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Subjects:
Cardiac & Cardiovascular Systems
免疫检查点抑制剂（ICI）是靶向免疫细胞中检查点的抗体，其作用是激活先天和适应性臂的受抑制T细胞和其他细胞，从而强有力地激活免疫系统和产生性抗肿瘤免疫反应。然而，与 ICI 相关的心脏毒性已被公认为一种罕见但致命的后果。尽管基于不同类型的ICI进行了广泛的研究，但这些研究尚未表明心脏毒性是否对一种类型的癌症具有特异性。
- immune checkpoint inhibitors
- cardiotoxicity
- cardio-oncology
- cancer-type-specific
1. Introduction
Cardiovascular disease (CVD) and cancer are global health issues with high morbidity and mortality [1], and numerous studies suggest that there is an overlap in epidemiology, risk factors, and pathophysiologic processes (Figure 1) .
Figure 1. (a) Risk factors for CVD and cancer; (b) Common pathophysiologic processes of CVD and cancer.
With the widespread application of anticancer drugs, the survival of patients has significantly improved, but the related cardiotoxicity affects long-term therapeutic outcomes, and this has attracted considerable attention. Immune checkpoint inhibitors (ICIs), antibodies that target the checkpoints in immune cells, work to activate inhibited T-cells and other cells of the innate and adaptive arms, resulting in the robust activation of the immune system and productive antitumor immune responses. This new type of immunotherapy drug has significantly improved the survival of cancer patients [2][3][4]. However, their use is associated with adverse side effects involving different organs [5][6]. ICIs-related cardiotoxicity, which may develop even without a history of significant cardiac risk factors, includes myocarditis, pericarditis, heart failure, arrhythmias, and vasculitis [7]. In reported cases of adverse ICIs-related events, 6.2% were cardiac adverse events (CAEs), which can be the main determinants of quality of life and increased mortality [8][9][10].
2. Cardiotoxicity in Melanoma
In 16 studies, 24 of 6710 patients on ICIs [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] developed CAEs. This corresponded with an incidence of 0.20–4.93% in which grade 3–5 CAEs accounted for 41.7%. Commonly encountered cardiotoxicities included hypertension (50%), hypotension (16.7%), and myocarditis (8.3%). Treatment-related hypertension was linked to the application of lambrolizumab (58.3%) (PD-1). Nivolumab may have had a correlation with ICIs-related hypotension. Patients treated with a higher dose of ipilimumab, particularly 10 mg/kg × 4 doses/3 weeks, were more prone to fatal adverse events such as cardiac arrest (Table 1).
Table 1. Cardiotoxicity in melanoma.
| Author, Year | Study Type | Phase | Sample Size | Drug | Dose and Frequency | Non-CAE | CAE | Manifestation | 3–5 Grade CAE |
|---|---|---|---|---|---|---|---|---|---|
