Tumour flare reaction in cancer treatments: a comprehensive literature review

In the past decade, tumour flare reaction (TFR) was considered as a new side effect associated with immunomodulatory agents (IMiDs) and as a condition of chronic lymphocytic leukaemia (CLL). However, this phenomenon is also observed with immune checkpoint inhibitors in solid tumours. It is still poorly understood and its incidence is underestimated. TFR has been associated with morbidity, therefore, early recognition and management of patients with TFR is critical. An exhaustive literature research between 1985 and 2016 was performed using PubMed; American Society of Clinical Oncology and American Society of Hematology abstracts reporting TFR or pseudoprogression were identified. The incidence of TFR in CLL ranged from 28 to 58%. Tumour response in patients treated beyond progression was reported in 9.7% with ipilimumab, 10% with nivolumab, 6.7 and 12% with pembrolizumab, and in renal cell carcinoma 69% with nivolumab. Rare life-threatening or fatal cases were reported; symptoms were usually mild. Studies showed that treating patients beyond progression yielded tumour responses, considering TFR as predictive of response. Treatment with immunomodulatory agents is associated with TFR, often misinterpreted as progression. Therefore, the identification of appropriate clinical benefit criteria and the use of immune-related response criteria in prospective trials for a better understanding are compulsory.