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Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma

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Abstract

Fever is frequently observed in conjunction with interleukin-2 (IL-2)-based immunotherapy. Traditionally, fever has been regarded as an undesirable side effect and treated with fever-lowering drugs. However, new insights in tumor immunology suggest that elevated temperature may facilitate a more effective antitumor immune response. The purpose of this retrospective study was to examine the potential role of the IL-2-induced fever in melanoma patients treated with or without paracetamol in two consecutive cohorts. One hundred and seventy-nine patients with metastatic melanoma treated with a modified decrescendo regimen of IL-2 and Interferon (IFN) between 2004 and 2010 were retrospectively studied. 87 patients treated before 2007 received paracetamol as part of the treatment schedule, and 92 patients treated after 2007 did not receive paracetamol routinely. Body temperature was analyzed as dichotomized and continuous variables and correlated to objective tumor response and overall survival using logistic regression and Cox proportional hazard analysis. Patients experiencing peak temperature of ≥39.5 °C had a median OS of 15.2 months compared to 8.7 months among patients with lower temperatures (P = 0.01). In the multivariate analysis, peak temperature of ≥39.5 °C (HR 0.53; P = 0.026) and high mean temperature (HR 0.56; P = 0.004) were independent prognostic factors for improved survival. We suggest high fever as a biomarker for improved survival in melanoma patients treated with IL-2/IFN. The routine use of fever-reducing drugs during immunotherapy can therefore be questioned. More studies are needed to evaluate the role of fever and the use of antipyretics during cytokine-based immunotherapy.

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Abbreviations

AUC:

Area under the curve

CI:

Confidence interval

CR:

Complete response

CT:

Computed tomography

DC:

Dendritic cells

HR:

Hazard ratio

IFN:

Interferon alpha

IL-2:

Interleukin-2

LDH:

Lactate dehydrogenase

MU:

Million units

NK:

Natural killer cells

NSAIDs:

Non-steroidal anti-inflammatory drugs

OS:

Overall survival

PR:

Partial response

PS:

WHO performance status

RECIST:

Response criteria for solid tumors

SD:

Stable disease

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Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000, Århus, Denmark

    Anne Helene Køstner, Mai-Britt Bjørklund Ellegaard & Henrik Schmidt

  2. The Finsen Laboratory, Rigshospitalet and The Biotech and Research Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

    Ib Jarle Christensen

  3. Department of Oncology, Odense University Hospital, Odense, Denmark

    Lars Bastholt

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  1. Anne Helene Køstner
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  2. Mai-Britt Bjørklund Ellegaard
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Correspondence to Anne Helene Køstner.

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Køstner, A.H., Ellegaard, MB.B., Christensen, I.J. et al. Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma. Cancer Immunol Immunother 64, 349–355 (2015). https://doi.org/10.1007/s00262-014-1637-5

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  • DOI: https://doi.org/10.1007/s00262-014-1637-5

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