| Omid Hamid et al., 2017 [11] | Prospective study | II | 528 (178 vs. 179 vs. 171) | Pembrolizumab vs. Pembrolizumab vs. chemotherapy | 2 mg/kg/3 weeks vs. 10 mg/kg/3 weeks vs. standard dose | 528 | 0 | 0 | 0 |
| Caroline Robert et al., 2014 [12] | Prospective study | III | 418 (210 vs. 208) | Nivolumab vs. Dacarbazine |
3 mg/kg/2 weeks vs. standard dose | 308 (153 vs. 155) | 5 | Hypotension 1 vs. 4 | 0 |
| Jeffrey S Weber et al., 2015 [13] | Prospective study | III | 370 (268 vs. 102) | Nivolumab vs. ICC (Dacarbazine al) | 3 mg/kg/2 weeks vs. standard dose | 362 (181 vs. 81) | 0 | 0 | 0 |
| Paolo A Ascierto et al., 2017 [14] | Prospective study | III | 726 (364 vs. 362) | Ipilimumab | 10 mg/kg/4 doses/3 weeks vs. 3 mg/kg/4 doses/3 weeks | 514 (286 vs. 228) | 3 | Hypertension 1 vs. 0; Heart arrest 1 vs. 0; Pericarditis 1 vs. 0 | 3 |
| F Stephen Hodi et al., 2016 [15] | Prospective study | II | 142 (95 vs. 47) | Nivolumab + Ipilimumab vs. Ipilimumab + placebo | 1 mg/kg + 3 mg/kg/4 doses/3 weeks vs. 3 mg/kg + placebo/4 doses/3 weeks | 140 (94 vs. 46) | 7 | Hypotension 3 vs. 0; Ventricular arrhythmia 1 vs. 0; Ventricular tachycardia 1 vs. 0; Atrial fibrillation 1 vs. 0; Myocardial infarction 1 vs. 0 | 5 |
| Caroline Robert et al., 2015 [16] | Prospective study | III | 834 (278 vs. 277 vs. 256) | Pembrolizumab vs. Pembrolizumab vs. Ipilimumab | 10 mg/kg/2 weeks/doses vs. 10 mg/kg/3 weeks/ doses vs. 3 mg/kg/3 weeks/4 doses | 610 (221 vs. 202 vs. 187) | 4 | Hypertension 3 vs. 1 vs. 0 |
2 |
| J. Weber, M. et al., 2017 [17] | Prospective study | III | 906 (453 vs. 453) | Nivolumab vs. Ipilimumab | 3 mg/kg/4 doses/2 weeks vs. 10 mg/kg/4 doses/3 weeks | 884 (438 vs. 446) | 0 | 0 | 0 |
| J.D. Wolchok et al., 2017 [18] | Prospective study | III | 937 (313 vs. 313 vs. 311) | Nivolumab + Ipilimumab vs. Nivolumab + p vs. Ipilimumab + p p(placebo) |
1 mg/kg+3 mg/kg /3 weeks/4 doses vs. 3 mg/kg/2 weeks + placebo vs. 3 mg/kg/3 weeks/4 doses + placebo |
847 (300 vs. 279 vs. 268) | 0 | 0 | 0 |
| Jedd D Wolchok et al., 2010 [19] | Prospective study | II | 217 (73 vs. 72 vs. 72) | Ipilimumab | 10 mg/kg vs. 3 mg/kg vs. 0.3 mg/kg/3 weeks/4 doses | 115 (50 vs. 46 vs. 19) | 0 | 0 | 0 |
| Ines Pires da Silva et al., 2021 [20] | Retrospective study | NR (Not Reported) | 355 (193 vs. 162) | Ipilimumab + Nivolumab/Pembrolizumab/Atezolizumab vs. Ipilimumab | 3 mg/kg/3 weeks/4 doses + standard dose vs. 3 mg/kg/3 weeks/4 doses | 287 (163 vs. 124) | 1 (0 vs. 1) | Myocarditis 0 vs. 1 | 1 |
| Patrick Schöffski et al., 2022 [21] | Retrospective study | I/II | 255 (134 vs. 121) | LAG-3 inhibitor Ieramilimab vs. Ieramilimab + Spartalizumab |
