免疫检查点抑制剂治疗肿瘤的不良反应及管理策略

免疫检查点抑制剂（immune checkpoint inhibitors，ICPIs）是现今备受关注的肿瘤治疗新方法，其拓宽了肿瘤传统治疗的边界，开启了肿瘤免疫治疗的新时代。与传统化疗药物相比，其在显著延长患者生存期（overall survival，OS）的同时减轻了免疫相关不良反应（immune-related adverse events，irAEs）。由于ICPIs全新的作用机理，且上市时间较短，其不良反应尚未有标准化的处理方案。随着免疫治疗在临床上的广泛应用，irAEs日益获得关注。本文旨在对irAEs的处理原则予以综述，为ICPIs在临床上的安全应用提供理论依据。      

前瞻性临床研究中基于免疫检查点抑制剂治疗不可切除肝细胞癌的不良反应:系统综述和Meta分析

目的:调查不可切除肝细胞癌(HCC)患者使用免疫检查点抑制剂(ICIs)单药或联合治疗时不良反应发生率和不良反应谱。方法:该研究方案预先在国际前瞻性系统评价注册系统注册(CRD42022319255)。检索PubMed、Embase和Cochrane Library数据库自建库至2022年4月22日发表的临床试验。纳入至少包括一组接受ICIs单药或基于ICIs联合治疗的不可切除HCC患者,且报告了治疗相关不良反应(trAEs)发生率、trAEs谱或免疫相关AEs(irAEs)发生率、irAEs谱的研究。以所有级别和≥3级的trAEs发生率、trAEs谱作为主要研究结局。irAEs概况、导致治疗中止和治疗相关死亡的trAEs发生率作为次要研究结局。以随机效应模型分析汇总AEs发生率、AEs谱。研究中也开展了亚组分析和Meta分析。结果:系统检索共识别出2 464条记录。20项研究(4 146例HCC受试者)符合纳入标准。所有级别trAEs、≥3级trAEs、所有级别irAEs、≥3级irAEs的汇总发生率分别为80.1%(95%CI为73.8～85.2)、35.4%(95%CI为27.2...     

真实世界中免疫检查点抑制剂导致免疫相关不良反应病例分析

目的:探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）导致的免疫相关不良反应（immune-related adverse events,irAEs）的发生情况。方法:收集并分析2018年1月至2021年3月我院irAEs的具体情况,包括基本资料、用药情况、不良反应具体情况、治疗情况等。结果:63例irAEs,包括肺毒性3例、肝脏毒性9例、皮肤毒性23例、内分泌毒性15例、神经毒性4例、肾毒性3例、胃肠毒性1例、心脏毒性2例、血液毒性1例、眼毒性2例。男性47例,女性16例,中位发病年龄61岁,不良反应中位发生时间6.6周,17例需要大剂量糖皮质激素治疗。毒性级别1-2级49例,3-4级13例,5级1例。少见irAEs 14例,1例死于心肌炎。结论:irAEs涉及的器官或系统较多,多数在3级以下。常见不良反应预后较好。少见irAEs中,心肌炎可能导致患者死亡,需要临床予以重视。     

免疫相关中毒性表皮坏死松解症一例及文献复习

随着免疫检查点抑制剂(ICI)在临床越来越广泛的应用,ICI治疗使肿瘤患者临床获益的同时,也会出现一些免疫相关不良反应。本文报道了1例晚期肺鳞癌男性患者使用替雷利珠单抗治疗后致免疫相关性皮肤毒性——史蒂文斯-约翰逊综合征(SJS)/中毒性表皮坏死松解症(TEN),主要表现躯干和四肢皮肤皮疹、红斑、瘙痒、脱皮等,经治疗后好转。通过复习替雷利珠单抗相关不良反应的文献,进一步分析了替雷利珠单抗所致皮肤毒性的临床特点和治疗方法,为提高免疫治疗药物临床应用的安全性提供了参考。     

