Harm from acetaminophen is not just limited to children. Below is a quote from the second paragraph in this 2022 study from Spain - In this issue of Annals of Oncology, Bessede et al (7) report important, compelling, and concerning data that link the use of acetaminophen (APAP) with worse outcomes in patients with cancer treated with ICI (Cancer Immunotherapy). Acetaminophen was shown to reduce important cancer-fighting T-cells and increase levels of regulatory T-cells (Tregs). As Treg cells function to suppress immune activity, this would be considered detrimental in a cancer situation where it is advantageous to have elevated rather than reduced immune activity. Patients with even detectable levels of acetaminophen had worse outcomes compared to patients with no measurable levels of acetaminophen. Moreover, the authors demonstrated that healthy volunteers receiving 4 doses of acetaminophen experienced an increase in immune-suppressing TREG cells.
In summary, Bessede et al(7) provide data from a series of
analyses, including analysis of blood samples from three
prospectively enrolled trials of patients treated with ICI
where pretreatment APAP and APAP metabolite levels were
measured and associated with poorer response rates, PFS,
and OS. Further, the authors provide supportive orthogonal
data from in vivo mouse models, ex vivo analysis from
blood of healthy donors, and pre-on proteomic analysis
from patients treated with ICI. In all, the data support the
conclusions that APAP appears to blunt ICI effectiveness
perhaps through activating regulatory immune elements,
namely Tregs. The major weakness of this analysis is the
potential for confounding. While the authors attempted to
limit this by performing multivariate analysis and used data
from three distinct clinical trials, it is hard to tease out the effect of the fact that patients treated with APAP may be those with worse disease on some level. For example, the
most common use of APAP in patients with cancer is for
cancer-related pain, either as a single-agent or in combination with an opiate and/or nonsteroidal antiinflammatory drug, and it is possible that patients with disease severe enough to cause pain may also be associated with worse outcomes. Further, there are dozens of
metabolites shown, but not named, in the paper that are
associated with worse and better outcomes, and it is not
clear whether any of these are metabolites from agents
known to improve or worsen outcomes from ICI and
whether these may confound the data. Despite these limitations, however, the central conclusion from this comprehensive work is concerning and suggests that one of the most widely used drugs in patients may mitigate the
benefit of cancer immunotherapy. While this study requires
validation before we radically eliminate the use of APAP in
our patients, the data require all of us who treat patients
with ICIs to reexamine whether our patients on APAP really
need to be.