Pseudoprogression to immunotherapy - the tumor grows but the therapy works?

Pseudoprogression

Pseudoprogression (false tumor progression) is a phenomenon in which tumor changes at first glance appear to be progressing (growing) after treatment has begun, although the therapy is actually working. In other words, the tumor may initially increase in size on follow-up scans or new lesions may appear, but later – with continued treatment – the tumor size decreases. It is important to emphasize that pseudoprogression is not true disease progression. Unlike true progression, where the tumor continues to grow and the condition worsens despite therapy, in pseudoprogression, improvement is seen after the initial apparent deterioration – which means that the immunotherapy is still effective.

Why does pseudoprogression occur with immunotherapy?

Cancer immunotherapy works differently than chemotherapy or radiation – it activates the patient's own immune system to recognize and attack tumor cells. It is this enhanced immune response that can cause pseudoprogression. Namely, when defense cells (such as T lymphocytes) permeate the tumor and surrounding tissue, inflammation and tissue swelling occur. The tumor may then appear larger on scans (CT, MRI) for a while, but a good part of this increase is made up of immune cells and the inflammatory process, not just malignant cells. Similarly, immunotherapy can "illuminate" very small metastases that were previously invisible – new punctate lesions may appear on the scans, but they may represent places where the immune system attacked the tumor.

How common is it and in what situations does it occur?

Pseudoprogression is a relatively rare event. A large 2020 meta-analysis of clinical trials found that it occurs in an average of about 6% of patients treated with immunotherapy. A slightly higher incidence of pseudoprogression has been reported in patients with melanoma (up to about 10% of cases, according to some data), while it is less common in lung cancer and most other solid tumors (approximately 5% or less). The timing of pseudoprogression is most often early in the course of immunotherapy treatment – typically at the first or second follow-up radiological evaluation (after several cycles of therapy).

Figure 1. Immune response to tumor cells induced by immunotherapy.

How do doctors recognize and monitor pseudoprogression?

Oncologists are aware of this phenomenon and therefore apply adapted criteria for assessing response when interpreting findings in patients receiving immunotherapy. Specific immunological criteria (e.g. irRC, irRECIST, iRECIST) have been developed that take into account atypical patterns such as pseudoprogression. In practice, if the patient generally tolerates immunotherapy well and there is no dramatic worsening of clinical symptoms, the physician will suspect pseudoprogression as a possibility. In this case, therapy is usually continued for the next few weeks, with close monitoring of the patient, and an earlier follow-up scan is planned.

New research and findings

Several important studies have been published on this phenomenon in recent years. For example, a 2023 study analyzed patterns of pseudoprogression in different types of tumors treated with immunotherapy. Other studies are also looking for biomarkers that can distinguish pseudoprogression from true progression without having to wait weeks for follow-up scans. One recent study focused on circulating tumor DNA (ctDNA)—traces of tumor DNA that can be measured in a patient’s blood—has shown encouraging results.

Inclusive

For patients on immunotherapy, it is important to know that apparent deterioration at first check-ups does not necessarily mean treatment failure. Pseudoprogression is confusing, but potentially good news – a sign that immunotherapy is activating the immune system to fight cancer. Oncologists are familiar with this phenomenon and carefully monitor the course of the disease before drawing conclusions.

Literature

1. Chiou VL, Burotto M. Pseudoprogression and Immune-Related Response in Solid Tumors. J Clin Oncol. 2015;33(31):3541–3.

2. Hodi FS, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 2010;363:711–23.

3. Seymour L, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143–52.

4. Gettinger SN, et al. Pseudoprogression in patients with advanced NSCLC treated with nivolumab. J Clin Oncol. 2016;34(suppl; abstr 9038).

5. Nishino M, et al. Immune-related response evaluations during immune-checkpoint inhibitor therapy: establishing a 'common language' for the new arena of cancer treatment. J Immunother Cancer. 2016;4:27.

6. Hellmann MD, et al. Tumor response dynamics and circulating tumor DNA in patients with NSCLC treated with nivolumab. Cancer Discov. 2018;8(10):1140–53. the patient

Related articles :

What is immunotherapy?

Do you need more information on this topic? Contact us .