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Does Control of Inflammation Lower Cancer Risk?

Nov 23, 2021 5:17 pm

Dr. Jonathan Kay's provocative video addresses whether the increased cancer risk associated with tofacitinib (Tofa) seen in the Pfizer Oral Surveillance (1133) study represents a real increased risk, an increased risk relative to a decreased risk with TNF inhibitors (TNFi) or an actual decreased cancer risk (unknown as there was no placebo comparator in this trial).

Much of the damning data from the 1133 study (increased risk of CV events, MACE, mortality, VTE, all cancers (specifically lung and skin cancers and lymphoma) ascribed to the Tofa group can either be seen as a Tofa increase or a TNFi decrease, with Tofa not quite as good as the TNFi treated high risk patients.  The untoward events were also heavily influenced by prior history of adverse events, smoking and being elderly.   This trial was designed to elicit a CV signal in older, at risk patients, and that goal was accomplished.

However, the outcome raises the alternative interpretation that TNFi were better at preventing these serious adverse events (SAE) than Tofa.  It is well known that inflammation drives risk; moreso than the drugs often associated with such SAEs.  So while many still believe that TNFi are associated with an increased risk of cancer, the data clearly shows that RA has an inflammation related risk and that using a TNFi (in patients with high enough inflammation to get a TNFi) mirrors that same risk frequency.  The interpretation being that it's RA inflammation and not the TNFi that associates with a low but significant risk of cancer (especially, Lung, Lymphoma and skin Cancer - the same cancers seen in the 1133 study and all RA studies).

But if inflammation is controlled by a drug, shouldn't the risk of CV events, serious infections and cancer go down?  The answers have taken a long time, but data clearly shows that effective control of RA (over many months) by methotrexate or TNFi can lower the CV event and CV mortality risk.  Moreover, all of the newly developed biologics, anticytokine therapies and JAK inhibitors have demonstrated serious infection rates that are equal to the placebo group and at lower rates (3 SIE per 100 PY or lower) than that seen in the prebiologic era (3-9 SIE/100 PY).  Lastly, a report from Sweden last year showed that prolonged use of TNFi and non-TNFi biologics actually associates with a lower lymphoma risk over time. 

While the cautionary FDA directives stemming from the Oral Surveillance study merit caution and discussion with patients, I believe these data are not necessarily damning to the benefit to risk value of aggressive therapies in high-risk RA patients. 

See Dr. Kay's video on this hot-button issue!


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