Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada

Abstract

Purpose

People with cancer face an elevated risk of infection and severe sequelae from COVID-19. Dexamethasone is commonly used for antiemetic prophylaxis with systemic therapy for cancer. However, dexamethasone is associated with increased risk of viral and respiratory infections, and causes lymphopenia, which is associated with worse outcomes during COVID-19 infections. Our purpose was to minimize dexamethasone exposure during antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic, while maintaining control of nausea and emesis.

Methods

We convened an expert panel to systematically review the literature and formulate consensus recommendations.

Results

No studies considered the impact of dexamethasone-based antiemetic regimens on the risk and severity of COVID-19 infection. Expert consensus recommended modifications to the 2019 Cancer Care Ontario Antiemetic Recommendations.

Conclusion

Clinicians should prescribe the minimally effective dose of dexamethasone for antiemetic prophylaxis. Single-day dexamethasone dosing is recommended over multi-day dosing for regimens with high emetogenic risk excluding high-dose cisplatin, preferably in combination with palonosetron, netupitant, and olanzapine. For regimens with low emetogenic risk, 5-HT3 antagonists are recommended over dexamethasone.

Introduction

The COVID-19 pandemic is growing exponentially, with over two million infections and 130,000 deaths worldwide as of April 15, 2020 [1]. Early evidence suggests that patients with cancer face an elevated risk for COVID-19 infection and a higher risk of adverse events after diagnosis [2,3,4,5], potentially because of nosocomial spread and suppressed immunity.

Several guidelines for pandemic era cancer care have been recently released [6,7,8,9,10,11,12,13]. These guidelines make prudent recommendations on optimizing the delivery of systemic therapy during the COVID-19 pandemic, including to:

  1. 1.

    Favor oral agents over intravenous agents when efficacy and toxicity profiles are similar [6, 7].

  2. 2.

    Deliver oral agents and supportive medications directly to the homes of patients, rather than have them picked up in person at the pharmacy [6].

  3. 3.

    Favor regimens with less frequent over more frequent IV dosing when efficacy and toxicity profiles are similar [6].

  4. 4.

    Favor intermittent treatment strategies and breaks over continuous strategies when efficacy and toxicity profiles are similar and patients are stable [6, 7].

  5. 5.

    Defer the use of medications whose primary role is to reduce the risk of long-term complications such as bone disease, where appropriate [6].

  6. 6.

    Favor neoadjuvant over adjuvant treatment strategies when efficacy and toxicity profiles are similar, to facilitate the delay of surgical dates and increase the availabilities of hospital beds and ventilators [7].

  7. 7.

    Use GCSF for primary prophylaxis in high-risk regimens [7].

We convened an expert panel to formulate recommendations on modifications to antiemetic prophylaxis during the COVID-19 pandemic to protect cancer patients. We recognize the limitations of such a document, given the rapidly evolving environment and paucity of data.

Methods

An expert panel was convened to review potential modifications to antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic. The panel included medical oncologists, infectious disease physicians, and pharmacists from the Princess Margaret Cancer Centre and Cancer Care Ontario.

We conducted a systematic literature search to evaluate all current literature on COVID-19 and antiemetics, including peer-reviewed and published studies in PubMed (https://www.ncbi.nlm.nih.gov/pubmed/, accessed April 15, 2020) and pre-prints in medRxiv (https://www.medrxiv.org/, accessed April 15, 2020). We searched (“COVID” or “SARS-COV-2” or “Coronavirus”) and “Cancer” and (“antiemetics” or “nausea” or “vomiting” or “emesis”) in PubMed on April 15, 2020 and combinations of each of these terms in medRxiv. We also reviewed the websites of provincial (BC Cancer [9], Cancer Care Ontario [11]) and international (ESMO [8], American Society of Clinical Oncology [7], National Comprehensive Cancer Network [10]) oncology organizations.

We developed recommendations based on the literature review and expert consensus. Recommendations were developed through virtual meetings and email correspondence until full consensus was achieved.

Given the paucity of data on COVID-19 and antiemetic prophylaxis, recommendations were based on expert opinion and the modification of recent evidence-based guidelines developed before the COVID-19 pandemic, in particular the Cancer Care Ontario guidelines for Antiemetics [14].