Ieramilimab (escalating 1–15 mg/kg)/2 weeks or once/4 weeks vs. Ieramilimab + Spartalizumab q2w or q3w or q4w or Ieramilimab q2w + Spartalizumab q4w | 159 (75 vs. 84) | 0 | 0 | 0 |
| Alexander M.M. et al., 2020 [22] | Prospective study | III | 1011 (509 vs. 502) | Pembrolizumab vs. placebo | 200 mg/3 weeks for 18 doses | 235 (190 vs. 45) | 1 (1 vs. 0) | Myocarditis 1 vs. 0 | NR |
| Omid Hamid et al., 2013 [23] | Prospective study | I | 135 (57 vs. 56 vs. 22) | Lambrolizumab | 10 mg/kg/2 weeks vs. 10 mg/kg/3 weeks vs. 2 mg/kg/3 weeks | 132 (55 vs. 55 vs. 22) | 7 (2 vs. 4 vs. 1) | Hypertension (2 vs. 4 vs. 1) | NR |
| Margaret K. et al., 2018 [24] | Retrospective study | I | 94 (53 vs. 41) | Ipilimumab + Nivolumab Nivolumab (Niv) Ipilimumab (Ipi) |
Niv+Ipi(escalating doses)/3 weeks for four doses, followed by Niv 3 weeks for four doses, then Niv + Ipi/12 weeks for eight doses vs. Niv 1 mg/kg + Ipi 3 mg/kg/3 weeks for 4 doses, followed by Niv 3 mg/kg/2 weeks |
87 | 0 | 0 | 0 |
| Ulrich Keilholz et al., 2019 [25] | Prospective study | I | 51 | Avelumab | 10 mg/kg for one-hour intravenous infusion/2 weeks | 39 | 0 | 0 | 0 |
| Hussein A et al., 2022 [26] | Retrospective study | II-III | 714 (355 vs. 359) | Relatlimab + Nivolumab vs. Nivolumab | Relatlimab 160 mg + Nivolumab 480 mg vs. Nivolumab 480 mg | 504 (288 vs. 216) | 0 | 0 | 0 |
3. Cardiotoxicity in Lung Cancer
A total of 11 studies [27][28][29][30][31][32][33][34][35][36][37] included 5404 patients on ICIs, and 101 developed CAEs for an incidence of 0.15–37.78% in which grade 3–5 CAEs accounted for 55.4%. Commonly encountered cardiotoxicities included arrhythmia (32.7%), cardiac-related chest pain (24.8%), elevated cTnI or myocarditis (23.8%), cardiomyopathy (20.8%), pericardial disease (11.9%), and acute coronary syndrome (10.9%). One study indicated that major adverse cardiovascular events (MACEs) were dose-independent of nivolumab and pembrolizumab in lung cancer patients [27]. Those treated with a higher dose of durvalumab, particularly 10 mg/kg × 4 doses/2 weeks, were more prone to fatal adverse events such as a cardiac arrest and cardiogenic shock [31]. One patient treated with pembrolizumab at 10 mg/kg for 3 weeks underwent a myocardial infarction, which led to death (Table 2) [33].
| Author, Year | Study Type | Phase | Sample Size | Drug | Dose and Frequency | Non-CAE | CAE | Manifestation | 3–5 Grade CAE |
|---|---|---|---|---|---|---|---|---|---|
| 卡利安R等人，2019[27] | 回顾性研究 | 星期日 | 252 （117 与. 135） | Non-ICI vs. ICI （Nivolumab/Pembrolizumab） Nivolumab （Niv） Pembrolizumab （Pem） |
标准剂量与增加剂量（Niv < 540 mg;540~1440 mg;> 1440 mg Pem < 600 mg;600~1707 mg;>1707 mg） | 星期日 | 93 （42 与. 51） | 心律失常 31 vs. 25;心脏相关胸痛 12 vs. 25;瓣膜性心脏病4 vs. 2;心肌病13 vs. 20;心包疾病11;心包疾病8;心肌炎1;瓣膜病2;静脉动脉血栓栓塞事件 8 | 40（主要 CAE） |
