Behind The Criteria – Pseudoprogression

January 18, 2022 – Since radiologic imaging plays a critical role in assessing the success of cancer therapy, it is critical to understand how immunotherapy has altered the way response to therapy is being determined. Immunotherapy has emerged as a new and powerful weapon against cancer by targeting the checkpoints that prevent the immune system from attacking tumors by essentially releasing the brakes and allowing killer T-cells to target and destroy cancer cells. The results in some cancers have been truly remarkable to the point that many of these new drugs, known as checkpoint inhibitors, have already become the standard of care for such cancers as melanoma, non-small cell lung cancer, head and neck squamous cell cancer, and a few others. However, despite such promising results, immunotherapy is only successful in 20-40% of patients. Results can be improved when combining more than one checkpoint inhibitor, but it remains unclear why some tumors respond to the treatment while others demonstrate little or no response at all.

For many years, drug developers and regulators have relied on the Response Assessment in Solid Tumors Criteria (RECIST) and its updated version RECIST 1.1 to determine response to cancer therapy by measuring the size of the target tumors in their single longest axis. Per RECIST1.1, if the tumor burden grows at pre-designated levels or new tumors appear, it indicates progression. If the tumor burden regresses at pre-designated levels or tumors disappear all-together, it means a partial or complete response, respectively. Immunotherapy has challenged this methodology by introducing the notions of pseudo-progression and hyper-progression inherent in the mechanism of action of these drugs, where immune and T-cell activation may lead to unusual patterns of response akin to tumor flares. As the name indicates, pseudo-progression means that the treated tumor initially grows or that new tumors appear typically within 12 weeks after initiation of therapy, before subsequently decreasing in size with a commensurate decrease in tumor burden; whereas in hyper-progression, the process of pseudo-progression is accelerated and is even more pronounced.

Given the rigor necessary to interpret images in the context of clinical trials, it is imperative for imaging CROs and radiologists to be familiar with the patterns of pseudo-progression and hyper-progression, as failure to properly recognize this potential response to immunotherapy could lead to premature discontinuation of a drug that may in fact be benefitting the patient, with potentially devastating consequences. The stakes are therefore quite high. Fortunately, recent data from large clinical trials conducted in a variety of cancer types including melanoma, lung cancer, renal cell carcinoma, and other cancers suggests that pseudo-progression was found to be present in less than 10% of the cases with most cancers in the 2-6% range.

In order to address the unusual patterns of response to immunotherapy in a standardized way, the RECIST working group created a modified criteria named iRECIST followed shortly thereafter by imRECIST that continues to use RECIST 1.1 principles for most tumor response assessment but adds very important categories such as unconfirmed progressive disease (iUPD) to specifically account for patterns of pseudo-progression or hyper-progression, and distinguish it from true progression or confirmed progressive disease (iCPD). In such scenarios where progression is followed by tumor shrinkage (iUPD) when compared to the baseline scan, rather than continued progression, and the classic definition of complete or partial response under RECIST 1.1 is met, the bar is reset thereby allowing atypical responses to be identified early and treatment to be continued. Modified versions of RECIST 1.1 are immensely valuable “biologic tests of time” that is well known both in clinical oncology and cancer therapy. It is, therefore, incumbent upon all physicians involved in the management of cancer patients with immunotherapy to become familiar with these revised criteria, especially as more drugs become available and immunotherapy grows within routine clinical care.