外周血标志物对晚期非小细胞肺癌免疫相关不良反应的预测作用及与生存结局的相关性分析

目的 探讨NLR、PLR和LDH检测对晚期非小细胞肺癌(NSCLC)发生免疫相关不良反应(irAEs)的预测作用,并分析其与生存结局的相关性。方法 回顾性分析2017年1月1日—2021年1月1日在潍坊市人民医院接受PD-1/PD-L1抑制剂治疗的169例晚期NSCLC患者临床资料,将169例患者分为irAEs组(n=61)和非irAEs组(n=108),比较两组临床资料,绘制ROC曲线确定基线外周血参数预测irAEs发生的临界值,多因素logistic回归分析外周血标志物与irAEs发生的关系,使用Cox回归模型分析无进展生存期(PFS)和总生存期(OS)的影响因素。结果 irAEs组患者的基线外周血NLR、PLR较非irAEs组低,LDH较非irAEs组高(P<0.05);治疗前NLR、PLR、LDH预测irAEs发生的最佳临界值分别为3.18(AUC=0.80)、181.56(AUC=0.62)和209.50(AUC=0.63),多因素logistic回归分析显示低NLR和高LDH是irAEs发生的独立危险因素(P<0.05);低NLR组、低PLR组和低LDH组的PF...     

TNF-α抑制剂在免疫检查点治疗中的应用研究进展

免疫检查点抑制剂显著提高了晚期恶性肿瘤患者的预后,但同时也会出现由免疫系统激活引起的脱靶毒性,即免疫相关的不良事件（irAEs）。严重的irAEs将导致免疫治疗暂时或永久性终止,极大影响了其在临床中的应用。目前临床上处理irAEs 主要应用糖皮质激素,一方面严重的不良反应对患者身体造成严重的损害,另一方面大量应用糖皮质激素影响了免疫检查点抑制剂的疗效。近年来TNF-α抑制剂在减轻不良反应等方面取得了较好的效果,本文就TNF-α在防治irAEs应用进展作一综述。     

恶性肿瘤患者免疫检查点抑制剂导致肝损伤的临床处理2例

免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）作为一种新的抗肿瘤药物,目前在临床的使用日益广泛。然而,ICIs过度激活的免疫系统会攻击人体正常器官,引起相关的免疫不良反应,这种免疫损伤可以累及身体的各个部位,引起相应的症状,被称之为ICIs相关不良反应（immunocheckpoint inhibitors related adverse effects,irAEs）。肝损伤作为irAEs其中一种,临床治疗是以糖皮质激素为主,但是对于≥3级以上肝损伤的治疗以及出现激素耐药后的解救治疗仍会让临床医生感到棘手。本研究分析2例经免疫治疗后出现肝损伤的案例,包括激素敏感型1例,激素耐药型1例,后经免疫球蛋白解救治疗成功。      

免疫检查点抑制剂所致胃肠道不良反应的机制及治疗对策

近年来免疫检查点抑制剂已成为恶性肿瘤免疫治疗的热点,临床应用广泛,已使多种晚期恶性肿瘤患者受益.同时,治疗过程中出现的免疫相关不良事件(irAEs)也明显增多,其中最常见的是胃肠道irAEs.由于临床上对胃肠道irAEs认识不足或重视不够,导致相关死亡事件发生.全文综述胃肠道irAEs的临床表现、形成机制、诊断及治疗策...     

抗PD-1/PD-L1疗法致免疫相关不良反应机制及预测标志物的研究进展

抗程序性细胞死亡受体-1(programmed cell death protein-1,PD-1)和抗程序性死亡受体配体-1(programmed cell death ligand-1,PD-L1)是目前广泛使用的免疫检查点抑制剂,在肿瘤免疫治疗方面取得了巨大的成就,但同时也导致免疫相关不良反应(immune-related adverse events, irAEs),严重者甚至会导致患者死亡。因此,明确irAEs的发生机制,提早预测irAEs非常重要。本文由细胞、免疫系统、个体水平层面对抗PD-1/PD-L1疗法致irAEs的发生机制进行了总结,并从一般临床特征、免疫细胞因素、细胞因子相关、基因表达结果等方面汇总了irAEs的预测指标。     

免疫检查点抑制剂相关内分泌不良反应的研究进展

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）作为癌症治疗领域最重要的进展，为癌症患者带来新的希望。ICIs主要针对细胞程序性死亡受体-1（programmed cell death receptor-1，PD-1）、程序性死亡配体-1（programmed death-ligand 1，PDL1）以及细胞毒性T淋巴细胞相关蛋白-4（cytotoxic T-lymphocyte antigen-4，CTLA-4）。随着使用ICIs增加，越来越多的免疫相关不良反应（immune-related adverse effects，irAEs）被报道，其中内分泌腺体的累及尤为常见。这些irAEs的发病机制不完全明确，临床表现复杂，需要得到临床医生的充分重视。本文就ICIs作用机制及irAEs中的内分泌相关不良反应的研究进展作一综述，归纳总结其现有发病机制研究、流行病学及临床表现。      

