Table of ContentsView AllTable of ContentsOverviewDiagnosisManagement and TreatmentPrognosisCoping
Table of ContentsView All
View All
Table of Contents
Overview
Diagnosis
Management and Treatment
Prognosis
Coping
Pseudoprogressiondescribes when cancer appears to get worse when it is actually improving. This can lead some individuals to stop their cancer treatment early. With the exception of a type of brain cancer, it wasn’t until the introduction ofimmunotherapydrugs—like checkpoint inhibitors—that it became relatively common to see an increase in the size of a tumor or number ofmetastaseson imaging tests, that was not due to the growth or spread of the cancer.
This article offers an overview of pseudoprogression related to immunotherapy. It also covers how this condition is diagnosed and managed and how to cope.
Pseudoprogression vs. True ProgressionWith pseudoprogression, tumors, or abnormal growths, increase in size only to decrease in size or total amount with continued treatment. With true progression, treatment results in tumors continuing to grow as expected as if no treatment was given.
Pseudoprogression vs. True Progression
With pseudoprogression, tumors, or abnormal growths, increase in size only to decrease in size or total amount with continued treatment. With true progression, treatment results in tumors continuing to grow as expected as if no treatment was given.
Verywell / Laura Porter
The introduction of immunotherapy drugs has been a game-changer in cancer treatment but has brought concepts not seen with prior treatment options.
Other than pseudoprogression, some of these include:
Unfortunately, while there are tests that may help predict who will best respond to these drugs, there aren’t any objective ways to predict who may develop hyperprogression or pseudoprogression.
Definitions of Pseudoprogression
There is not a universally accepted definition of pseudoprogression.
Tumor BurdenTumor burden, or load, refers to the amount of cancer cells within the body or the size of the tumor.
Tumor Burden
Tumor burden, or load, refers to the amount of cancer cells within the body or the size of the tumor.
Pseudoprogression Mechanism
Pseudoprogression may occur due to more than one mechanism:
Immune Infiltration
Pseudoprogression is thought to be due to the immune cells that infiltrate and surround a tumor in response to immunotherapy drugs. While the tumor may appear to increase in size on imaging tests, the apparent increase may be becauseimaging testsare seeing both the tumorandsurrounding immune cells. On biopsy samples taken during pseudoprogression, the actual size of the tumor may have actually decreased significantly.
When new metastases are seen on imaging with pseudoprogression, it’s thought that small metastases (micrometastases) were already present before immunotherapy was started, but due to the surrounding immune cells, are now large enough to be seen on imaging studies.
How CAR T-Cell Therapy ‘Cured’ 2 Cancer Patients
Delayed Response
Unlike checkpoint inhibitors, treatments such aschemotherapyand radiation cause the death of cancer cells almost immediately with treatment, and a response may be seen quickly.
Checkpoint Inhibitors and Pseudoprogression
Pseudoprogression related to immunotherapy was first noted in people with metastatic melanoma treated with the checkpoint inhibitor Yervoy (ipilimumab). Since then, the phenomenon has also been seen with other drugs in this category.
There are three subcategories of checkpoint inhibitors that are currently FDA approved for the treatment of cancer.
PD-1 Inhibitors:
PD-L1 Inhibitors:
CTLA-4 Inhibitor:
What Is Pseudoprogression in Brain Cancer?
Pseudoprogression has been seen for some time withglioblastoma, a type of brain cancer, and even more so with newer treatments options for it. People with glioblastoma treated with the combination of the chemotherapy drug Temodor (temozolomide) and radiation have a high incidence of pseudoprogression.
Chemo vs Radiation for Cancer Treatment
Targeted Therapies and Pseudoprogression
Unlike chemotherapies that end up killing cancer cells and normal cells, targeted therapies are designed to hit a particular protein of the cancer cell. This leads to destroying the bad cells in a more directed way. Immunotherapy works in a more directed way, as well as it unleashes the body’s own defense cells to fight cancer.
