Radiation recall reactions: An oncologic enigma

Radiation recall reactions (RRR) are uncommon but are a well-known phenomenon to oncologists. Tissue damage in a prior irradiation portal is 'recalled' after the administration of a drug, historically cytotoxics, or more recently, targeted or immunotherapeutic agents. Even COVID-19 vaccines are a reported cause. RRR are enigmatic in that their cause is unknown, but they generally have the histopathological and clinical features of acute or chronic inflammation. They can occur in a variety of tissues, the commonest being skin, which accounts for two-thirds of reported cases. They are generally relatively mild and self-limiting once the trigger drug is stopped, although severe cases with tissue necrosis have occurred. Rechallenge with drug does not necessarily cause reactivation of the reaction. Symptomatic treatment with steroids and antihistamines are usually effective, but their impact on the clinical course is unclear. Various hypotheses have been proposed as to the mechanism of RRR; a non-immune fixed drug reaction-like condition, dysregulated release of reactive oxygen species, abnormalities of tissue vasculature and impaired DNA repair. All could lead to a characteristic inflammatory microenvironment, resulting in dysfunction of tissue stem cells, keratinocyte necrosis and dermal abnormalities. Alternatively or in addition, low levels of inflammatory tissue cytokines induced by previous irradiation might be further upregulated by drug exposure. Most information in this review refers to data derived from cutaneous RRR, since they are the most common form reported.