归因于感染因子。此外，据报道，一些新药会引起非感染性肺部并发症。虽然在大量接受磷酸肌醇-3-激酶抑制剂治疗的患者中观察到药物诱导的间质性肺炎，但IRAE也可能影响肺部。血管生成途径的抑制剂增加了药物组合。然而，血管形成对于再生和组织修复也是必不可少的。因此，严重的血管副作用，包括血栓栓塞事件、胃肠道出血或穿孔、高血压和充血性心力衰竭，会损害抗肿瘤疗效。由于对与新癌症药物相关的危及生命的并发症的病理生理学和管理知识有限，需要为ICU工作人员、肿瘤学家和器官专家提供基于证据的算法。
Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature. While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions. Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs. Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy. The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.