Recommendations: how should COVID-19 impact antiemetic prophylaxis?

Recommendation 1

Prescribe the minimal effective dose of glucocorticoids (Table 1).

Table 1 Changes to the Cancer Care Ontario antiemetic guidelines during the COVID-19 Pandemic. Changes from the general CCO guidelines are emphasized in bold

Recommendation 2

If nausea or vomiting occurs despite the recommended regimens, increase or add non-glucocorticoid agents such as an NK1 agent or olanzapine, before increasing the glucocorticoid dose.

Recommendation 3

If no nausea or vomiting occurs with prior cycles, consider further reductions in dexamethasone.

Evidence summary

No studies identified through the systematic review assessed the impact of antiemetic dosing and the risk or severity of COVID-19 in cancer patients.

Our recommendations focus on minimizing glucocorticoid use for oncology patients because data support a dose-dependent association between glucocorticoids and viral and respiratory infections [15,16,17]. Glucocorticoids cause immunosuppression through multiple complex mechanisms, in particular by altering gene transcription of pro-inflammatory genes like interleukins and nuclear factor-kappa-B. Glucocorticoids also deplete T and B cells essential for the immune response to viruses [18].

In COVID-19, lymphopenia is common and associates with more severe disease [19], suggesting the importance of lymphocytes in the immunological response. Currently, guidelines recommend against using glucocorticoids to treat respiratory failure associated with COVID-19 in the absence of acute respiratory distress syndrome or patient-specific indications like concomitant chronic obstructive pulmonary disease exacerbation [20]. This recommendation is based on a signal of harm when using glucocorticoids to treat other viral infections, including influenza [21] and SARS [22].

To determine glucocorticoid dosing for chemotherapy during the COVID-19 pandemic, we started with the 2019 Antiemetic Recommendations for Chemotherapy-Induced Nausea and Vomiting from Cancer Care Ontario (CCO) [14]. The CCO guidelines are based on the latest evidence and are generally consistent with those of the American Society for Clinical Oncology [23] (ASCO) and the Multinational Association of Supportive Care in Cancer and European Society of Medical Oncology [24] (MASCC/ESMO) guidelines. CCO provides a classification of emetogenic risk for anticancer regimens (https://www.cancercareontario.ca/en/AntiemeticGuideline, accessed March 27, 2020).

We modified the 2019 CCO guidelines for highly emetogenic chemotherapy to include single-day dosing of dexamethasone for all regimens except high-dose cisplatin based on meta-analyses that show similar efficacy between single- versus multiple-day dosing of dexamethasone [25, 26]. The 2019 CCO guidelines recommended single-day dosing only for anthracycline and cyclophosphamide combinations, where the evidence is strongest. However, we have extended single-day dosing to all highly emetogenic chemotherapies given the potential risks of dexamethasone during the COVID-19 pandemic and because the meta-analyses included trials that showed similar efficacy for single-day dexamethasone dosing across a variety of moderately and highly emetogenic regimens, including carboplatin, oxaliplatin, paclitaxel, and irinotecan [27,28,29]. Single-day dexamethasone in these trials was investigated in combination with NEPA, a combination of palonosetron (a longer-acting 5-HT3 agent) and netupitant (an NK1 agent). Therefore, we have recommended NEPA as the preferred agent in combination with single-day dexamethasone. We have included other 5-HT3 and NK1 agents as acceptable alternatives to NEPA because concomitant use of an NK1 agent prolongs the half-life of dexamethasone [30] and we recommend standing and as needed olanzapine, which is effective for any breakthrough nausea and vomiting that occurs [31]. We excluded high-dose cisplatin from the recommendation because a trial showed inferior outcomes with single- versus multiple-day dosing [32].

Further reduction of dexamethasone dosing below 12 mg on day 1 may increase nausea and vomiting, which could lead to hospitalizations and increased risk of COVID-19. For example, a randomized controlled double-blinded randomized trial compared 4, 8, 12, or 20 mg of dexamethasone IV combined with ondansetron during cisplatin [33]. Rates of nausea with 8 versus 12 mg of dexamethasone were 61.0 and 66.9%, respectively, while rates of vomiting were 69.1% and 78.5%, respectively.

