Pseudo-Progression With Cancer Treatment

When Cancer Only Appears to Worsen on Checkpoint Inhibitors

T cells attacking cancer cell can cause the appearance of pseudoprogression

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Pseudoprogression of cancer, or the apparent worsening of a cancer when it's actually improving, is a relatively new concept in cancer treatment. With the exception of a type of brain cancer, it wasn't until the introduction of immunotherapy drugs such as checkpoint inhibitors that it became relatively common to see tumors increase in size on imaging studies initially, only to decrease in size (or number of metastases) later on.

Pseudoprogression is important to understand and manage appropriately as it must be distinguished from true progression. With true progression, continuing checkpoint inhibitors would be continuing a therapy that isn't effective. But continuing checkpoint inhibitors with pseudoprogression is important as the tumors will eventually respond to these drugs, sometimes with dramatic and durable responses (lasting improvement in the cancer).

Overview

The introduction of immunotherapy drugs has been a game-changer in cancer treatment, but has brought with it concepts not seen (at least not often) with prior treatment options. Some of these include:

  • Durable responses: A "durable response" is a term that refers to a response to treatment that is long-lasting. A number of people (but still a minority) with very advanced cancers have seen their tumors well controlled and sometimes disappear completely without evidence of return. And with checkpoint inhibitors, unlike treatments such as chemotherapy, the treatment may continue to work even after the medication is discontinued. There has even been talk that some people treated with these drugs may be cured of their stage 4 cancers. This isn't surprising; there have been rare cases of spontaneous remission of cancer, and the mechanism appears to be similar to that of immunotherapy drugs.
  • Hyperprogression: In a small percentage of people, receiving checkpoint inhibitors has resulted in very rapid growth of their cancers—more rapid than would be expected if the cancer had progressed at its own pace.
  • Pseudoprogression: Pseudoprogression of a cancer refers to an increase in the size of a tumor or number of metastases on imaging tests, that is not due to the growth or spread of the cancer.

Unfortunately, while there are tests that may help predict who will best respond to these drugs, there aren't any objective ways at this time to predict who may develop hyperprogression or pseudoprogression.

Definitions of Pseudoprogression

There is not a universally accepted definition of pseudoprogression, and the precise definition varies between studies.

In a 2019 study looking at people with non-small cell lung cancer, pseudoprogression was diagnosed if a Response Criteria in Solid Tumors (RECIST)-defined response occurred after a RECIST-defined progression, with a decrease in the largest diameter of targeted lesions by at least 30% from the time of determination of progression (not from baseline).

In a 2018 study in people with metastatic melanoma, pseudoprogression was defined as an increase in tumor burden on imaging of 25% or more at week 12, that was not confirmed as progressive disease on later imaging studies.

Mechanism

Pseudoprogression may occur due to more than one mechanism:

Immune Infiltration

Pseudoprogression is thought to often be due to the immune cells that infiltrate and surround a tumor in response to immunotherapy drugs. While the size of a tumor may appear to increase in size on imaging tests, the apparent increase may be because imaging tests are detecting both the tumor and surrounding 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.

While this concept is confusing, we have seen how immune cells can cause a "mass" in a different setting in the past. The enlarged lymph nodes or "swollen glands" often found with viral infections or strep throat are related to the accumulation of immune cells in the nodes.

The concept of pseudoprogression can be challenging to understand as it requires us to think about tumors in a new way. In the past, most discussions about cancer focused on the tumor alone. At the current time, we are learning that the tumor microenvironment—the "normal" cells in the area surrounding a tumor—play a very important role in both tumor growth and response to treatment. It is this tumor microenvironment that is likely responsible for the findings seen with pseudoprogression in at least some cases.

Delayed Response

Understanding how immunotherapy drugs (checkpoint inhibitors) work compared with other cancer treatments is also helpful when looking at the response to these drugs. Treatments such as chemotherapy and radiation cause the death of cancer cells almost immediately with treatment, and a response may be seen quickly. Since checkpoint inhibitors work by essentially taking the brakes off the body's own immune system, it can take longer for these treatments to work. Once the immune cells are able to recognize cancer cells, they must multiply as well as travel to infiltrate a tumor before causing the death of cancer cells. During this time, a tumor may continue to grow (delayed response) before responding to the drug.

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 (though with different indications).

PD-1 Inhibitors:

PD-L1 Inhibitors:

  • Tecentriq (atezolizumab)
  • Imfinzi (durvalumab)
  • Bavencio (avelumab)

CTLA-4 Inhibitor:

  • Yervoy (ipilimumab)

Glioblastoma (Brain Cancer) and Pseudoprogression

While this article focuses on checkpoint inhibitors and pseudoprogression, it has been seen for some time with glioblastoma (a type of brain cancer), and even more so with newer treatments. People with glioblastoma treated with the combination of the chemotherapy drug Temodor (temozolomide) and radiation have a high incidence of pseudoprogression. This differs from the pseudoprogression discussed below in that tests such as perfusion MRI may be used to distinguish pseudoprogression from true progression.

Targeted Therapies and Pseudoprogression

An increase in the size of tumors followed by stabilization has also been seen with the targeted therapy drugs known as tyrosine kinase inhibitors. In fact, this is the reason why these drugs are sometimes continued even if a cancer appears to progress on imaging studies.

