Skip to main content

Advertisement

SpringerLink
Log in

Toxicity of Immune Checkpoint Inhibitors: Considerations for the Surgeon

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The use of immunotherapeutic agents, specifically immune checkpoint inhibitors (ICIs) for solid malignancies, is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies.

Methods

In this report the diverse spectrum of irAEs is highlighted using two patients with metastatic melanoma undergoing treatment with ICIs. We supplement these case reports with a brief literature review of the data regarding the safety of surgical intervention in patients taking irAEs.

Results

The report describes the basic approach to the detection and management of irAEs, notes important perioperative considerations, and discusses the safety of surgical intervention for these patients.

Conclusions

Overall, these irAEs represent a diverse group of pathologies with variable timing and sometimes subtle presentation requiring careful monitoring and heightened clinical suspicion for potential toxicity by all providers, including surgeons.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–68.

    CAS  PubMed  Google Scholar 

  2. Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pauken KE, Dougan M, Rose NR, et al. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 2019;40:511–23.

    CAS  PubMed  Google Scholar 

  4. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–86.

    CAS  PubMed  Google Scholar 

  5. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4:1721–8.

    PubMed  PubMed Central  Google Scholar 

  6. Chen TW, Razak AR, Bedard PL, et al. A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol. 2015;26:1824–9.

    CAS  PubMed  Google Scholar 

  7. Ernstoff MS, Gandhi S, Pandey M, et al. Challenges faced when identifying patients for combination immunotherapy. Future Oncol. 2017;13:1607–18.

    CAS  PubMed  Google Scholar 

  8. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.

    CAS  PubMed  Google Scholar 

  10. Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45:160–9.

    CAS  PubMed  Google Scholar 

  11. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–8.

    CAS  PubMed  Google Scholar 

  12. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.

    CAS  PubMed  Google Scholar 

  13. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55.

    PubMed  PubMed Central  Google Scholar 

  14. Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28:583–9.

    CAS  PubMed  Google Scholar 

  15. Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.

    PubMed  Google Scholar 

  16. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Thompson JA. New NCCN Guidelines: recognition and management of immunotherapy-related toxicity. J Natl Compr Cancer Netw. 2018;16:594–6.

    Google Scholar 

  18. Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2018;29:iv264–6.

    CAS  PubMed  Google Scholar 

  19. Williams KJ, Grauer DW, Henry DW, et al. Corticosteroids for the management of immune-related adverse events in patients receiving checkpoint inhibitors. J Oncol Pharm Pract. 2019;25:544–50.

    CAS  PubMed  Google Scholar 

  20. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33:3193–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35:785–92.

    CAS  PubMed  Google Scholar 

  22. Park J, Kwon M, Kim KH, et al. Immune checkpoint inhibitor-induced reinvigoration of tumor-infiltrating CD8(+) T cells is determined by their differentiation status in glioblastoma. Clin Cancer Res. 2019;25:2549–59.

    PubMed  Google Scholar 

  23. McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol. 2008;20:131–7.

    PubMed  Google Scholar 

  24. Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345–61.

    PubMed  Google Scholar 

  25. Abu-Sbeih H, Ali FS, Wang X, et al. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2019;7:93.

    PubMed  PubMed Central  Google Scholar 

  26. Abou Aliwi S, Martini DJ XW, Nassar A, Bakouny Z, Steinharter JA, Nuzzo PV, et al. Safety and efficacy of restarting (CPI) after immune-related adverse events (irAEs) in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2019;37:652.

    Google Scholar 

  27. Santini FC RH, Wilkins O, et al. Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(l)-1 therapy. ASCO 2019. Abstract 9012, 2019.

  28. Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28:368–76.

    CAS  PubMed  Google Scholar 

  29. Som A, Mandaliya R, Alsaadi D, et al. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7:405–18.

    PubMed  PubMed Central  Google Scholar 

  30. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis. 2018;24:1695–705.

    PubMed  Google Scholar 

  31. Abu-Sbeih H, Ali FS, Luo W, et al. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2018;6:95.

    PubMed  PubMed Central  Google Scholar 

  32. Bott MJ, Cools-Lartigue J, Tan KS, et al. Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. Ann Thorac Surg. 2018;106:178–83.

    PubMed  PubMed Central  Google Scholar 

  33. Elias AW, Kasi PM, Stauffer JA, et al. The feasibility and safety of surgery in patients receiving immune checkpoint inhibitors: a retrospective study. Frontiers Oncol. 2017;7:121.

    Google Scholar 

  34. Gyorki DE, Yuan J, Mu Z, et al. Immunological insights from patients undergoing surgery on ipilimumab for metastatic melanoma. Ann Surg Oncol. 2013;20:3106–11.

    PubMed  PubMed Central  Google Scholar 

  35. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24:1649–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24:1655–61.

    CAS  PubMed  Google Scholar 

  37. Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16:2861–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ismael H, Horst M, Farooq M, et al. Adverse effects of preoperative steroid use on surgical outcomes. Am J Surg. 2011;201:305–8. (discussion 308–9).

    CAS  PubMed  Google Scholar 

  40. Jeong H, Choi JW, Ahn HJ, et al. The effect of preventive use of corticosteroids on postoperative complications after esophagectomy: a retrospective cohort study. Sci Rep. 2019;9:11984.

    PubMed  PubMed Central  Google Scholar 

  41. Yamamoto T, Teixeira FV, Saad-Hossne R, et al. Anti-TNF and postoperative complications in abdominal crohn’s disease surgery. Curr Drug Targets. 2019;20:1339–48.

    CAS  PubMed  Google Scholar 

  42. Puar TH, Stikkelbroeck NM, Smans LC, et al. Adrenal crisis: still a deadly event in the 21st century. Am J Med. 2016;129:339 e1–9.

    Google Scholar 

  43. Galon J, Bruni D. Approaches to treat immune hot, altered, and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18:197–218.

    CAS  PubMed  Google Scholar 

  44. Wang Y, Deng W, Li N, et al. Combining immunotherapy and radiotherapy for cancer treatment: current challenges and future directions. Front Pharmacol. 2018;9:185.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA

    Beth A. Helmink MD, PhD, Christina L. Roland MD, MS, Colleen M. Kiernan MD, MPH & Jennifer A. Wargo MD, MSc

  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA

    Jennifer A. Wargo MD, MSc

Authors
  1. Beth A. Helmink MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina L. Roland MD, MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colleen M. Kiernan MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer A. Wargo MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer A. Wargo MD, MSc.

Ethics declarations

Disclosures

Beth A. Helmink, MD, PhD, was supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support Grant (P30 CA016672). Colleen M. Kiernan, MD, MPH, reports no disclosures. Christina L. Roland, MD, MS, receives research support from Bristol Myers Squibb. Jennifer A. Wargo, MD, MSc, reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Exelixis, and Bristol-Myers Squibb. She serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, and Microbiome DX; receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis; and has a U.S. patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Helmink, B.A., Roland, C.L., Kiernan, C.M. et al. Toxicity of Immune Checkpoint Inhibitors: Considerations for the Surgeon. Ann Surg Oncol 27, 1533–1545 (2020). https://doi.org/10.1245/s10434-019-08183-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-019-08183-0

Keywords

Search

Navigation