We modified the 2019 CCO guidelines for low emetogenic risk regimens to substitute a 5-HT3 agent rather than dexamethasone, consistent with the ASCO [23] and MASCC/ESMO [24] guidelines, which recommended either 4–8 mg of dexamethasone or a 5-HT3 agent based on consensus among the expert panel. There are no randomized controlled studies or meta-analysis of antiemetic prophylaxis among low-emetogenic risk regimens.

These recommendations should be individualized for each patient, considering patient-specific risk factors or prediction models for emesis [34]. Prior nausea and vomiting with chemotherapy [35], female sex, and younger age are associated with a higher risk of emesis [34, 36]. Prescribers should also consider the potential toxicities and interactions of the agents substituted for dexamethasone.

Discussion

Cancer patients face an elevated risk of infection, serious complications, and death from COVID-19. Our Recommendations aim to protect cancer patients from the harms of COVID-19 by reducing their exposure to dexamethasone. Given the rapid advances in COVID-19 research, we will update these recommendations continuously as new information becomes available.

References

  1. 1.

    Dong E, Du H, Gardner L (2020) An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 20:533–534. https://doi.org/10.1016/S1473-3099(20)30120-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Liang W, Guan W, Chen R, Wang W, Li J, Xu K, Li C, Ai Q, Lu W, Liang H, Li S, He J (2020) Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 21(3):335–337. https://doi.org/10.1016/S1470-2045(20)30096-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Yu J, Ouyang W, Chua MLK, Xie C (2020) SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2020.0980

  4. 4.

    Zhao X, Zhang B, Li P, Ma C, Gu J, Hou P, Guo Z, Wu H, Bai Y (2020) Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. medRxiv:2020.2003.2017.20037572. https://doi.org/10.1101/2020.03.17.20037572

  5. 5.

    Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, Jia P, Guan HQ, Peng L, Chen Y, Peng P, Zhang P, Chu Q, Shen Q, Wang Y, Xu SY, Zhao JP, Zhou M (2020) Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol 31:894–901. https://doi.org/10.1016/j.annonc.2020.03.296

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    National Institute for Health and Care Excellence (2020) COVID-19 rapid guideline: delivery of systemic anticancer treatments. https://www.nice.org.uk/guidance/ng161. Accessed 27 Mar 2020

  7. 7.

    American Society of Clinic Oncology (2020) COVID-19 Provider & Practice Information. https://www.asco.org/asco-coronavirus-information/provider-practice-preparedness-covid-19. Accessed 27 Mar 2020

  8. 8.

    ESMO (2020) COVID-19: supporting oncology professionals. https://www.esmo.org/newsroom/covid-19-and-cancer/supporting-oncology-professionals. Accessed 27 Mar 2020

  9. 9.

    BC Cancer (2020) COVID-19 Information for health professionals in cancer care. http://www.bccancer.bc.ca/health-professionals/clinical-resources/provincial-cancer-clinical-management-guidelines-in-pandemic-situation-(covid-19). Accessed 27 Mar 2020

  10. 10.

    Ueda M, Martins R, Hendrie PC, McDonnell T, Crews JR, Wong TL, McCreery B, Jagels B, Crane A, Byrd DR, Pergam SA, Davidson NE, Liu C, Stewart FM (2020) Managing cancer care during the COVID-19 pandemic: agility and collaboration toward a common goal. J Natl Compr Cancer Netw 18:1–4. https://doi.org/10.6004/jnccn.2020.7560

    Article  Google Scholar 

  11. 11.

    Cancer Care Ontaro (2020) Pandemic planning clinical guideline for patients with cancer. https://www.accc-cancer.org/docs/documents/cancer-program-fundamentals/oh-cco-pandemic-planning-clinical-guideline_final_2020-03-10.pdf. Accessed April 3, 2020

  12. 12.