Cancers for Which Pseudoprogression Has Been Documented

Pseudoprogression has been seen with a number of different cancers treated with checkpoint inhibitors including:

  • Melanoma
  • Non-small cell lung cancer
  • Hodgkin's lymphoma
  • Bladder cancer (urothelial carcinoma)
  • Kidney cancer (renal cell carcinoma)

Incidence

The incidence of pseudoprogression is somewhat difficult to define as there is no universally accepted definition and measures vary between studies. The incidence also appears to vary between different types of cancer. What's more certain, is that it's likely both the occurrence of pseudoprogression and our understanding of the phenomenon will 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 large 2019 study published in the Journal of Thoracic Oncology looked at responses to Opdivo (nivolumab) in people treated for advanced non-small cell lung cancer. In the study, 20% of people responded to the drug whereas 53% experienced progression. The rate of pseudoprogression was 3%, and was most often seen early on (1 month) with a response seen by 3 months.

A different 2018 study published in JAMA Oncology found the incidence to be 4.7%.

Other Cancers

Pseudoprogression has also been noted uncommonly in Kidney cancer (renal cell carcinoma) and Bladder cancer (urothelial carcinoma). 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.

When Does It Occur?

Pseudoprogression is most common in the first weeks after initial 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 6 months.

Diagnosis

Before starting immunotherapy, it's difficult to know whether pseudoprogression may occur. Though there are tests that have some value in predicting who may respond to these drugs (such as PD-L1 levels (expression), tumor mutation burden, tumor infiltrating lymphocytes, etc.), these tests haven't been associated with the presence of absence of pseudoprogression to date.

Therefore, 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 becomes important to try to distinguish pseudoprogression from true progression of the tumor; a process that is still challenging despite the development of immune-related response criteria that have been developed.

Imaging Tests

It has been thought that since PET scans are a "functional test" (they detect metabolic activity of a tumor) instead of a "structural" test (such as CT or MRI), PET scans may help distinguish pseudoprogression from true progression. Unfortunately, the infiltration of immune cells into and around a tumor can lead to increased metabolic activity and PET scan results can mimic 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 (for example, in the brain, bones, or other organs), increases the chance that a change represents true progression. That said, the appearance of small metastases may be due to immune cells congregating around a site of metastasis that was present before treatment was started, but still too small to be detected by imaging tests available.

Tissue Biopsy Results

A biopsy of a tumor taken during pseudoprogression may show infiltration of lymphocytes into the tumor. That said, biopsies are invasive and are sometimes very difficult to perform depending on the location of the tumor.

Clinical Symptoms

A very important variable when trying to distinguish between pseudoprogression and true progression is a patient's 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 weeks or eight weeks, but it may be longer than this before it's known whether an increase in tumor burden is due to pseudoprogression or true progression.

Circulating Tumor DNA (ctDNA)

In the future, circulating tumor DNA detected in blood samples (liquid biopsy specimens) may be helpful in distinguishing pseudoprogression from true progression, at least with some cancers.

A 2018 study published in JAMA Oncology 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 (if the tumor was actually growing and worsening). The study found that ctDNA was very sensitive (90%) in that very few people who had true progression had a favorable ctDNA profile. Likewise, ctDNA was found to be very sensitive (100%) in that all of the people who had pseudoprogression had a favorable ctDNA profile.

Measuring ctDNA was only applicable for those who had tumor mutations that could be identified (70% of those with melanoma), and is unlikely (at this time, anyway) to be a good method for evaluating pseudoprogression in people with tumors that don't have identifiable mutations.

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. At the current time, there isn't a blood test or signs on imaging films that are helpful in making these distinctions. The differential diagnosis of pseudoprogression includes:

  • True progression: A true progression means that a tumor is continuing to grow despite the use of immunotherapy, with growth similar to what would be expected if no treatment was given.
  • Hyperprogression: In a small number of people given checkpoint inhibitors, a tumor may grow faster than would be expected if no treatment was given. Hyperprogression doesn't have a universally accepted definition, but measures that have been used in studies include a time to treatment failure of less than two months, an increase of at least 50% in tumor burden compared with that prior to treatment, or a more than two-fold increase in the pace or rate of progression.
  • Interstitial lung disease: Immunotherapy can sometimes cause interstitial lung disease an an adverse effect. Findings might be difficult to distinguish at first from a lung tumor (or lung metastases) that are growing.

Decision Making

There aren't specific guidelines on how to approach possible pseudoprogression, but 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 in the past often led 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; sometimes with responses that were rarely seen before in the treatment of advanced cancer.

Management/Treatment

The management of a tumor (or metastases) that appear to be increasing in size on imaging studies depends on careful clinical judgment, and needs to be individualized for each person.

If pseudoprogression is suspected but a patient is stable, immunotherapy is usually continued but with careful follow-up imaging tests. There isn't a set protocol at this time, but many physicians will check scans in four weeks to eight weeks. That said, in some cases a response to treatment has not been seen for as long as 12 weeks with pseudoprogression.

Prognosis

People who have pseudoprogression certainly do better than those who have true progression, but many people wonder about the outcomes of those who have pseudoprogression when compared with people who respond right away to these drugs. 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, but indicated a high likelihood that people would survive more than one year.

Coping

While treatments for advanced cancers such as lung cancer and melanoma have improved greatly in recent years, they have also brought with them the anxiety of waiting. Often times, initial testing for these cancers includes next-generation sequencing, testing that 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 and other genomic alterations 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 connecting with others, especially those who have faced a similar waiting game can be priceless. Some people may have support groups in their community, but online cancer support communities allow people to get in touch with others facing a very similar journey 24/7.

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. Hopefully, as these newer therapies become better known to the public the historic view—that treatment should be started immediately and if a treatment isn't working immediately it should be stopped—will be replaced by an understanding of why this has now changed.

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Article Sources

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