Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Petrelli, Fausto; Signorelli, Diego; Ghidini, Michele; Ghidini, Antonio; Pizzutilo, Elio Gregory; Ruggieri, Lorenzo; Cabiddu, Mary; Borgonovo, Karen; Dognini, Giuseppina; Brighenti, Matteo; Toma, Alessandro De; Rijavec, Erika; Garassino, Marina Chiara; Grossi, Francesco; Tomasello, Gianluca

doi:10.3390/cancers12030546

Cited by 193 publications

(137 citation statements)

References 43 publications

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“…The systemic administration of synthetic glucocorticoids such as dexamethasone and prednisolone has been associated with poorer outcomes in patients with ICI-treated cancer. 8 It has been shown that both synthetic and endogenous glucocorticoids can inhibit anticancer immune response through an impairment of the antigen presentation by dendritic cells or the activation of T-cells. 9 Given that endogenous glucocorticoids is produced by the adrenal glands, one might hypothesize the adrenal gland microenvironment might be immunosuppressive and acts as a sanctuary site for ICI-treated neoplasms tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Cohen

Jonchère

Fouchardière

et al. 2021

J Immunother Cancer

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Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.

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Section: Discussionmentioning

confidence: 99%

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Cohen

Jonchère

Fouchardière

et al. 2021

J Immunother Cancer

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“…Recently, a meta-analysis explored the impact of steroids across 16 studies with melanoma and NSCLC patients [ 16 ]. Overall, the patients treated with steroids had a higher risk of both progression and death, but only the intercurrent steroids for palliative purposes were related to the greater risk of death compared to patients receiving steroids for brain metastasis or irAEs.…”

Section: Discussionmentioning

confidence: 99%

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Giglio

Mezquita

Auclin

et al. 2020

Cancers

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Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

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“…A retrospective study showed that the patients who received prednisone >10 mg at the start of immunotherapy had a shorter median OS than those who received 0-10 mg of prednisone (4.9 vs. 11.2 months) (42). However, a recent meta-analysis pointed out that the use of steroids to mitigate adverse events did not negatively affect OS (43). Moreover, some studies showed that the use of antibiotics often leads to worse treatment response and OS in patients treated with ICIs (44,45).…”

Section: Clinical Managementmentioning

confidence: 99%

Pneumonitis Induced by Immune Checkpoint Inhibitors: From Clinical Data to Translational Investigation

Zhu

et al. 2020

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) have been applied to clinical practice and achieved significant therapeutic benefit in a variety of human malignancies. These drugs not only enhance the body's antitumor immune response but also produce side effects called immune-related adverse events (irAEs). Although checkpoint inhibitor pneumonitis (CIP) has a low clinical incidence, it is likely to cause the delay or termination of immunotherapy and treatment-related death in some severe cases. An increasing number of CIP cases have been reported since 2015, which are attributed to the augmentation of approvals and uses of ICIs, but a comprehensive understanding of CIP is still lacking. This review focuses on the epidemiology, clinical characteristics, treatment strategies, and underlying mechanisms of CIP to strengthen the recognition of pulmonary toxicity among clinicians and researchers.

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Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Cited by 193 publications

References 43 publications

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Pneumonitis Induced by Immune Checkpoint Inhibitors: From Clinical Data to Translational Investigation

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