PD-L1 inhibitors-induced hypophysitis in a patient with small cell lung cancer: a case report and literatures review

Abstract

Abstract:

This paper reports a case of immune-related hypophysitis (irH) after 7 cycles of treatment with Duva-lizumab, a PD-L1 (programmed cell death-ligand 1) inhibitor in a patient with small cell lung cancer. The patient showed fatigue, anorexia, hypotension, with lower serum levels of adrenocorticotropic hormone (ACTH) (3.8 ng/L) and thyroid stimulating hormone（TSH）(0.266 μIU/mL) than those before treatment (48 ng/L, 4.64 μIU/mL). The patient′s condition gradually improved with hydrocortisone replacement treatment. PubMed, Wanfang, and CNKI databases were searched.A total of 316 cases have been reported in recent 10 years, including 10 cases with irH caused by PD-1/PD-L1 in 84 lung cancer patients, mainly manifested as fatigue, anorexia, weight loss, and hypotension. Compared with cytotoxic T lymphocyte associated protein 4 antibody blocker treatment, the incidence of PD-1/PD-L1 induced-irH is low, and onset of irH is later. Pituitary MRI images mostly showed no abnormality. However, the condition of the patients was often critical or even life-threatening, which need to pay attention to.

Key words:Programmed cell death-ligand 1 inhibitor,Small cell lung cancer,Immune-related hypophysitis

CLC Number:

R735

ZHANG Meiling, ZHU Xiaobang, SHONG Ailing, ZHOU Jianping, LI Qingyun. PD-L1 inhibitors-induced hypophysitis in a patient with small cell lung cancer: a case report and literatures review[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(06): 741-745.

Figures/Tables3

检测项目	ICI治疗前	irH确诊时	糖皮质激素治疗irH 20 d	糖皮质激素停药15 d	参考值
垂体-肾上腺轴激素皮质醇（nmol/L）
8 AM	406.0	39^a）	148.5	224.5	133~537
4 PM	402.1	37.8^a）	/		68.2~327
0 AM	400.6	39.6^a）	/	258.4	/
促肾上腺皮质激素（ACTH）（ng/L）
8 AM	48	3.8^a）	2.89^a）	<1.0^a）	7.2~63.3
4 PM	/	1.72^a）	/	2.46^a）	5.0~40.0
0 AM	/	1.52^a）	/	1.19^a）	5.0~10.0
垂体-甲状腺轴激素
促甲状腺激素（TSH）（μIU/mL）	4.64	0.266^a）	3.71	0.948	0.27~4.2
总甲状腺素（TT₄）（nmol/L）	78.29	59.48^a）	80.44	53.16^a）	66~181
三碘甲状腺原氨酸（TT₃）（nmol/L）	1.38	0.632^a）	1.01^a）	1.00^a）	1.3~3.1
游离甲状腺素（FT₄）（pmol/L）	13.56	10.68^a）	16.79	13.41	12.0~22.0
游离三碘甲状腺原氨酸（FT₃）（pmol/L）	14.92	2.44^a）	2.99^a）	2.61^a）	3.1~6.8
垂体-性腺轴激素
黄体生成素（LH）（mIU/mL）	/	19.31^a）	/	5.05	1.24~8.62
卵泡刺激素（FSH）（mIU/mL）		39.19^a）		22.45	2.64~13.13
泌乳素（PRL）（ng/mL）		0.55^a）		11.23	2.64~13.13
孕酮（P）（ng/mL）		0.03^a）		0.05^a）	0.14~2.06
睾酮（T）（ng/mL）		2.29		0.61^a）	1.75~7.81
雌二醇（S）（pg/mL）		17.91		22.36	15~38.95

