Clinical analysis of immune-related adverse events in gastrointestinal cancer

doi:10.3969/j.issn.1006-7795.2023.02.024

Abstract

Abstract: Objective To identify the characteristics and risk factors associated with immune-related adverse events (irAEs) in gastrointestinal cancer patients treated with immune checkpoint inhibitors (ICIs). Methods We retrospectively investigated clinical data of 95 gastrointestinal cancer patients from April 2019 to October 2021 in Peking University Cancer Hospital. The clinical characteristics and irAEs data of these patients were analyzed. Binary Logistic regression analysis was used to identify irAEs and endocrine irAEs risk factors. Results In the 95 patients enrolled, the total number and median number of ICIs treatment cycles were 458 and 3(range:1-33). The incidence of irAEs and grade 3-4 irAEs were 55.8% and 9.5%, respectively. The most common irAEs were skin irAEs (27.4%) and endocrine irAEs (22.1%). Among endocrine irAEs, hypothyroidism occurred most frequently (16.8%), while adrenocortical dysfunction (2.1%) and hypophysitis (1.1%) were rare. Most irAEs occurred in the early stage of immunotherapy, and 78.2% occurred within 12 weeks. The earlier onset irAEs were allergy and skin irAEs, with a median occurrence time of 2 weeks (range:0.9－3.1 weeks) and 3.8 weeks (range:0.9－17.9 weeks), respectively. The median onset time of endocrine irAEs was 6.9 weeks (range:3.0－52.1 weeks). Multivariate analysis revealed that female(OR=5.197,95%CI：1.166－23.154,P=0.031） and microsatellite instability-high (MSI-H）(OR=35.048, 95%CI：2.756－445.787, P=0.006）were independent risk factors of endocrine irAEs. Immunotherapy combined with chemotherapy (OR=0.107, 95%CI：0.021－0.412, P=0.001） was an independent protective factors. Conclusion The application of ICIs in patients with gastrointestinal cancer was well tolerated. Female and MSI-H patients have an increased risk of endocrine irAEs. Immunotherapy combined with chemotherapy may reduce the risk of endocrine irAEs.

Key words: gastrointestinal cancer, immune checkpoint inhibitors, immune-related adverse events

CLC Number:

R730
R735

Sun Jing, Shi Youwu, Du Feng, Yang Ying, Sun Zhiwei, Yu Jing, Xiao Yanjie, Zhang Xiaodong, Jia Jun. Clinical analysis of immune-related adverse events in gastrointestinal cancer[J]. Journal of Capital Medical University, 2023, 44(2): 343-350.

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URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2023.02.024