    Al-Shamsi HO, Alhazzani W, Alhuraiji A, Coomes EA, Chemaly RF, Almuhanna M, Wolff R, Nuhad IK, Chua MLK, Hotte SJ, Meyers BM, Elfiki T, Curigliano G, Eng C, Grothey A, Xie C (2020) A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: an international collaborative group. Oncologist. 25:e936–e945. https://doi.org/10.1634/theoncologist.2020-0213

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Penel N, Bonvalot S, Minard V, Orbach D, Gouin F, Corradini N, Brahmi M, Marec-Berard P, Briand S, Gaspar N, Llacer C, Carrere S, Dufresne A, Le Cesne A, Blay JY (2020) French sarcoma group proposals for management of sarcoma patients during COVID-19 outbreak. Ann Oncol 31:965–966. https://doi.org/10.1016/j.annonc.2020.03.308

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Cancer Care Ontaro (2019) Antiemetic recommendations for chemotherapy-induced nausea and vomiting: a clinical practice guideline

  15. 15.

    Fardet L, Petersen I, Nazareth I (2016) Common infections in patients prescribed systemic glucocorticoids in primary care: a population-based cohort study. PLoS Med 13(5):e1002024. https://doi.org/10.1371/journal.pmed.1002024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Stuck AE, Minder CE, Frey FJ (1989) Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 11(6):954–963. https://doi.org/10.1093/clinids/11.6.954

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Wolfe F, Caplan L, Michaud K (2006) Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 54(2):628–634. https://doi.org/10.1002/art.21568

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Olnes MJ, Kotliarov Y, Biancotto A, Cheung F, Chen J, Shi R, Zhou H, Wang E, Tsang JS, Nussenblatt R, Consortium CHI (2016) Effects of systemically administered hydrocortisone on the human Immunome. Sci Rep 6:23002. https://doi.org/10.1038/srep23002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Ruan Q, Yang K, Wang W, Jiang L, Song J (2020) Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 46:846–848. https://doi.org/10.1007/s00134-020-05991-x

    Article  CAS  Google Scholar 

  20. 20.

    Poston JT, Patel BK, Davis AM (2020) Management of critically ill adults with COVID-19. JAMA. https://doi.org/10.1001/jama.2020.4914

  21. 21.

    Lansbury L, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS (2019) Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev 2:CD010406. https://doi.org/10.1002/14651858.CD010406.pub3

    Article  PubMed  Google Scholar 

  22. 22.

    Auyeung TW, Lee JS, Lai WK, Choi CH, Lee HK, Lee JS, Li PC, Lok KH, Ng YY, Wong WM, Yeung YM (2005) The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. J Inf Secur 51(2):98–102. https://doi.org/10.1016/j.jinf.2004.09.008

    Article  Google Scholar 

  23. 23.

    Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Somerfield MR, Lyman GH (2017) Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 35(28):3240–3261. https://doi.org/10.1200/JCO.2017.74.4789

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Roila F, Molassiotis A, Herrstedt J, Aapro M, Gralla RJ, Bruera E, Clark-Snow RA, Dupuis LL, Einhorn LH, Feyer P, Hesketh PJ, Jordan K, Olver I, Rapoport BL, Roscoe J, Ruhlmann CH, Walsh D, Warr D, van der Wetering M, participants of the MECCC (2016) 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol 27(suppl 5):v119–v133. https://doi.org/10.1093/annonc/mdw270

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Gu YL, Xie JM, Ren J, Cao H, Wei JR, Chen C, Shao LN, Jiang GQ (2019) Dexamethasone-sparing regimen is an effective and safe alternative in overall antiemetic protection: a systematic review and meta-analysis. Medicine (Baltimore) 98(39):e17364. https://doi.org/10.1097/MD.0000000000017364

    Article  CAS  Google Scholar 

  26. 26.

