Expert Explains Evolving Role of Radiotherapy in NSCLC

James Urbanic, MD

Incorporating radiotherapy into the treatment of patients with oligometastatic or metastatic non—small cell lung cancer (NSCLC) is standard practice, but its optimal placement in the paradigm is less clear with the advent of immunotherapy and other treatment advances, said James Urbanic, MD.

To determine whether it should be used upfront or in later lines of treatment, researchers are exploring how the addition of immunotherapy changes the role of radiation. Advances in targeted therapies, such as osimertinib (Tagrisso) and alectinib (Alecensa), are also likely to impact radiation’s role in treatment. Better blood-brain penetration with these agents enables radiation oncologists to hold off on treating brain metastases, resulting in less incidence of whole-brain radiotherapy and treatment-emergent adverse events.

Advances in radiation techniques and technology are also refining the use radiation in NSCLC. “The speed of delivery, and the complexity that we can deliver the radiation to the patient from different angles, are changing as both the software and hardware improve,” explained Urbanic.

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In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Urbanic, associate professor of Radiation Medicine and Applied Sciences, University of California, San Diego, discussed the evolving role of radiotherapy in patients with oligometastatic and metastatic NSCLC.Urbanic: I spoke about when we should use radiation treatment in metastatic NSCLC, particularly in the setting in which a patient might have 1 to 3 relatively small metastases. Historically, chemotherapy has had modest effectiveness. Initially, surgeons pioneered this idea of taking out a few small metastatic sites. As radiation treatment has gotten better over the past number of years, we have gotten better at picking off small areas of disease with very high-dose radiation treatments.

What is the prevalence of patients with oligometastatic disease?

How have techniques evolved?

Has tolerability with radiation therapy improved?

Will radiation become more of a multimodality approach?

We now have the opportunity to control those spots 9 out of 10 times. As chemotherapy is getting better, it makes more sense to integrate the use of radiation treatment into the patients’ overall treatment plan. Some of those patients with small amounts of metastatic disease have particularly long and durable survival rates. They are fairly common, but there are multiple types of them. There are some patients who have a small line of brain metastases and no other systemic sites. There are other patients who have 2 or 3 sites throughout the body. For the radiation oncologist, it depends in part on the referral base and the acceptance of looking at a local therapy as a good treatment rationale for these patients. This is in terms of how many patients I'll see in any given year. Clearly, over the past number of years, we are seeing more and more of these [types of] patients. Radiation techniques are all about stereotactic radiosurgery, given in either 1 treatment or a short course of 1 to 5 treatments. What that means is trying to give a very high dose to the tumor itself in a very steep, rapid-dose gradient, or fall off from the high-dose area to the low-dose area. You're treating the tumor itself with the lethal dose of radiation to those cells. Those techniques are being further refined. There are some limitations to how much more you can refine x-rays.It's all location dependent. There are many patients we can treat for a very small target; those patients have very limited risk. As we start treating more sites, larger tumors, and disease in parts of the body that don't have a lot of redundancy, the risk goes up. For example, if you treat a metastasis in the brain stem, that patient is going to have a fairly high risk of toxicity. If you treat a tumor in the main stem bronchus, you have a risk of causing injury to that part of the lung; that has a high risk of serious toxicity. For the most part, risks are fairly limited for many small and isolated tumors.Yeah, it is pretty interesting. A lot of the trials that were done recently on radiation in oligometastatic lung cancer were done in the era of maintenance chemotherapy. In a couple randomized phase II trials, we looked at maintenance therapy alone or maintenance therapy plus consolidation radiation treatment. The data are pretty promising. The progression-free survival was clearly longer in both The University of Texas Southwestern study and in The University of Texas MD Anderson Cancer Center study.

The data that we had generated out of the Comprehensive Cancer Center at Wake Forest Baptist Health was very encouraging, as well. Now that we have immunotherapy, we're sort of starting all over again with where to integrate radiation treatment. Is it upfront in trying to generate a heightened immune response, or is it further into the treatment course as a means to restimulate efficacy after immunotherapy? Is it after we've shrunken larger tumors to a size that is amenable to radiation treatment?

Is there any rationale for combinations of osimertinib or alectinib, both of which cross the blood-brain barrier, with radiation therapy?

Studies are looking so good. Data from a recent study published in the New England Journal of Medicine looking at chemotherapy versus chemotherapy plus immunotherapy suggested a benefit that exceeds anything that has ever been seen in metastatic lung cancer. This will impact how physicians think about interdigitating radiation. It is going to make it more important, as more patients with a historically worse prognosis are put into a group of patients with—what I'm scared to say—may be a curable disease or a disease that can have a long lifespan to it. Patients with [EGFR] mutations who are getting osimertinib represents a whole different issue from the immunotherapy issue. For some patients, we may not need to treat their brain metastasis right away. We can see what kind of response we're going to get from their targeted therapy and then use radiation to pick off those resistant areas. That's becoming more comfortable for radiation oncologists. A few years ago, we would have been hesitant to wait and see if the systemic therapy was going to work in the brain.

It's also going to further minimize the use of whole-brain radiotherapy and reduce the side effects of the treatment there. It will make us more heavily rely on radiosurgery. I've had a couple of patients with ALK-positive disease in which we didn’t treat all of their metastasis [with radiation], but some of their larger metastasis with radiosurgery. Their ALK-targeted therapy took care of the smaller amounts of disease.

What other ongoing radiotherapy-focused trials are you excited about?

In one of my patients, we had gone back and treated additional brain metastasis. I correlated that the spots we were treating the second time around weren't a recurrence of the original metastasis, which was fascinating. The drug is doing a good job on its own. How we integrate that is changing rapidly. In terms of oligometastatic lung cancer, NRG-LU002 is a randomized phase II/III trial that was recently opened nationally through NRG Oncology. That trial is looking at consolidation radiation—primarily with radiosurgery and stereotactic body radiation therapy—with maintenance chemotherapy versus maintenance chemotherapy alone. We're opening that here at the University of California, San Diego.

Because these things take so long to develop, that trial is going to change in the near future. I have good insight that they're going to have to add an immunotherapy component because patients are getting immunotherapy. I'm very excited about that trial because it's a chance for us radiation oncologists to stick our flag in the sand and say that we have a real role to play in this disease.