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2023/V44/I2/343

References

［1］Arnold M, Abnet C C, Neale R E, et al. Global burden of 5 major types of gastrointestinal cancer［Ｊ］. Gastroenterology, 2020, 159(1):335-349.e15.
［2］Vrána D, Matzenauer M, Neoral C∨, et al. From tumor immunology to immunotherapy in gastric and esophageal cancer［Ｊ］. Int J Mol Sci, 2018, 20(1):13.
［3］Hsu A, Mendelson L, Almhanna K. Immune checkpoint inhibitors in the treatment of gastrointestinal malignancies: a review of current and future therapies［Ｊ］. R I Med J (2013), 2020, 103(3):33-37.
［4］Suazo-Zepeda E, Bokern M, Vinke P C, et al. Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis［Ｊ］. Cancer Immunol Immunother, 2021, 70(11):3069-3080.
［5］Fujisawa Y, Yoshino K, Otsuka A, et al. Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab［Ｊ］. J Dermatol Sci, 2017, 88(2):225-231.
［6］Cappelli L C, Dorak M T, Bettinotti M P, et al. Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis［Ｊ］. Rheumatology (Oxford), 2019, 58(3):476-480.
［7］Tarhini A A, Zahoor H, Lin Y, et al. Baseline circulating IL-１7 predicts toxicity while TGF-β1 and IL-１0 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma［Ｊ］. J Immunother Cancer, 2015, 3: 39.
［8］Ghosh N, Chan K K, Jivanelli B, et al. Autoantibodies in patients with immune-related adverse events from checkpoint inhibitors: a systematic literature review［Ｊ］. J Clin Rheumatol, 2022, 28(2):e498-e505.
［9］Von Itzstein M S, Khan S, Gerber D E. Investigational biomarkers for checkpoint inhibitor immune-related adverse event prediction and diagnosis［Ｊ］. Clin Chem, 2020, 66(6):779-793.
［10］National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v5.0［EB/OL］. (2021-04－１9)［2021-11-29］. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
［11］Brahmer J R, Abu-Sbeih H, Ascierto P A, et al. Society forImmunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events［Ｊ］. J Immunother Cancer, 2021, 9(6):e002435.
［12］Haanen J B A G, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up［Ｊ］. Ann Oncol, 2017, 28(Suppl 4):iv119-iv142.
［13］中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)免疫检查点抑制剂相关的毒性管理指南: 2021［M］. 北京: 人民卫生出版社, 2021: 1－１66.
［14］Postow M A, Sidlow R, Hellmann M D. Immune-related adverse events associated with immune checkpoint blockade［Ｊ］. N Engl J Med, 2018, 378(2):158－１68.
［15］Khoja L, Day D, Chen T W W, et al. Tumour-and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review［Ｊ］. Ann Oncol, 2017, 28(10):2377-2385.
［16］Das S, Ciombor K K, Haraldsdottir S, et al. Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with food and drug administration-approved indications for immunotherapy［Ｊ］. Oncologist, 2020, 25(8):669-679.
［17］Arnaud-Coffin P, Maillet D, Gan H K, et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors［Ｊ］. Int J Cancer, 2019, 145(3):639-648.
［18］Eigentler T K, Hassel J C, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-１ antibody therapy［Ｊ］. Cancer Treat Rev, 2016, 45: 7－１8.
［19］Wang D Y, Salem J E, Cohen J V, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis［Ｊ］. JAMA Oncol, 2018, 4(12):1721－１728.
［20］Byun D J, Wolchok J D, Rosenberg L M, et al. Cancer immunotherapy-immune checkpoint blockade and associated endocrinopathies［Ｊ］. Nat Rev Endocrinol, 2017, 13(4):195-207.
［21］Girotra M, Hansen A, Farooki A, et al. The current understanding of the endocrine effects from immune checkpoint inhibitors and recommendations for management［Ｊ］. JNCI Cancer Spectr, 2018, 2(3):pky021.
［22］Valpione S, Pasquali S, Campana L G, et al. Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade［Ｊ］. J Transl Med, 2018, 16(1):94.
［23］Muir C A, Clifton-Bligh R J, Long G V, et al. Thyroid immune-related adverse events following immune checkpoint inhibitor treatment［Ｊ］. J Clin Endocrinol Metab, 2021, 106(9):e3704-e3713.
［24］Postow M A, Sidlow R, Hellmann M D. Immune-related adverse events associated with immune checkpoint blockade［Ｊ］. N Engl J Med, 2018, 378(2):158－１68.
［25］Maekura T, Naito M, Tahara M, et al. Predictive factors of nivolumab-induced hypothyroidism in patients with non-small cell lung cancer［Ｊ］. In Vivo, 2017, 31(5):1035－１039.
［26］Kimbara S, Fujiwara Y, Iwama S, et al. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab［Ｊ］. Cancer Sci, 2018, 109(11):3583-3590.
［27］Cortellini A, Buti S, Santini D, et al. Clinical outcomes of patients with advanced cancer andpre-existing autoimmune diseases treated with anti-programmed death-１ immunotherapy: a Real-World transverse study［Ｊ］. Oncologist, 2019, 24(6):e327-e337.
［28］Saxena P, Singh P K, Malik P S, et al. Correction to: immunotherapy alone or in combination with chemotherapy as first-line treatment of non-small cell lung cancer［Ｊ］. Curr Treat Options Oncol, 2020, 21(11):91.
［29］Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab pluschemotherapy for squamous non-small-cell lung cancer［Ｊ］. N Engl J Med, 2018, 379(21):2040-2051.
［30］Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab pluschemotherapy in metastatic non-small-cell lung cancer［Ｊ］. N Engl J Med, 2018, 378(22):2078-2092.
［31］Reck M, Rodríguez-Abreu D, Robinson A G, et al. Pembrolizumab versuschemotherapy for PD-L1-positive non-small-cell lung cancer［Ｊ］. N Engl J Med, 2016, 375(19):1823－１833.
［32］Mok T S K, Wu Y L, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042):a randomised, open-label, controlled, phase 3 trial［Ｊ］. Lancet, 2019, 393(10183):1819－１830.