Cancers for Which Pseudoprogression Has Been Documented
Pseudoprogression has been seen with a number of different cancers treated with checkpoint inhibitors, including:
How Common Is Pseudoprogression?
The incidence of pseudoprogression is somewhat difficult to define as there is no universally accepted definition. The incidence also appears to vary between different types of cancer. Both the occurrence of pseudoprogression and the understanding of the phenomenon will likely increase as these drugs become more commonly used.
Melanoma
The incidence of pseudoprogression on immunotherapy appears to be highest for melanoma, with rates ranging from 4% to 10% depending on the study.
Lung Cancer
A different 2018 study published inJAMA Oncologyfound the incidence to be 4.7%.
Other Cancers
Pseudoprogression has also been noted uncommonly in kidney cancer and bladder cancer. Since the first immunotherapy drug was approved for breast cancer in 2019, it won’t be known for some time what the true incidence is in these other cancers.
How Long Does Pseudoprogression Last?
Pseudoprogression is most common in the first weeks after the start of immunotherapy treatment but has been seen as late as 12 weeks after initiation of treatment.The average time to response on imaging tests (when the tumor begins to decrease in size on scans) is six months.
Before starting immunotherapy, it’s difficult to know whether pseudoprogression may occur. It’s not usually until an increase in tumor size is seen on a scan that the diagnosis of pseudoprogression may be suspected.
At that time, it’s important to try to distinguish pseudoprogression from true progression of the tumor. However, this process is still challenging despite the development of specific criteria.
Imaging Tests
It is thought thatpositron emission tomography (PET) scans, which look at tissues at a cellular level, may help distinguish pseudoprogression from true progression. Unfortunately, the infiltration of immune cells into and around a tumor can lead to increased metabolic activity, which indicates cancer. This means that PET scan results can mimic the true progression of a tumor.
In some cases, changes on imaging tests may indicate a true progression is more likely. New metastases in organs where metastases were not previously present increases the chance that it is true progression. That said, the appearance of small metastases may be due to immune cells gathering around a site of metastasis that was there before treatment was started, but weren’t large enough to be seen on imaging tests.
Tissue Biopsy Results
Abiopsy, or tissue sample, of a tumor taken during pseudoprogression may show infiltration oflymphocytes, or small white blood cells, into the tumor. That said, biopsies are invasive and are sometimes very difficult to perform depending on the location of the tumor.
Pseudoprogression Symptoms
If a person has imaging tests that show an increase in the size of a tumor but is stable or improving, it’s more likely to be pseudoprogression. In contrast, if a tumor is increasing and a person has worsening symptoms, new symptoms, or a general decline in health, it’s more likely to be a true progression.
Confirmation of Pseudoprogression
If pseudoprogression is suspected, follow-up scans are usually done, but there aren’t general guidelines on the frequency of these scans. Some physicians recommend a scan in four or eight weeks. However, it may be longer than eight weeks before it’s known whether an increase in tumor burden is due to pseudoprogression or true progression.
Circulating Tumor DNA (ctDNA)
Circulating tumor DNA detected in blood samples (liquid biopsysamples) may be helpful in distinguishing pseudoprogression from true progression with some cancers.
A study found that measuring ctDNA could reliably distinguish pseudoprogression from true progression in people with metastatic melanoma who were treated with checkpoint inhibitors.
With pseudoprogression, it would be expected that the amount of circulating tumor DNA (pieces of DNA from the tumor in the bloodstream) would decrease, whereas it would be expected to increase in true progression. The study found that very few people who had true progression had a favorable ctDNA profile, whereas people who had pseudoprogression had a favorable ctDNA profile.
Measuring ctDNA was only applicable for those who had tumor mutations that could be identified.
Differential Diagnosis
If progression is seen on imaging studies, it’s important to attempt to distinguish whether it is because of a true progression, hyperprogression, a side effect of the immunotherapy drug, or pseudoprogression.
