RT Options Evolving in Oligometastatic Lung Cancer Landscape and Beyond

Billy W. Loo Jr, MD, PhD

On its own, stereotactic ablative radiotherapy (SABR) has been established in the field as a go-to radiation option for patients with lung cancer, especially in those with oligometastatic disease, explains Billy W. Loo Jr, MD, PhD.

Now, the precise, technological advance is continuing to be explored in novel methods, including in combination with immunotherapy in an effort to delay disease recurrence.

For example, an ongoing phase II clinical trial is randomizing patients with stage I, selected stage IIa, or isolated lung parenchymal recurrent non—small cell lung cancer to the combination of the PD-1 inhibitor nivolumab (Opdivo) plus SABR versus SABR alone (NCT03110978). The primary endpoint of the trial is event-fee survival, with secondary endpoints being overall survival and safety.

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OncLive: Please provide an overview of your presentation.

Loo, an associate professor of radiation oncology at Stanford Medicine, shed light on the advancements in radiation therapy (RT) options for patients with lung cancer, how SABR has improved outcomes for patients, and the intriguing combinations being explored with RT and immunotherapy. Loo discussed these topics in an interview during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer.Loo: I talked about one particular development in RT, which is ablative radiotherapy—SABR—and some of the indications, how it developed first for treatment of early-stage lung cancer for patients primarily who were not candidates for surgery, and how additional emerging indications have come out. These include RT for certain patients with metastatic disease.

What are some of these strategies to make SABR more precise?

I talked a bit about some of the technical developments that allow us to do this type of very precise treatment and the strategies that we use to make the treatments extremely accurate and precise. These allow us to give a high enough dose intensity to ablate the tumors without causing excessive collateral damage to the normal organs. That has been the key technical advance that allows us to use this new type of treatment. The key principle of SABR is that we’re treating relatively small tumors, and what we're doing is using focused radiation to physically isolate the tumors from the surrounding normal organs. We focus the radiation beams by using beams from many different angles, all of which intersect where the tumor is. That allows us to keep the dose at the tumor very high and, meanwhile, keep it low to the surrounding areas.

The key behind this is to do it very accurately. We gain accuracy by doing what we call image guidance. We use imaging before and during the treatment to ensure that the radiation beams are going exactly where they should go.

We also eliminate sources of uncertainty. For example, we are always treating moving targets when we are treating in the lung. Over time, we have implemented what we refer to as motion management strategies. These include, first of all, imaging to understand how tumors move as patients breathe. There are additional strategies we use to track the tumor to follow it with the radiation beam and turn the beam on or off—to correspond with when the tumors are in a given location. We refer to that as respiratory gating.

What next steps do you anticipate with SABR?

We coach patients using biofeedback to get them to hold their breath with the tumor at a given location. There are a lot of different strategies we have implemented over time to make these treatments as precise as possible. SABR was first developed, at least in the context of lung cancer, as a treatment for patients with early-stage lung cancer. Normally these patients would go to surgery, but many patients are unable to tolerate surgery because of medical comorbidities. Therefore, SABR emerged as an alternative for those patients as opposed to the conventional RT that we have done in the past, which was an alternative but really not an optimal one.

The outcomes of SABR, with experience now, have become sufficiently good and quite comparable to surgery, and it has become the standard of care for patients who can’t have surgery. In fact, it is becoming an option for many patients who are more borderline candidates and have reasons to avoid surgery or who have contraindications of surgery.

One of the new areas that has come up in recent years is this concept of oligometastases—patients with metastatic disease, but a limited burden of it. What we found, with a lot of emerging data, is that some of those patients not only derive long-term benefit, but some are even cured if they’re treated aggressively—if all of the sites of metastatic disease are treated with curative or ablative intent. As we are seeing more and more systemic therapies, that actually increases the potential for adding in effective local therapies to convert some patients, who would otherwise be getting essentially palliative or maintenance therapy, to possible curative therapy.

What is the potential of immunotherapy combined with RT in patients with lung cancer?

We are also learning how to optimize SABR. A lot has been learned in recent years about how to optimize the dose for certain tumor size, location, and histology, and we are learning a lot about interactions of SABR with newer, molecular-targeted and immunotherapy-type treatment approaches. There are a couple of really interesting things. One that I alluded to in the context of oligometastatic disease, where there’s a limited disease burden, is that it could potentially be treated with high-intensity aggressive, locally aggressive, or ablative-type treatments, like SABR. These patients have a high risk of microscopic disease. There is a potential for interaction. The better we are at controlling the microscopic disease with systemic therapy, the higher the potential with the addition of local therapies. Some of these patients could be converted to either long-term control or even cures in some cases.

An interesting, emerging area is there are actually biologically synergistic effects between radiation and some of these novel therapies. Again, in disease that is oligometastatic or oligoprogressive (patients with even widespread metastatic disease but who are well controlled—it is in pocketed areas, and [there] are a number of progressive regions), there are emerging data that show that local therapy to those oligoprogressive sites will extend the overall duration of usefulness of a given line of targeted therapy. Therefore, you don’t necessarily have to switch from a therapy that is otherwise working if we can target limited areas of resistant disease.

In the context of immunotherapy, there is a lot of [discussion] about biological potential synergy, where the radiation may, in fact, create sort of an in situ vaccine and augment the immunologic response. It is not necessarily restricted just to the area that has been irradiated, but potentially to other lesions that have not been irradiated—so waking up the immune response.

What do you hope community oncologists took from your lecture to apply to practice?

There are a lot of interesting biological data coming out on that—the potential for understanding how to create that optimal effect. There has historically been a lot of anecdotal data of what we call an abscopal effect; you treat 1 lesion and other lesions respond. Really, these are rare observations; many of us have observed them, but they are quite rare. It makes sense that this might be due to an immune effect, as we understand the biology better. The hope is that we understand how to make it not a rare effect, but a consistent effect. All of us aim to have personalized therapy and understand how to individualize treatments for given patients. One of the takeaways is to understand that there are options out there and newer treatments available to some patients [who] we recognize might benefit from some newer approaches. These include some patients with oligometastatic disease. We shouldn’t necessarily assume that they go from 1 systemic therapy to another, [especially] if there is an opportunity to do something a little bit more effective for properly selected patients.