In the last decade, TFR was described as a side-effect associated with immunomodulatory agents IMiDs (thalidomide and lenalidomide), and as a specific condition to chronic lymphocytic leukemia (CLL). However, this phenomenon is seen with the use of new immunotherapy (checkpoints inhibitors) in solid tumors, in addition, cases of TFR were reported in advanced gynecologic, prostate cancer and lymphoid malignancies. TFR is defined as an increase of lesion size related to treatment which simulates disease progression. This phenomenon that occurs after initiating cancer therapy is poorly understood and incidence is under-estimated, since not captured by Recist. It has been suggested that TFR may be the results of immune system activation and may precede tumor shrinkage. TFR is associated with morbidity, severe cases were reported, some of them life-threatening or leading to death. So, early recognition and initial management of patients presenting with TFR, is critical.
From 1985 to 2016, a search was performed in the Pubmed, ASCO and ASH abstracts to identify publications reporting TFR or pseudoprogression.
The incidence of all grades of TFR in CLL, ranged from 28% in a study to 58% in another trial. In CLL, painful lymph nodes and/or spleen enlargement were reported with a sudden onset after the first dose. Following initial progression (TFR), tumor response in patients treated beyond progression, was reported in melanoma trials: 9.7% with ipilimumab, 10% with nivolumab, 6.7% and 12% with pembrolizumab, and in renal cell carcinoma 69% with nivolumab. Even if rare cases of life-threatening or fatal TFR were reported, symptoms are usually mild. While correct diagnosis and adequate management are critical, it is important to better recognize TFR, and avoid an effective treatment discontinuation. Some studies showed that treating patients beyond progression yielded tumor responses, considering TFR as predictive of response.
Treatment with immunomodulatory agents is associated with TFR. This is likely to be misinterpreted as progression, hence the need to identify appropriate clinical benefit criteria and the use of immune-related RECIST (irRC) in prospective trials for a better understanding.
Clinical trial identification
Legal entity responsible for the study
Amina TALEB MD
All authors have declared no conflicts of interest.