| 斯科特N等人，2015[28] | 前瞻性研究 | 我 | 129 （33 对 37 对. 59） | 尼沃鲁单抗 | 1 mg/kg vs. 3 mg/kg vs. 10 mg/kg，静脉使用/2 周，8 周周期，最长 96 周。 | 91 （21 与. 25 与. 45） | 0 | 0 | 0 |
| Tony S K Mok et al.， 2019[29] | 前瞻性研究 | 第三 | 1251 （636 与. 615） | 彭布利珠单抗与铂类化疗 | 200毫克/3周，最多35个周期，而铂类化疗4至6个周期。 | 1112 （515 与. 597） | 1 （1 与 0） | 心肌炎 1 vs. 0 | 1 |
| Achim Rittmeyer et al.， 2017[30] | 前瞻性研究 | 第三 | 1187 （609 与. 578） | 阿替利珠单抗 vs. 多西他赛 | 1200毫克/3周对比75毫克/米2/3 周 | 886 （390 与. 496） | 0 | 0 | 0 |
| S.J. Antonia et al.， 2017[31] | 前瞻性研究 | 第三 | 718 （475 与. 234） | 杜瓦鲁单抗 vs. 安慰剂 |
10 毫克/公斤/2 周，最长 12 个月，与 安慰剂相比 |
421 （301 与. 120） | 26 （21 与. 5） | ACS 9 对 2;心律失常 7 对 1;心力衰竭 7 vs. 0;心脏骤停 2 vs. 1;心源性休克1对0;心肌病1 vs. 0;心肌炎 0 vs. 1;心包积液 2 vs. 0 | 星期日 |
| 石岳全等， 2021[32] | 观察性研究 | 星期日 | 1905 （1162 对 743） （598 对 455 对 273 对 176 对 125 对 81 对 62 对 34 对 23） |
仅 ICI（Pembrolizumab/Nivolumab/Camrelizumab/Treprizumab/Tisilizumab/Atezolizumab/Durvalumab/Ipilimumab）仅与联合治疗 | 至少一剂 | 647 | 22 （22 与. 0） | cTnI 升高或心肌炎 22 | 9 |
| Roy S Herbst et al.， 2016[33] | 前瞻性研究 | 二/三 | 991 （339 与. 343 与. 309） | 彭布罗利珠单抗 vs. 多西他赛 | Pem 2毫克/千克，Pem 10毫克/千克与多西紫杉醇75毫克/米2/3 周 | 690 （215 与. 225 与. 250） | 1 （0 对 1 对 1） | 心肌梗死 0 对 1 对 0;急性心力衰竭 0 vs. 0 vs. 1 | 1 |
| Martin Reck et al.， 2016[34] | 前瞻性研究 | 第三 | 304 （154 与. 150） | 彭布利珠单抗与铂 类化疗 |
200 毫克/3 周与标准剂量相比 | 52 （45 与. 7） | 0 | 0 | 0 |
| H. Borghaei et al.， 2015[35] | 前瞻性研究 | 第三 | 555 （278 与. 268） | 尼沃鲁单抗 vs. 多西他赛 | 3 毫克/千克/2 周对比 75 毫克/米2/3 周 | 432 （196 与. 236） | 3 （3 与. 0） | 心脏压塞 1 vs. 0;心包积液 1 vs. 0 心动过速 1 vs. 0 |
3 |
| Julie Brahmer et al.， 2015[36] | 前瞻性研究 | 第三 | 272 (135:137) | 尼沃鲁单抗 vs. 多西他赛 | 3 毫克/千克/2 周对比 75 毫克/米2/3周。 | 187 （76 与. 111） | 0 | 0 | 0 |
| D.P. Carbone et al.， 2017[37] | 前瞻性研究 | 第三 | 530 （267 与. 263） | 尼沃鲁单抗与化疗（铂类） | 3毫克/ kg / 2周与标准剂量相比，六个周期。 | 431 （188 与. 243） | 2 （2 与. 0） | 心肌梗死 1 vs. 0;心包积液恶性 1 vs. 0 | 2 |
4. 肾细胞癌的心脏毒性
在七项研究中[38][39][40][41][42][43][44]包括1971名ICIs肾细胞癌患者，14名开发CAE，发病率为0.20-2.19%，其中3-5级CAE占35.7%。常见的心脏毒性包括高血压（85.7%）和心肌炎（7.1%）。治疗相关的高血压与纳武鲁单抗加伊匹利单抗治疗（100%）有关。与黑色素瘤和肺癌相比，ICI治疗在肾细胞癌中引起轻度心脏毒性。未发现致命的 CAE。
5. 尿路上皮癌的心脏毒性
在七项研究中[45][46][47][48][49][50][51]在接受ICI治疗的2550名尿路上皮癌患者中，有111例发展为CAE，发病率为0.22-10.60%，其中3-5级CAE占52.3%。常见的心脏毒性包括高血压（28.8%），心律失常（14.4%）和低血压（6.3%）。血压的波动与阿替珠单抗治疗有关。21例患者出现高血压，7例患者应用atezolizumab后出现低血压。用200mg pembrolizumab治疗3周（最多35个周期）或每3周以1200mg治疗的患者更容易发生致命的不良事件，如心脏骤停。
6. 其他类型癌症的心脏毒性
在血液系统恶性肿瘤中，最常遇到的与ICIs相关的心脏毒性类型是高血压[52][53][54][55].在其他癌症中，如肝细胞癌和恶性胸膜间皮瘤，相关研究并未提出很多病例。[56][57][58][59][60][61];这些几乎都是心肌炎的病例报告[62][63][64].
This entry is adapted from the peer-reviewed paper 10.3390/jcdd9070203
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