Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis

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Abstract

Background

The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma.

Methods

Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs.

Results

Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively).

Conclusions

While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.

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Meta-analysis is of fundamental importance to obtain an unbiased assessment of the available evidence. In general, the use of meta-analysis has been increasing over the last three decades with mental health as a major research topic. It is then essential to well understand its methodology and interpret its results. In this publication, we describe how to perform a meta-analysis with the freely available statistical software environment R, using a working example taken from the field of mental health. R package meta is used to conduct standard meta-analysis. Sensitivity analyses for missing binary outcome data and potential selection bias are conducted with R package metasens. All essential R commands are provided and clearly described to conduct and report analyses. The working example considers a binary outcome: we show how to conduct a fixed effect and random effects meta-analysis and subgroup analysis, produce a forest and funnel plot and to test and adjust for funnel plot asymmetry. All these steps work similar for other outcome types. R represents a powerful and flexible tool to conduct meta-analyses. This publication gives a brief glimpse into the topic and provides directions to more advanced meta-analysis methods available in R.

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Author and article information

Contributors

Jennifer Strouse: URI : https://loop.frontiersin.org/people/2913867Role: Role: Role: Role: Role:

Karmela Kimi Chan: Role: Role: Role: Role:

Rachel Baccile: Role: Role: Role: Role: Role: Role:

Gong He: URI : https://loop.frontiersin.org/people/2889734Role: Role: Role: Role:

Diana K. N. Louden: URI : https://loop.frontiersin.org/people/2848796Role: Role: Role: Role:

Mihai Giurcanu: URI : https://loop.frontiersin.org/people/2431253Role: Role: Role: Role: Role: Role:

Arohi Singh: URI : https://loop.frontiersin.org/people/2915087Role: Role: Role:

John Rieth: Role: Role: Role:

Noha Abdel-Wahab: Role: Role: Role:

Tamiko R. Katsumoto: URI : https://loop.frontiersin.org/people/2024316Role: Role: Role: Role: Role: Role: Role:

Namrata Singh: URI : https://loop.frontiersin.org/people/2071085Role: Role: Role: Role: Role: Role:

Sherin Rouhani: Role: Role: Role: Role: Role: Role: Role: Role:

Pankti Reid: URI : https://loop.frontiersin.org/people/1793303Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 16 December 2024

Publication date Collection: 2024

Volume: 15

Electronic Location Identifier: 1499478

Affiliations

[1] ¹ Division of Immunology, University of Iowa , Iowa City, IA, United States

[2] ² Division of Rheumatology, Department of Medicine, Hospital for Special Surgery , New York, NY, United States

[3] ³ Center for Health and The Social Sciences, University of Chicago , Chicago, IL, United States

[4] ⁴ Division of Hematology and Oncology, University of Michigan , Ann Arbor, MI, United States

[5] ⁵ University Libraries, University of Washington , Seattle, WA, United States

[6] ⁶ Department of Public Health Sciences, University of Chicago , Chicago, IL, United States

[7] ⁷ University of Chicago Medicine , Chicago, IL, United States

[8] ⁸ Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa Health Care , Iowa City, IA, United States

[9] ⁹ Section of Rheumatology & Clinical Immunology, Department of General Internal Medicine, and Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center , Houston, TX, United States

[10] ¹⁰ Department of Rheumatology & Rehabilitation, Assiut University Hospitals, Assiut University Faculty of Medicine , Asyut, Egypt

[11] ¹¹ Division of Immunology and Rheumatology, Department of Medicine, Stanford University , Stanford, CA, United States

[12] ¹² Division of Rheumatology, University of Washington , Seattle, WA, United States

[13] ¹³ Mass General Cancer Center, Massachusetts General Hospital , Boston, MA, United States

[14] ¹⁴ Division of Rheumatology, Department of Medicine, University of Chicago , Chicago, IL, United States

Author notes

Edited by: Dimitrios Ziogas, National and Kapodistrian University of Athens, Greece

Reviewed by: Alexa Meara, The Ohio State University, United States

Hester Doyle, Yale University, United States

Takemichi Fukasawa, The University of Tokyo Hospital, Japan

*Correspondence: Pankti Reid, Pankti.reid@ 123456bsd.uchicago.edu

Article

DOI: 10.3389/fimmu.2024.1499478

PMC ID: 11682972

PubMed ID: 39737191

SO-VID: d8f53780-18d1-4399-aec5-0e82b85772c5

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 20 September 2024

Date accepted : 25 November 2024

Page count

Figures: 6, Tables: 2, Equations: 0, References: 89, Pages: 22, Words: 9989

Funding

Funded by: National Institute for Health and Care Research , doi 10.13039/501100000272;

Award ID: 5KL2TR002387-05

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. NS is supported by the National Institute of Arthritis And Musculoskeletal And Skin Diseases of the National Institutes of Health under Award Number K23AR079588. NA-W is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K01AI163412 and received the University of Texas MD Anderson Cancer Center DoIM Development & Translational Science award, Bridge Funding award, Cancer Survivorship Seed Money Grant, Institutional Research Grant, Prioritizing Research Innovation and Mentoring Excellence (PRIME) award, Melanoma SPORE Career Enhancement Program (CEP) award, and the Cyrus Scholar Award for Outstanding Clinical Research. PR has received funding form COVID-19 Funds to Retain Clinical Scientists by the SECURED (Supporting Early Career University Researchers to Excel through Disruptions) Steering Committee as well as the University of Chicago Institute of Translational Medicine Clinical and Translational Science Award K12/KL2 Grant 5KL2TR002387-05.

Custom metadata

section-in-acceptance Cancer Immunity and Immunotherapy

ScienceOpen disciplines: Immunology

Keywords: cancer immunotherapy,tumor outcome,steroid-sparing agents,disease-modifying antirheumatic drugs (dmards),immune related adverse events (iraes),ici toxicity,tnf inhibitors (tnfi),biologics

Data availability:

ScienceOpen disciplines: Immunology

Keywords: cancer immunotherapy, tumor outcome, steroid-sparing agents, disease-modifying antirheumatic drugs (dmards), immune related adverse events (iraes), ici toxicity, tnf inhibitors (tnfi), biologics

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Impact of steroid-sparing immunosuppressive agents on tumor outcome in the context of cancer immunotherapy with highlight on melanoma: a systematic literature review and meta-analysis

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Cancer Immunotherapy

Most cited references 88

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