Expert Unveils Untapped Potential in Radiotherapy for NSCLC

Ashley A. Weiner, MD, PhD

Although the standard of care for patients with stage III unresectable non—small cell lung cancer (NSCLC) has been concurrent chemoradiotherapy at 60 Gy at 2 Gy/fraction, the addition of immunotherapy for those who have not progressed on chemoradiotherapy can offer an increased benefit, explains Ashley A. Weiner, MD, PhD.

Results of the phase III PACIFIC trial showed that, regardless of PD-L1 status, patients with locally advanced, unresectable stage III NSCLC responded to the PD-L1 inhibitor durvalumab (Imfinzi). Objective response rate, as assessed by blinded independent central review, was also significantly higher with durvalumab (28.4% vs 16.0%; P <.001).

“It has been shown that there is some immune response— some innate release of immune markers in response to radiation in lung cancer and other disease sites that can help immunotherapy efforts&mdash;and that is really empowering,” says Weiner.

Proton radiotherapy has also been emerging in the field. While Weiner explains that it has many potential benefits, such as sparing the contralateral lungs and heart, there are challenges with its use in NSCLC.

OncLive^®: Can you speak to the use of radiotherapy in patients with NSCLC?

Can stereotactic body radiation boosts enable dose escalation?

How have the competing theories of radiation administration evolved?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Weiner, assistant professor, Department of Radiation Oncology, University of North Carolina (UNC) at Chapel Hill School of Medicine, UNC Lineberger Comprehensive Cancer Center, discussed the expansions and limitations of radiotherapy in patients with NSCLC and ongoing efforts to enhance administration and efficacy.Weiner: We are currently treating locally advanced or stage III lung cancer at 2 Gy/fraction at 60 Gy, and we’ve been doing that for a while. It’s safe and effective, but we’re looking to see if there is a more convenient and more efficacious approach for patients. We’re looking at ways to safely increase doses; some of these have been limited thus far with negative studies. Nonetheless, we’re investigating ways to administer higher doses per fraction, or use hypofractionation.It’s possible. There is a study run out of a single institution but opened at several institutions looking at that. It’s not something I would do off of a protocol. In that study, they found what they would claim to be the maximum-tolerated dose (MTD), but it hasn’t found its way into the standard of care yet.A lot of people are still proponents of MTD. There is no evidence that exceeding 60 Gy at 2 Gy/fraction and potential fractionation is beneficial. You could perhaps go to 66 Gy, but in terms of reaching a higher MTD, you have to look at different strategies with some sort of boost or hypofractionation.

Can you discuss some clinical trials that have examined the use of radiotherapy in this patient population?

It would be very difficult to study a lower radiation dose unless it was a higher dose/fraction so that it was biologically equivalent. For example, it would be difficult to do a trial looking at 40 Gy using 2 Gy/fraction because that is not enough for a local control.A lot of clinical trials have looked at the use of radiotherapy in stage III lung cancer. One of the first trials, RTOG 7301, examined the use of 60 Gy conformal radiotherapy. There was the CALGB 8433 trial, which facilitated the use of sequential chemotherapy with a platinum-based doublet, followed by radiation; this showed an overall survival benefit. In comparison with sequential chemotherapy radiation, the RTOG trial studied the addition of concurrent chemotherapy with radiation.

The next landmark trial was RTOG 0617, which was an earlier phase II trial examining the use of 74 Gy. There was no increase in toxicity, and outcomes were better than historical controls.

What goes into determining the dose and volume of radiation?

The response could be a result of heart-dose symmetry, but the exact biological role has yet to be determined.I give patients with stage III lung cancer on concurrent chemoradiotherapy 60 Gy at 2 Gy/fraction based on the data from RTOG 0617; that’s my standard. It’s perfectly acceptable to go up as high as 66 Gy, but there are no data that show it’s any better or worse. In terms of treatment volume and designing a patient’s treatment planning, all of my patients have a PET/CT scan prior to coming in. My treatment target is the primary tumor and any involved lymph nodes.

What about combining modalities with radiotherapy and immunotherapy?

I also take a CT scan that tracks tumor movement during the course of a patient’s breathing cycle. I need to be able to track the tumor throughout the whole breathing cycle and make sure I’m treating a volume that the tumor will always be within. I ultimately combine the CT volume with the PET volume, plus the volume of the motion. I then create a margin to account for my microscopic disease and a margin to account for what we call setup uncertainty.The PACIFIC trial is very exciting for radiation as a whole, even though it’s not a radiation trial. The details of the radiotherapy are limited. The only description is that they were to receive 56 to 66 Gy of radiation during the course of the study.

How has proton radiotherapy entered the landscape?

Participants were to receive at least 2 cycles of platinum doublet chemotherapy, but we don’t know what the radiation given was. In the PACIFIC trial, there was some immune response following radiation, and this is most evident with regard to the patients who showed a response regardless of their PD-L1 expression. You wouldn’t think that a tumor without PD-L1 expression would respond to an anti—PD-L1 agent, but the expression didn’t really matter in PACIFIC. This shows that there was something in the immune system that was provoked by the chemoradiation beforehand.Proton radiotherapy is a hot topic in the field of radiation oncology, but it can be challenging in lung cancer treatment. Protons are very sensitive to changes in tissue and air. If you’re treating in the lung, you’re going to go through tissue and air.

Are there other radiotherapy adverse events (AEs) besides pneumonitis you would like to emphasize?

If the tumor changes size, your dose-symmetry could change. If the patient develops an effusion, the dose-symmetry could change. There’s a lot of work going into the details of treatment planning. It would be interesting to have trials that show a clinical benefit; we’re still working toward that. There is certainly a theoretical benefit with careful treatment planning now.When my patients with stage III lung cancer come in to discuss chemoradiation, I usually leave it to my colleagues in oncology to discuss the chemotherapy AEs as they can be dependent on the regimen. In terms of radiation, I inform patients that they will get tired. It’s not going to happen day 1 of treatment, but they might want to go to bed early or take a nap 2 to 3 weeks in. I wouldn’t expect them to be bedbound with fatigue, but fatigue certainly happens.

Where should clinical trials focus their efforts?

The other main AE is esophagitis, and that is certainly related to dose. The mediastinal lymph nodes in patients with stage III lung cancer are typically right next to the esophagus. I always tell them that the radiation that is used to treat the cancer will reach their esophagus. As a result, some patients have pain with swallowing, the feeling of sticking with swallowing, and they may require a liquid intake toward the end of their radiation treatment. It’s very rare for these patients to need a feeding tube [as] patients with head and neck cancer [may].We need to investigate better integration of radiation and immunotherapy. The timing of radiation and immunotherapy has always been a question. Some people think it might be better to start immunotherapy before and some during. We already have some data backing its use afterwards. Looking at concurrent immunotherapy could help establish its role. This, in conjunction with hypofractionated radiation, could be a real benefit. The only caveat is a successful investigation of hypofractionation strategies. I don’t think hypofractionation strategies could really be done off of a clinical trial, especially since these would be deviations from the standard of care.

Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919- 1929. doi: 10.1056/NEJMoa1709937.