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Bunn Weighs in on Managing Pseudoprogression and Hyperprogression in Patients With Lung Cancer

Shannon Connelly
Published Online:4:32 PM, Thu September 14, 2017

Paul A. Bunn, MD
When treating patients with immunotherapy, the phenomenon of pseudoprogression can make it difficult for physicians to determine if a patient is benefitting from the treatment.

Pseudoprogression, which occurs in less than 10% of patients with lung cancer, is when an early scan shows tumor growth that may be due to a delayed benefit of the immunotherapy treatment or inflammation of the tumor as T cells become active. Though tumor growth may prompt a physician to stop or change treatment, when a patient does respond to immunotherapy, the benefits can be long lasting.

In an interview with Targeted Oncology during the 18th Annual International Lung Cancer Congress, Paul A. Bunn, MD, said it is important for physicians to be able to identify the difference between true progression and pseudoprogression. But until investigators learn more about this condition, it will take a bit of trial and error, he added.

“If the patient is doing well, their symptoms go away, and they seem to be benefitting, you could continue [immunotherapy] for 1 or 2 more treatments and repeat the CT scan. If the patient is deteriorating and the scan is getting worse, you obviously stop the treatment,” advises Bunn, professor, James Dudley Chair in Cancer Research, Division of Medical Oncology, University of Colorado Denver School of Medicine.

Hyperprogression, which also occurs in a small subset of patients with lung cancer, is also a concern when treating patients with immunotherapy. Hyperprogression is when a patient experiences a significantly increased rate of tumor growth following immunotherapy treatment. A recent study published in Clinical Cancer Research defined it as time-to-treatment failure of less than 2 months, at least a 50% increase in tumor burden compared with pre-immunotherapy imaging, and a more than 2-fold increase in progression pace.

“When it works, immunotherapy works for a long time, but when it doesn't work, it doesn't work,” Bunn says. “In these patients who are getting symptomatic and having a declining performance status, you don't want to deprive them of the opportunity to get something else that might be effective.”

The ultimate goal is to identify biomarkers to help determine which patients will respond to immunotherapy, and which will not.
During the interview, Bunn discussed why pseudoprogression and hyperprogression are concerns when treating patients with immunotherapy, and weighed in on what to do in each situation.

TARGETED ONCOLOGY:  How do you define pseudoprogression?

Bunn: Pseudoprogression is when it appears that the tumor is getting larger, but the patient is responding. If you have a tumor and the lymphocytes come in and kill the cancer, because of all the lymphocytes, the tumor might seem bigger in the scan, whereas the tumor may actually be smaller. That seems to happen more often in melanoma, but it clearly can happen in lung cancer and there are definitely cases.

One of the advantages of neoadjuvant care is you have the scan, but you also have the surgical specimen. If there are a bunch of lymphocytes in the surgical specimen and the tumor is gone or much smaller, you can actually see that. It's a true indication of the response. From preliminary data on less than 50 patients and 2 trials, there is no question that you can have major pathologic responses in the absence of a CT response because of all the infiltration of lymphocytes. 

TARGETED ONCOLOGY:  Why is pseudoprogression a concern when you're treating patients with immunotherapy?

Bunn: For those people that benefit from immunotherapy, the responses frequently last a very long time. They do occur in the minority of patients, so if they do occur, you don't want to deprive the patient of the ability to have a long response. You certainly would like to make sure the treatment isn't working when you stop it, because if it does work, it can work for a very long time.

TARGETED ONCOLOGY:  How often does pseudoprogression occur in lung cancer?

Bunn: True pseudoprogression in lung cancer is not that common. It is true that patients with Response Evaluation Criteria in Solid Tumors (RECIST) stable disease may have a true pathologic response. We've seen that in the early neoadjuvant trials, but with stable disease and immunotherapy, if the patient is doing well, you continue the treatment. The big issue is if the tumor is 20% or more larger, which is RECIST progression, if that patient is having pseudoprogression because of the lymphocytes, you don't want to stop the treatment. Having it get 20% bigger and have a response is not that common, but it can occur. So what do you do? When that happens, it occurs early, so if the patient is doing well, their symptoms go away, and they seem to be benefitting, you could continue for 1 or 2 more [cycles of] treatments and repeat the CT scan. If the patient is deteriorating and the scan is getting worse, you obviously stop the treatment.

TARGETED ONCOLOGY:  What should community oncologists know about the difference between pseudoprogression and real progression?

Bunn: They should know that if the patient's tumor got bigger and the patient has not gotten better, they should stop the treatment. But if early on the tumor got 25% bigger and the patient's symptoms went away, they can consider continuing.
Another thing that isn't standard of care yet, but some of these studies have documented, is that if you have a molecular abnormality, that can be determined to be circulating tumor DNA in a liquid biopsy. In pseudoprogression, that has gone down. If the circulating tumor DNA is going down, but on scan the tumor got a little bigger and the patient is doing well, obviously you are going to continue. If the circulating tumor DNA goes up and the CT scan gets worse, time to stop. Circulating tumor DNA may be helpful in the future as we get more data about this.

TARGETED ONCOLOGY:  Why is hyperprogression a concern when treating patients with immunotherapy?

Bunn: When it works, immunotherapy works for a long time, but when it doesn't work, it doesn't work. In these patients who are getting symptomatic and having a declining performance status, you don't want to deprive them of the opportunity to get something else that might be effective. You don't want to deprive them of benefit from the immunotherapy, but you also don't want to deprive them of the opportunity to deprive them of something else. Again, you have the CT scan and if that is getting worse and the patient is getting worse and/or the circulating tumor DNA is getting worse, it's time to stop. If the circulating tumor DNA is getting better and the patient is getting better, but the scan isn't, it's OK to continue for 2 more cycles and repeat. 

TARGETED ONCOLOGY:  As we better understand immunotherapy, is there more that investigators are still learning about pseudoprogression and hyperprogression?

Bunn: Yes. If you have high levels to begin with, circulating tumor DNA can be very helpful. It’s possible there will be other markers. For example, in the peripheral blood, we can look at subsets of T cells or we can look at cytokines in the blood and we might be able to tell from other biomarkers in the future which is true progression and which is pseudoprogression, and hopefully be more accurate than that.
 
Reference:
Kato S, Goodman A M, Walavalkar V, et al. Hyper-Progressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017. doi:10.1158/1078-0432.CCR-16-3133.


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