Thedifferential diagnosisof pseudoprogression includes:
Decision Making
There aren’t specific guidelines on how to approach possible pseudoprogression. Instead, the changes on imaging, clinical symptoms, and other findings need to be weighed for each person.
While a lack of a prompt response to treatment may lead to the conclusion that a treatment was ineffective, it’s important with immunotherapy drugs not to stop a treatment that could turn out to be effective.
Themanagement of a tumoror metastases that appear to be increasing in size in imaging studies depends on careful clinical judgment, and needs to be individualized for each person.
If pseudoprogression is suspected, but an individual is stable, immunotherapy is usually continued but with careful follow-up imaging tests. There isn’t a set protocol, but many physicians will check scans in four to eight weeks. That said, in some cases a response to treatment has not been seen for as long as 12 weeks with pseudoprogression.
What Is Oncology?
Pseudoprogression can be seen as a good thing. People who have pseudoprogression tend to do better than those who have true progression. Overall, people who have pseudoprogression tend to have similar outcomes to those who don’t have pseudoprogression.
A 2016 study looking at people with different advanced cancers including melanoma, non-small cell lung cancer, small cell lung cancer, and breast cancer treated with checkpoint inhibitors found that pseudoprogression was relatively uncommon. However, it indicated a high likelihood that people would survive more than one year.
While treatments for advanced cancers have improved greatly, they have also brought with them the anxiety of waiting. Often times, initial testing for these cancers may not return results for two to four weeks.
This waiting time, though long, is important in order to properly treat the disease. For example, people with non-small cell lung cancer who have gene mutations in their tumors are usually better served with targeted therapies and immunotherapy could cause more harm than good.
In a different way, waiting to see if an increase in the size of a tumor on a scan is pseudoprogression or not can be heart-wrenching, as people wonder whether the treatment they are receiving is doing anything at all. Already familiar with the anxiety related to waiting for scan results (scanxiety), this can be challenging.
There’s not a simple solution to anxiety, but it may be helpful to:
For friends and family, the anxiety can be intense as well, and you may find yourself trying to educate loved ones about why waiting is important.
Summary
Looking at an individual’s symptoms, as well as scans can help a healthcare provider diagnose pseudoprogression. However, waiting for scans can lead to anxiety. If you or loved one may be experiencing pseudoprogression, there are many ways to cope.
8 SourcesVerywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Fujimoto D, Yoshioka H, Kataoka Y, et al.Pseudoprogression in previously treated patients with non–small cell lung cancer who received nivolumab monotherapy.J Thoracic Oncol.2019;14(3):468-474. doi:10.1016/j.jtho.2018.10.167Lee 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 Oncology.2018;4(5):717-721. doi:10.1001/jamaoncol.2017.5332National Cancer Institute.Tumor burden.Park HJ, Kim KW, Pyo J, et al.Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: a systematic review and meta-analysis.Radiology. 2020;297(1):87-96. doi:10.1148/radiol.2020200443Beer L, Hochmair M, Prosch H.Pitfalls in the radiological response assessment of immunotherapy.Memo. 2018;11(2):138-143. doi:10.1007/s12254-018-0389-xFerrara 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 Oncology.2018;4(11):1543-1552. doi:10.1001/jamaoncol.2018.3676Jia W, Gao Q, Han A, Zhu H, Yu J.The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy.Cancer Biol Med. 2019;16(4):655-670. doi:10.20892/j.issn.2095-3941.2019.0144Kurra V, Sullivan RJ, Gainor JF, et al.Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes.J Clin Oncol.2016;34(15_suppl):6580. doi:10.1200/jco.2016.34.15_suppl.6580