    Celio L, Bonizzoni E, Zattarin E, Codega P, de Braud F, Aapro M (2019) Impact of dexamethasone-sparing regimens on delayed nausea caused by moderately or highly emetogenic chemotherapy: a meta-analysis of randomised evidence. BMC Cancer 19(1):1268. https://doi.org/10.1186/s12885-019-6454-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Komatsu Y, Okita K, Yuki S, Furuhata T, Fukushima H, Masuko H, Kawamoto Y, Isobe H, Miyagishima T, Sasaki K, Nakamura M, Ohsaki Y, Nakajima J, Tateyama M, Eto K, Minami S, Yokoyama R, Iwanaga I, Shibuya H, Kudo M, Oba K, Takahashi Y (2015) Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron. Cancer Sci 106(7):891–895. https://doi.org/10.1111/cas.12675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Celio L, Frustaci S, Denaro A, Buonadonna A, Ardizzoia A, Piazza E, Fabi A, Capobianco AM, Isa L, Cavanna L, Bertolini A, Bichisao E, Bajetta E, Italian Trials in Medical Oncology G (2011) Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial. Support Care Cancer 19(8):1217–1225. https://doi.org/10.1007/s00520-010-0941-7

    Article  PubMed  Google Scholar 

  29. 29.

    Furukawa N, Kanayama S, Tanase Y, Ito F (2015) Palonosetron in combination with 1-day versus 3-day dexamethasone to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin. Support Care Cancer 23(11):3317–3322. https://doi.org/10.1007/s00520-015-2760-3

    Article  PubMed  Google Scholar 

  30. 30.

    McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA (2003) Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 74(1):17–24. https://doi.org/10.1016/S0009-9236(03)00066-3

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Navari RM, Nagy CK, Gray SE (2013) The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 21(6):1655–1663. https://doi.org/10.1007/s00520-012-1710-6

    Article  PubMed  Google Scholar 

  32. 32.

    Ito Y, Tsuda T, Minatogawa H, Kano S, Sakamaki K, Ando M, Tsugawa K, Kojima Y, Furuya N, Matsuzaki K, Fukuda M, Sugae S, Ohta I, Arioka H, Tokuda Y, Narui K, Tsuboya A, Suda T, Morita S, Boku N, Yamanaka T, Nakajima TE (2018) Placebo-controlled, double-blinded phase III study comparing dexamethasone on day 1 with dexamethasone on days 1 to 3 with combined neurokinin-1 receptor antagonist and palonosetron in high-emetogenic chemotherapy. J Clin Oncol 36(10):1000–1006. https://doi.org/10.1200/JCO.2017.74.4375

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Italian Group for Antiemetic Research (1998) Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. Italian Group for Antiemetic Research. J Clin Oncol 16(9):2937–2942. https://doi.org/10.1200/JCO.1998.16.9.2937

    Article  Google Scholar 

  34. 34.

    Dranitsaris G, Bouganim N, Milano C, Vandermeer L, Dent S, Wheatley-Price P, Laporte J, Oxborough KA, Clemons M (2013) Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11(1):14–21. https://doi.org/10.1016/j.suponc.2012.05.001

    Article  PubMed  Google Scholar 

  35. 35.

    Morrow GR, Roscoe JA, Hickok JT, Stern RM, Pierce HI, King DB, Banerjee TK, Weiden P (1998) Initial control of chemotherapy-induced nausea and vomiting in patient quality of life. Oncology (Williston Park) 12(3 Suppl 4):32–37

    CAS  Google Scholar 

  36. 36.

    Pollera CF, Giannarelli D (1989) Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer 64(5):1117–1122. https://doi.org/10.1002/1097-0142(19890901)64:5<1117::aid-cncr2820640525>3.0.co;2-r

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors contributed to the study conception and design. Robert Grant performed the literature review and wrote the first draft of the manuscript. All authors commented on subsequent versions of the manuscript and read and approved the final manuscript.

Corresponding author

Correspondence to Jennifer Knox.

Ethics declarations

Conflict of interest

Monika Krzyzanowska reports receiving funding to the University Health Network from Eisai and Exelixis; and receiving personal fees from Eisai outside the submitted work

The remaining authors declare that they have no conflicts of interest.

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

Verify currency and authenticity via CrossMark

Cite this article

Grant, R.C., Rotstein, C., Liu, G. et al. Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada. Support Care Cancer (2020). https://doi.org/10.1007/s00520-020-05588-6

Download citation

Keywords

  • COVID-19
  • Antiemetic
  • Supportive care
  • Chemotherapy
  • Glucocorticoids