Predictors of Chemotherapy Induced Adverse Events in Pediatric Osteosarcoma Patients

Objective: To investigate the prevalence of chemotherapy-induced adverse events and the associated risk factors in pediatric patients with osteosarcoma. Methods: This retrospective cross-sectional study enrolled 90 pediatric osteosarcoma patients (with 1,017 chemotherapy cycles) treated at Srinagarind Medical Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand, between January 1, 2008 and December 31, 2018. The prevalence of major adverse events and a correlation between baseline characteristics and adverse events were analyzed using a generalized estimating equation model. Result: The prevalence of adverse events in 90 pediatric osteosarcoma patients (with 1,017 chemotherapy cycles) was determined as chemotherapy-induced nausea and vomiting (29.2%; n=296), hepatotoxicity (21.2%; n=215), anemia (70.69%; n=719), neutropenia (26.65%; n=271), and thrombocytopenia (13.65%; n=139). Factors associated with chemotherapy-induced hepatotoxicity included methotrexate dose ≥ 12 g/m2 (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.22–1.39; P<0.001), plasma concentration of methotrexate at 72 hours >0.1 μM (OR 1.22; 95% CI 1.19–1.25; P<0.001), and pre-hydration rate ≤ 125 mL/m2/h (OR 1.10; 95% CI 1.07–1.12; P<0.001). Conclusion: Major adverse events are becoming more common in pediatric osteosarcoma patients, and risk factors include larger chemotherapy doses, higher plasma methotrexate concentrations, and a slower pre-hydration rate. The outcomes of the study could aid in the better treatment of toxicity in children with osteosarcoma.     

Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma

Background

Ipilimumab is a novel FDA-approved recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 and has been used to treat patients with metastatic melanoma. Immune-related neurological adverse effects include inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis–type syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy. To date, there is no report for ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), or concurrent myositis and myasthenia gravis–type syndrome. Our objective is to raise early recognition of atypical neurological adverse events and to share our therapeutic approach.

Methods

We report 3 cases of metastatic melanoma treated with ipilimumab in which the patients developed CIDP, TM, and concurrent myositis and myasthenia gravis–type syndrome, respectively, at the MD Anderson Cancer Center between July 2012 and June 2013. Patients consented to release of medical information for publication/educational purposes.

Results

Our 3 cases of metastatic melanoma treated with ipilimumab developed CIDP, TM, and concurrent myositis and myasthenia gravis–type syndrome, respectively. The median time to onset of immune-related adverse events following ipilimumab treatment ranged from 1 to 2 weeks. Ipilimumab was discontinued due to the severe neurological symptoms. Plasmapheresis was initiated in the patients with CIDP and concurrent myositis and myasthenia gravis–type syndrome; high-dose intravenous steroids were given to the patient with TM, and significant clinical response was demonstrated.

Conclusions

Ipilimumab could induce a wide spectrum of neurological adverse effects. Our findings support the standard treatment of withholding or discontinuing ipilimumab. Plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipilimumab-related neurological adverse events. Improvement of neurological symptoms may be seen within 2 weeks.     

Indications for salvage surgery during treatment for intracranial germ cell tumors

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.     

肿瘤免疫治疗引起的常见免疫不良事件及相关问题总结分析

免疫检查点抑制剂在某些恶性肿瘤治疗中带来令人瞩目的成果，为癌症的研究和治疗方案的发展开辟了一个新的时代。随着越来越多地使用这类药物，广泛的免疫相关不良事件随之产生，甚至部分患者被迫终止治疗，影响预后，这引起了研究者们的密切关注，由于免疫相关不良事件的发生机制尚不明确，所以现阶段暂无公认有效的控制途径。本文综述了免疫检查点抑制剂治疗中常见的相关不良事件，对重点问题总结分析，以期尽早做出诊断及处理，提高患者生存率。     