8 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Fujimoto D, Yoshioka H, Kataoka Y, et al.Pseudoprogression in previously treated patients with non–small cell lung cancer who received nivolumab monotherapy.J Thoracic Oncol.2019;14(3):468-474. doi:10.1016/j.jtho.2018.10.167Lee 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 Oncology.2018;4(5):717-721. doi:10.1001/jamaoncol.2017.5332National Cancer Institute.Tumor burden.Park HJ, Kim KW, Pyo J, et al.Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: a systematic review and meta-analysis.Radiology. 2020;297(1):87-96. doi:10.1148/radiol.2020200443Beer L, Hochmair M, Prosch H.Pitfalls in the radiological response assessment of immunotherapy.Memo. 2018;11(2):138-143. doi:10.1007/s12254-018-0389-xFerrara 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 Oncology.2018;4(11):1543-1552. doi:10.1001/jamaoncol.2018.3676Jia W, Gao Q, Han A, Zhu H, Yu J.The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy.Cancer Biol Med. 2019;16(4):655-670. doi:10.20892/j.issn.2095-3941.2019.0144Kurra V, Sullivan RJ, Gainor JF, et al.Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes.J Clin Oncol.2016;34(15_suppl):6580. doi:10.1200/jco.2016.34.15_suppl.6580
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
Fujimoto D, Yoshioka H, Kataoka Y, et al.Pseudoprogression in previously treated patients with non–small cell lung cancer who received nivolumab monotherapy.J Thoracic Oncol.2019;14(3):468-474. doi:10.1016/j.jtho.2018.10.167Lee 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 Oncology.2018;4(5):717-721. doi:10.1001/jamaoncol.2017.5332National Cancer Institute.Tumor burden.Park HJ, Kim KW, Pyo J, et al.Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: a systematic review and meta-analysis.Radiology. 2020;297(1):87-96. doi:10.1148/radiol.2020200443Beer L, Hochmair M, Prosch H.Pitfalls in the radiological response assessment of immunotherapy.Memo. 2018;11(2):138-143. doi:10.1007/s12254-018-0389-xFerrara 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 Oncology.2018;4(11):1543-1552. doi:10.1001/jamaoncol.2018.3676Jia W, Gao Q, Han A, Zhu H, Yu J.The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy.Cancer Biol Med. 2019;16(4):655-670. doi:10.20892/j.issn.2095-3941.2019.0144Kurra V, Sullivan RJ, Gainor JF, et al.Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes.J Clin Oncol.2016;34(15_suppl):6580. doi:10.1200/jco.2016.34.15_suppl.6580
Fujimoto D, Yoshioka H, Kataoka Y, et al.Pseudoprogression in previously treated patients with non–small cell lung cancer who received nivolumab monotherapy.J Thoracic Oncol.2019;14(3):468-474. doi:10.1016/j.jtho.2018.10.167
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 Oncology.2018;4(5):717-721. doi:10.1001/jamaoncol.2017.5332
National Cancer Institute.Tumor burden.
Park HJ, Kim KW, Pyo J, et al.Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: a systematic review and meta-analysis.Radiology. 2020;297(1):87-96. doi:10.1148/radiol.2020200443
Beer L, Hochmair M, Prosch H.Pitfalls in the radiological response assessment of immunotherapy.Memo. 2018;11(2):138-143. doi:10.1007/s12254-018-0389-x
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 Oncology.2018;4(11):1543-1552. doi:10.1001/jamaoncol.2018.3676
Jia W, Gao Q, Han A, Zhu H, Yu J.The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy.Cancer Biol Med. 2019;16(4):655-670. doi:10.20892/j.issn.2095-3941.2019.0144
Kurra V, Sullivan RJ, Gainor JF, et al.Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes.J Clin Oncol.2016;34(15_suppl):6580. doi:10.1200/jco.2016.34.15_suppl.6580
Meet Our Medical Expert Board
Share Feedback
Was this page helpful?Thanks for your feedback!What is your feedback?OtherHelpfulReport an ErrorSubmit
Was this page helpful?
Thanks for your feedback!
What is your feedback?OtherHelpfulReport an ErrorSubmit
What is your feedback?