参考文献	年龄（岁）	性别	诊断	使用药物	发生时间	临床症状	MRI 表现	激素及电解质水平									激素恢复情况
参考文献	年龄（岁）	性别	诊断	使用药物	发生时间	临床症状	MRI 表现	ACTH	F	TSH	FT₄	FSH/LH	GH	PRL	钠	钾	激素恢复情况
[ 15 ]	69	女	ADE	Nivolumb	16周	乏力、纳差	前叶萎缩，垂体高度2.2 mm	↓	↓	↓	↑	-	-	-	-	-	NA
[ 16 ]	75	男	ADE	Nivolumb	26周	乏力、纳差、低血压	垂体无明显异常	↓	↓	↑	-	-	-	↓	-	-	TSH、PRA 恢复，ACTH 未恢复
[ 17 ]	63	男	ADE	Nivolumb	15周	纳差、乏力、低血压、发热	垂体无明显异常	↓	↓	-	-	-	-	-	↓	-	NA
[ 18 ]	58	女	SCLC	Nivolumb+ ipilimab	6周	头痛、恶心呕吐、纳差	垂体增大1.5 cm，垂体柄增粗4 mm	↓	↓	↓	-	↓	-	↑	-	-	NA
[ 19 ]	65	男	NSCLC	Atezolizumab	56周	乏力、纳差	垂体前叶萎缩	↓	↓	-	-	-	-	-	-	-	24个月后 ACTH 未恢复
[ 19 ]	70	男	NSCLC	Atezolizumab	54周	乏力、纳差	垂体无明显异常	↓	↓	-	-	↑	-	-	-		13个月后 ACTH 未恢复
[ 20 ]	55	男	NSCLC	Nivolumab	66周	乏力、体重下降	垂体无明显异常	↓	↓	↓	↑	-	-	-	-	-	TSH恢复
[ 21 ]	59	男	NSCLC	Pembrolizumab	16周	乏力、纳差、发热	垂体无明显异常	↓	↓	↑	↓	-	-	-	↓	-	NA
[ 22 ]	79	男	SCC	Nivolumab	20周	乏力、纳差、低血压	垂体无明显异常	↓	↓	-	-	-	-	-	↓	-	ACTH恢复
[ 23 ]	61	男	SCLC	Nivolumab	13周	乏力、纳差、低血压	垂体无明显异常	↓	↓	-	-	↑	-	↑	-	-	10个月 ACTH未恢复