索拉菲尼治疗肝癌常见不良反应及处理的研究进展

索拉菲尼是一种口服多激酶抑制剂。通过作用于Raf激酶直接抑制肿瘤细胞增殖,还可作用于血管内皮生长因子受体1,2,3（VEGFR-1, -2, -3）,以及血小板源生长因子受体-β（PDGFR-β）、受体酪氨酸激酶、抑制肿瘤新生血管生成。索拉菲尼通过抑制肿瘤细胞增殖和抗血管生成的双重作用,从而达到抗肿瘤的目的。已被多个国家批准作为首个系统治疗肝细胞肝癌的分子靶向药物。其常见不良反应包括皮肤反应、恶心、腹泻、体质量减轻、高血压等,影响了患者的长期使用依从性,进而影响治疗效果。正确地认识和管理索拉非尼的不良反应则有助于发挥索拉非尼的治疗作用,提高临床效果。本文从索拉菲尼靶向治疗的常见不良反应、发生机制及处理方法等方面进行综述。      

Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion

Interferon-alpha-2b (IFNalpha2b) is the only effective adjuvant therapy for melanoma patients at high risk of recurrence that has been approved by regulatory authorities worldwide. However, IFN toxicities increase the risk of poor treatment compliance and impair the potential for benefit from this agent. A review of the literature demonstrated little recent attention to supportive care in the management of IFN toxicities. An international group of experts with extensive personal experience in the use of IFNs worked together to develop practical guidelines for the use of IFNs. Practical recommendations were developed for patient education on the use of IFN; initial patient assessment and monitoring, including contraindications to the use of IFN, monitoring and managing adverse events, and IFN dose modification and discontinuation; IFN injection procedures; treatment of elderly patients; and use during pregnancy and nursing. Successful adjuvant therapy of melanoma with high-dose IFN requires close compliance with the treatment regimen. Recommendations for the recognition and management of adverse events are designed to enable more patients to complete the full planned course of treatment.     

Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-��2a compared with sunitinib

Background:

Bevacizumab plus interferon-α2a (IFN) prolongs progression-free survival to >10 months, which is comparable with sunitinib as first-line treatment of metastatic renal cell carcinoma (RCC). The two regimens have different tolerability profiles; therefore, costs for managing adverse events may be an important factor in selecting therapy.

Methods:

Costs of managing adverse events affecting patients with metastatic RCC eligible for treatment with bevacizumab plus IFN or sunitinib were evaluated using a linear decision analytical model. Management costs were calculated from the published incidence of adverse events and health-care costs for treating adverse events in the United Kingdom, Germany, France and Italy.

Results:

Adverse event management costs were higher for sunitinib than for bevacizumab plus IFN. The average cost per patient for the management of grade 3–4 adverse events was markedly lower with bevacizumab plus IFN compared with sunitinib in the United Kingdom (€1475 vs €804), Germany (€1785 vs €1367), France (€2590 vs €1618) and Italy (€891 vs €402). The main cost drivers were lymphopaenia, neutropaenia, thrombocytopaenia, leucopaenia and fatigue/asthaenia for sunitinib; and proteinuria, fatigue/asthaenia, bleeding, anaemia and gastrointestinal perforation for bevacizumab plus IFN.

Conclusion:

The costs of managing adverse events are lower for bevacizumab plus IFN than for sunitinib. The potential for cost savings should be considered when selecting treatments for RCC.     

Cutaneous adverse events in lung cancer patients on the therapy based on PD-1/PD-L1 inhibitors: A prospective observational cohort study

AimThis is a prospective study of cutaneous adverse events (CAEs) in lung cancer patients treated by programmed cell death-1(PD-1) inhibitors and programmed cell death-ligand 1(PD-L1) inhibitors-based single or combination therapy.Patients & methodsIt were included that lung cancer patients who developed CAEs from January 2019 to July 2021 after applying PD-1/PD-L1 inhibitors in our institution.ResultsA total of 107 patients with 112 CAEs were enrolled, of which 71 patients received PD-1/PD-L1 inhibitors plus chemotherapy, 31 patients received PD-1/PD-L1 inhibitors plus anti-angiogenic/targeted therapy, and 5 patients received PD-1/PD-L1 inhibitors monotherapy. The median time to CAEs onset was 8.7w (0.3w-70.7w) for PD-1/PD-L1 inhibitors plus chemotherapy, 10.1w (0.4w-103.0w) for PD-1/PD-L1 inhibitors plus anti-angiogenic/targeted therapy, and 13.6w (0.7w-50.6w) for PD-1/PD-L1 inhibitors monotherapy. The most common CAEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (30.8%, 33/107), followed by eczematous (21.5%, 23/107) and pruritus only (15.9%, 17/107). 7 patients (6.5%, 7/107) had grade 3-4 CAE.ConclusionMost CAEs are mild to moderate and easily controlled. Early diagnosis and intervention for CAEs are important.