Pseudoprogression in Patients Treated with Immunotherapy

Defining Pseudoprogression

The introduction of immunotherapy to the field of oncology has ushered in new patterns of radiologic response to treatment that have required clinicians to rethink how tumors respond to cancer therapy. Pseudoprogression has emerged as a distinct radiologic response pattern best defined as radiologic tumor progression from baseline that is not confirmed as progression on subsequent radiologic assessment. It has been described in the context of patients receiving immune checkpoint blockade drugs and is felt to be the consequence of treatment-activated immune cells infiltrating the tumor milieu eliciting a radiographic increase in tumor volume, including lesions not recognized on previous imaging. Pseudoprogression has been reported to involve epithelial solid tumors, melanoma, glioblastoma as well as hematologic malignancies such as Hodgkin’s Lymphoma.

Pseudoprogression Incidence

The relevance of pseudoprogression to both patients and clinicians in the immuno-oncology age has become clear. Three retrospective studies on the matter have reported a pseudoprogression rate of 7% in melanoma.^1-3 The incidence of pseudoprogression in epithelial malignancies such as non-small cell lung cancer (NSCLC) and urothelial carcinoma has been reported at a much lower rate of 1.5 – 3.0%.3 A recent retrospective French study reported pseudoprogression in 4.7% of patients with NSCLC treated with PD1 or PDL1 inhibitors.⁴ Attempts to elucidate which patients are more likely to experience a pseudoprogression event have rendered inconclusive results. Potential markers of immune response such as PD-L1 expression level and tumor infiltrating lymphocytes have failed to correlate with the rates of pseudoprogression.

Distinguishing Pseudoprogression from Disease Progression

While the incidence of pseudoprogression is relatively low for most tumor types it remains clinically important to distinguish between pseudoprogression and true progressive disease to avoid continuation of ineffective treatment. A patient experiencing an increase in cancer-related symptoms or functional decline often signals true disease progression. New central nervous system (CNS), bone or visceral lesions not associated with an organ previously recognized as harboring disease should raise concern for treatment failure and prompt a change of therapy. In contrast, if a “flare” of new lesions appears in proximity to a previously identified target lesion or a target lesion increases in size but the clinical assessment of the patient is improved or unchanged, consideration should be given to a pseudoprogression event. In my practice I find that short interval scans are useful in this scenario and recommend re-assessment with cross-sectional imaging at 4 weeks to determine the trajectory of tumor growth.

It is important to keep in mind that the average time to response in those with pseudoprogression is 6 months and therefore clinical diligence is warranted. Advanced biomarkers such as circulating tumor DNA may also help to discern between pseudoprogression and true progressive disease provided a baseline sample and reliable marker is available.² To date, evidence suggests that patients who experience pseudoprogression have similar outcomes compared to those who have responded to treatment without experiencing pseudoprogression. Thus, thoughtful consideration should be given to the broader clinical picture when considering the likelihood of this phenomenon.

Ryan Weight, DO, MS, is an assistant professor in the Department of Medical Oncology at the University of Colorado specializing in the treatment of cutaneous malignancies, including melanoma. He is a member of the Training & Education Working Group.

References

1. Kurra V, Sullivan RJ, et al. Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes. J Clin Oncol 34, 2016 (suppl; abstr 6580).
2. Lee JH, Long GV, Menzies AM, et al. Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with anti–programmed cell death 1 antibodies. JAMA Oncol. 2018;4(5):717–721. doi:10.1001/jamaoncol. 2017.5332.
3. Hodi SF, Ballinger M, et al. Immune-modified response evaluation criteria in solid tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy. J Clin Oncol. 2018;36(9):850-858.
4. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non–small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. Published online September 06, 2018. doi:10.1001/jamaoncol.2018.3676.