EAU 2018: Systemic Immunotherapy in Urological Cancers: Basics and Beyond - How to Evaluate the Benefit
To date, there are no reliable clinical or biological marker to predict tumor response to check-point inhibitors. Correlations of objective tumor response with cancer-specific and overall survival if weak limiting the use of tumor size in imaging as an accurate surrogate. The best predictor of 12-month overall survival during checkpoint blockade is 6-month progression-free survival; but, for non-responders waiting 6 months to declare a treatment ineffective may lead to dangerous side effects and significant compromise of their oncological care. Furthermore, there are three distinct phenomena that occur with checkpoint inhibitors that tend to cloud any analysis of objective response: pseudo-progression, differential response and hyper-progression.
Pseudo-progression while on checkpoint therapy has been noted in up to 15% of patients treated. The phenomenon is described as either growth of pre-existent lesions or appearance of new lesions after initiation of therapy, followed by an eventual decrease in total tumor burden. The exact cause of the phenomenon is unclear, but some argue it may represent persistent growth of tumor before a robust immune response occurs, while others argue it represents tissue edema secondary to immune cell infiltration. This phenomenon has lead to a revision of the current RECIST criteria used for assessment of tumor response. A new immune RECIST (iRECIST) criteria have been introduced which considers this phenomenon, so patients are not declared as progressors and taken off treatment. In some cases there is a differential response is observed where a lesion may be shrinking while other lesions are growing or new ones are becoming apparent. This phenomenon creates a treatment dilemma since it is unclear if the patient should continue the therapy or stopped. Currently, this decision has been left to the treating physician. Lastly, a subset of patients experiences hyper-progression, defined as a 2-fold increase in tumor burden from the baseline imaging, and occurs in up to 9% of patients.
Following treatment initiation, it can be difficult to discern the difference between hyper-progression and pseudo-progression. This creates a treatment dilemma for the clinician who often is unsure if the therapy should be continued or stopped. Advances in measurement of circulation tumor free DNA (cfDNA) may provide a clue in which is occurring. A study by Lee at al. (Ann Oncol 2017), levels of cfDNA were measured during the first 12 months of treatment. The study showed that patients who have persistent cfDNA 5 weeks after starting therapy were more likely to progress than those who did not. On a follow-up evaluation (JAMA Oncol 2018) assessing the phenomena of pseudo and hyper-progression, the same group noted that patients experiencing pseudo-progression had no or minimal cfDNA after 5 weeks of treatment, whereas those who experienced hyper-progression continue to show elevated levels of cfDNA.
In summary, checkpoint inhibitors have changed the way we treat malignancies but we still learning on who to better select patients for treatment and identify those who will continue benefit from those who don’t. Advances in measurement of cfDNA and imaging may give insights into these important questions.
Speaker: Yohaan Loriot, Department of Cancer Medicine, Gustave Roussey, Cancer Campus, Gran Paris (France)
Written by: Andres F. Correa, MD, Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark