Stage IIIB Unresectable NSCLC After Chemoradiotherapy - Episode 2
Hossein Borghaei, DO, MS:The abscopal effect of radiation is actually a very interesting biological phenomenon that’s been demonstrated in experimental settings. And also, in certain diseases there are many case reports of patients with various malignancies benefiting from this abscopal effect. So what do we mean by abscopal effect? Basically, it means off-target benefit from radiation, such that if you are radiating a right-upper-lobe mass, you see shrinkage or response in a left-sided lymph node, for instance, in the case of a patient with lung cancer.
It is hard to say for sure what percentage of patients that we see actually benefit from the abscopal effect of radiation. Now that we have different radiation delivery mechanisms, different doses of delivery, we’re beginning to recognize that perhaps there might be a varying level of immune activation based on the dose of radiation used. Some of the literature out there support the fact that low-dose radiation is immune stimulatory and high-dose radiation could actually be immune inhibitory. I would say that this area is still under investigation, but in the era where we have very effective, well-tolerated checkpoint inhibitors, the concept of the abscopal effect of radiation is under intense investigation. I cannot tell you that in my practice I’ve seen a clear example of the abscopal effect, but again, as I said earlier, there are case reports and case series of patients benefitingnot a lot in lung cancer but definitely in some of the other malignancies.
So I think based on the experimental evidence and based on these case reports, there is an immune activation as a result of the use of radiation. What is that dose? Is it related to the site of radiation? Is it related to the kind of radiation used? I think these are all questions that we don’t have an answer to, but I do think that we get some level of immune activation. Why are we interested in this? But again, because we now have immunomodulatory agents, if we learn to harvest the power of these drugs and if we can learn to really understand the potential of abscopal effects of radiation, such combinations can be very powerful and beneficial to our patients. But I would say, at this point, it is a little bit investigational.
As I alluded to earlier, when you are using a method such as radiation where you think there might be immune activation, given our current understanding of the way things might work from that immune activation perspective, it is reasonable to assume that the use of a checkpoint inhibitor can actually lead to the usual activation of the T cells in the tumor microenvironment. And if you combine that with immune stimulatory effects of both chemotherapy and radiation, you might have a more profound immune response. With chemotherapy, we think because of what has been labeled immunogenic cell deathmeaning the cytotoxic chemotherapy can actually cause direct cell death of the cancer cells—and by virtue of the process of actually killing the cancer cells, there could be antigen presentation with neoantigens and that can lead to immune activation.
The same story applies to the effects of the radiation, combined with the fact that, again, we think that there might be some abscopal effect of radiation at distant sites away from the site or radiation. Then having a tumor milieu that’s ready, you come in with a checkpoint inhibitor that activates the T cells at the appropriate time. Then you could have a more profound immune activation. And therefore, the combination of chemotherapy and radiation followed by a checkpoint inhibitor is sort of an approach that I think has been attractive. And now we have a test that would prove that actually the outcomes could be better for patients who get a checkpoint inhibitor after chemotherapy and radiation.
And what that would suggest, to some extent, is that the theoretical basis of this argumentmeaning that both chemotherapy and radiation are immune stimulatory—could potentially be true because the outcome, as we’ve seen in the PACIFIC study, suggests that the use of a checkpoint inhibitor almost immediately after chemoradiation is highly effective.
Transcript edited for clarity.
Case: A 72-Year-Old Female With Stage IIIB NSCLC