Pseudo-Progression With Cancer Treatment

Pseudoprogression describes 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 of immunotherapy drugs—like checkpoint inhibitors—that it became relatively common to see an increase in the size of a tumor or number of metastases on 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.

Overview

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:

• Durable responses: A "durable response" is a term that refers to a response to treatment that is long-lasting. With checkpoint inhibitors, unlike other cancer treatments, they may continue to work even after the medication has been stopped.
• Hyperprogression: In a small percentage of people, receiving checkpoint inhibitors has resulted in the very rapid growth of their cancers—more rapid than would be expected if the cancer had progressed at its own pace.

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.

• In a 2019 study looking at people with non-small cell lung cancer, pseudoprogression was diagnosed if individuals responded to treatment within three months and if their tumors decreased in size by 30% from the time of progression.
• In a 2018 study in people with metastatic melanoma or skin cancer, pseudoprogression was defined as an increase in tumor burden on imaging of 25% or more at week 12. This increase was not confirmed as progressive disease on later imaging studies.

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 because imaging tests are seeing 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.

Delayed Response

Checkpoint inhibitors work by essentially taking the brakes off the body's own immune system. However, even when the immune cells recognize cancer cells, it can still take time before they are able to destroy them. 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.

PD-1 Inhibitors:

• Keytruda (pembrolizumab)
• Opdivo (nivolumab)
• Libtayo (cemiplimab)

PD-L1 Inhibitors:

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

CTLA-4 Inhibitor:

• Yervoy (ipilimumab)

What Is Pseudoprogression in Brain Cancer?

Pseudoprogression has been seen for some time with glioblastoma, 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.

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.

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:

• Melanoma
• Non-small cell lung cancer
• Hodgkin's lymphoma, a blood cancer that starts in the lymph nodes
• Urothelial carcinoma, or bladder cancer
• Renal cell carcinoma, or kidney cancer

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 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, and 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 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.

Diagnosis

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 that positron 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

A biopsy, or tissue sample, of a tumor taken during pseudoprogression may show infiltration of lymphocytes, 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 biopsy samples) 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.

The differential diagnosis of pseudoprogression includes:

• True progression: A true progression means that a tumor continues to grow despite immunotherapy's use, 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 expected if no treatment was given. Hyperprogression doesn't have a universal 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 before treatment, or a more than two-fold increase in the pace or rate of progression.
• Lung DiseaseInterstitial: Immunotherapy can sometimes cause interstitial lung disease or inflammation of lung tissue. Findings might be difficult to distinguish at first from a lung tumor that is growing.

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.

Management and Treatment

The management of a tumor or 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.

Prognosis

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.

Coping

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:

• Connect with others, especially those who have faced a similar waiting game
• Consider joining a support group in your community
• Consider joining an online cancer support community that allows you 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.

Summary

Pseudoprogression describes when cancer appears to worsen, despite actually improving. Immunotherapy drugs, such as checkpoint inhibitors, are associated with an increase in size and burden of tumors, followed by tumor regression.

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.