References28

[1]	Shen K, Cui J, Wei Y, et al. Effectiveness and safety of PD-1/PD-L1 or CTLA4 inhibitors combined with chemotherapy as a first-line treatment for lung cancer: a meta-analysis[J]. J Thorac Dis, 2018, 10(12):6636-6652. doi:10.21037/jtd.2018.11.72pmid:30746209
[2]	Pacheco J, Bunn P A. Advancements in small-cell lung cancer: The changing landscape following IMpower-133[J]. Clin Lung Cancer, 2019, 20(3):148-160. doi:S1525-7304(18)30356-5pmid:30686680
[3]	Ouyang T, Cao Y, Kan X, et al. Treatment-related serious adverse events of immune checkpoint inhibitors in clinical trials: a systematic review[J]. Front Oncol, 2021, 11:621639. doi:10.3389/fonc.2021.621639 URL
[4]	Park R, Lopes L, Cristancho C R, et al. Treatment-rela-ted adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis[J]. Front Oncol, 2020, 10:258. doi:10.3389/fonc.2020.00258 URL
[5]	Zhai Y, Ye X, Hu F, et al. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system[J]. J Immunother Cancer, 2019, 7(1):286. doi:10.1186/s40425-019-0754-2pmid:31694698
[6]	Di Dalmazi G, Ippolito S, Lupi I, et al. Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment[J]. Expert Rev Endocrinol Metab, 2019, 14(6):381-398. doi:10.1080/17446651.2019.1701434pmid:31842671
[7]	Mizukoshi T, Fukuoka H, Takahashi Y. Immune checkpoint inhibitor-related hypophysitis[J]. Best Pract Res Clin Endocrinol Metab, 2022, 36(3):101668. doi:10.1016/j.beem.2022.101668 URL
[8]	Bernhardt E B, Jalal S I. Small cell lung cancer[J]. Cancer Treat Res, 2016, 170:301-322. doi:10.1007/978-3-319-40389-2_14pmid:27535400
[9]	Li LY, Wang H, Chen X, et al. First-line atezolizumab plus chemotherapy in treatment of extensive small cell lung cancer: a cost-effectiveness analysis from China[J]. Chin Med J (Engl), 2019, 132(23):2790-2794.
[10]	Ott P A, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study[J]. J Clin Oncol, 2017, 35(34):3823-3829. doi:10.1200/JCO.2017.72.5069pmid:28813164
[11]	Peng M, Li X, Lei G, et al. The efficacy and safety of immune checkpoint inhibitor combination therapy in lung cancer: a systematic review and meta-analysis[J]. Onco Targets Ther, 2018, 11:7369-7383. doi:10.2147/OTT URL
[12]	Ready N, Farago A F, De Braud F, et al. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032[J]. J Thorac Oncol, 2019, 14(2):237-244. doi:S1556-0864(18)33181-2pmid:30316010
[13]	Horn L, Mansfield A S, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J]. N Engl J Med, 2018, 379(23):2220-2229. doi:10.1056/NEJMoa1809064 URL
[14]	Kanie K, Iguchi G, Bando H, et al. Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome[J]. Cancer Immunol Immunothe, 2021, 70(12):3669-3677. doi:10.1007/s00262-021-02955-y
[15]	Ohara N, Kobayashi M, Ohashi K, et al. Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the literature[J]. J Med Case Rep, 2019, 13(1):88. doi:10.1186/s13256-019-2002-2
[16]	Takaya K, Sonoda M, Fuchigami A, et al. Isolated adrenocorticotropic hormone deficiency caused by nivolumab in a patient with metastatic lung cancer[J]. Intern Med, 2017, 56(18):2463-2469. doi:10.2169/internalmedicine.8548-16 URL
[17]	Mishima Y, Fukaishi T, Inase N, et al. Nivolumab-induced hypophysitis, secondary adrenal insufficiency and destructive thyroiditis in a patient with lung adenocarcinoma[J]. Intern Med. 2019 Mar 1;58(5):693-697.
[18]	Valecha G, Pant M, Ibrahim U, et al. Immunotherapy-induced autoimmune hypophysitis[J]. J Oncol Pharm Pract, 2019, 25(1):217-220. doi:10.1177/1078155217727142pmid:28825378
[19]	Kanie K, Iguchi G, Bando H, et al. Two cases of atezolizumab-induced hypophysitis[J]. J Endocr Soc, 2017, 2(1):91-95. doi:10.1210/js.2017-00414 URL
[20]	Martins Machado C, Almeida Santos L, Barroso A, et al. Nivolumab-induced hypothyroidism followed by isolated ACTH deficiency[J]. BMJ Case Rep, 2019, 12(8):e231236. doi:10.1136/bcr-2019-231236 URL
[21]	Yamagata S, Kageyama K, Takayasu S, et al. Progression of hypopituitarism and hypothyroidism after treatment with pembrolizumab in a patient with adrenal metastasis from non-small-cell lung cancer[J]. Intern Med, 2019, 58(24):3557-3562. doi:10.2169/internalmedicine.3008-19 URL
[22]	Sato Y, Tanaka Y, Hino M, et al. A case of nivolumab-induced isolated adrenocorticotropic hormone (ACTH) deficiency[J]. Respir Med Case Rep, 2019, 26:223-226. doi:10.1016/j.rmcr.2019.01.021pmid:30740300
[23]	Zhu Y, Wu HH, Wang W. A case of small-cell lung cancer with adrenocorticotropic hormone deficiency induced by nivolumab[J]. Onco Targets Ther, 2019, 12:2181-2186. doi:10.2147/OTT URL
[24]	Fernandes S, Varlamov E V, Mccartney S, et al. A novel etiology of hypophysitis: immune checkpoint inhibitors[J]. Endocrinol Metab Clin North Am, 2020, 49(3):387-399. doi:10.1016/j.ecl.2020.05.002 URL
[25]	中华医学会内分泌学分会免疫内分泌学组. 免疫检查点抑制剂引起的内分泌系统免疫相关不良反应专家共识(2020)[J]. 中华内分泌代谢杂志, 2021, 37(1):1-16.
	Immune-endocrinology Group, Chinese Society of Endocrinology, Chinese Medical Association. Chinese expert consensus on the immune checkpoint inhibitors-induced endocrine immune-related adverse events (2020)[J]. Chin J Endocrinol Metab, 2021, 37(1):1-16.
[26]	Paschou S A, Stefanadi K, Psaltopoulou, et al. How we treat endocrine complications of immune checkpoint inhibitors[J]. ESMO Open, 2021, 6(1):100011. doi:10.1016/j.esmoop.2020.100011 URL
[27]	Shaverdian N, Lisberg A E, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial[J]. Lancet Oncol, 2017, 18(7):895-903. doi:S1470-2045(17)30380-7pmid:28551359
[28]	España S, Pérez Montes de OCA A, Marques-pamies M, et al. Endocrine adverse events related to immune-onco-logy agents: retrospective experience of a single institution[J]. Transl Lung Cancer Res, 2020, 9(1):103-110. doi:10.21037/tlcr URL