Emerging Strategies Seek to Build on Radiation Benefits in Lung Cancer

Katie Keane, MD

Progress made in radiotherapy planning and delivery technology has allowed for the safe and effective treatment of an increasing number of patients with lung cancer, according to Katie Keane, MD, who added that patient selection is key to identifying who will benefit most from aggressive local therapies.

“In the stage I disease setting, stereotactic body radiation therapy [SBRT] was developed for patients who were not candidates for resection. Traditionally, patients with stage I lung cancer were managed with a lobectomy; however, about 25% of patients in this setting are medically inoperable,” Keane explained. “For this population, SBRT is the standard of care.”

For patients with unresectable stage III non–small cell lung cancer, data from the phase 3 PACIFIC trial (NCT02125461) established adjuvant durvalumab (Imfinzi) as the standard of care following chemoradiation. Further findings from an unplanned subgroup analysis showed improved outcomes when durvalumab was initiated within 14 days of the chemoradiation; this may be due to improved performance status in those who were able to begin immunotherapy early, or it may be reflective of synergy between immunotherapy and chemoradiation, according to Keane.

“The question is: How can we improve treatment with SBRT?” said Keane. “Ongoing trials are evaluating the addition of immunotherapy to, as well as after, SBRT; [by doing this, they hope] to improve control rates and distant failure rates. We’re really encouraged by these trials and are hopeful that [these approaches] will improve outcomes for our patients.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Keane, an assistant professor in radiation oncology at Harvard Medical School, highlighted the evolving role of SBRT in the treatment of patients with stage I lung cancer, the utilization of immunotherapy with chemoradiation in stage III disease, and research evaluating SBRT in those with oligometastatic disease.

OncLive^®: How do you decide whether to use SBRT or a lobectomy in patients with stage I lung cancer?

Keane: To a certain extent, [the decision] depends on what the surgeon is comfortable with. If someone is medically inoperable, my sense has been that using the robot to resect won’t necessarily transform someone into an operable state. I believe a lot of [the decision] comes down to a discussion that takes place between the surgeon and the patient regarding the potential risks of surgery, along with the effect on breathing function and overall quality of life.

How have delivery techniques evolved in recent years?

With SBRT in general, advances in radiation have certainly helped quite a bit in terms of increasing the efficacy of the treatment while minimizing toxicity. SBRT is a very highdose conformal treatment, where the dose of radiation is delivered over only 3 to 5 treatments. Now we primarily use treatment techniques called volumetric modulated arc therapy and intensity-modulated radiation therapy. Improvements have also been made in terms of technology, which have allowed us to minimize long exposure and the exposure of normal tissue.

The historical way of administering radiation was through beams in the front and the back, and maybe from the side. However, that strategy exposed a lot of normal healthy tissue to the radiation. By using multiple beams from multiple angles, we’re able to concentrate the dose precisely at the tumor, while avoiding the normal healthy structures.

In terms of monitoring the tumor, advances made in respiratory gating have helped, as well. Respiratory gating is a technique where the radiation is delivered only during certain parts of a person’s breathing cycle. Typically, the radiation beam is on throughout the entire breathing cycle. However, with respiratory gating, we’re only turning the radiation beam on as someone is exhaling; this is particularly beneficial for those with large tumors.

Another area of improvement is that here at Massachusetts General Hospital, we use a technique that helps protect the chest wall and the ribs from radiation. Notably, when you have a tumor right up against the chest wall, there could be a risk of rib fracture and, in the population of patients we treat, that can be pretty significant. As such, we have developed a technique where we minimize the overlap of the planned treatment volume with the chest wall, which results in low rates of chest wall pain or rib fracture.

What was learned from the PACIFIC trial? Do any questions remain?

The PACIFIC trial was an enormous leap forward in this space, especially in terms of dramatic improvements in overall survival [OS] and progression-free survival [PFS] for patients with medically inoperable stage III lung cancer. The question is: How else can we improve and what can we do to improve? To this end, some studies have evaluated concurrent immunotherapy, chemotherapy, and radiation; those published thus far have been phase 1 dose-escalation trials. [However, results have] demonstrated higher rates of pneumonitis than we have seen in PACIFIC, so it’s certainly an area where we still need larger trials.

Despite this, we’re encouraged that there is potential and, if we can really increase the overlap among radiation, chemotherapy, and immunotherapy, we [believe that we] could further improve outcomes. The main limiting factor will be the toxicity, so this really needs to be done on a trial where patients are carefully assessed, because we know that the risk of pneumonitis is higher when there is an overlap in treatments.

What are some of the differences observed between sequential and concurrent therapy?

The dose of radiation and chemotherapy regimens has been the same. One study looked at concurrent and adjuvant pembrolizumab [Keytruda], and another looked at concurrent and adjuvant atezolizumab [Tecentriq]. The doses of radiation have, in general, been 60 Gy and 30 fractions, which is a standard dose. The chemotherapy regimens have also been the same. The difference is that more than 5% of patients have grade 3 or 4 toxicities compared with 3% of those reported on the PACIFIC trial. About one-third of patients experience grade 2 or higher immune-related adverse effects [AEs]. We must find the patients who will benefit the most from the overlap without being at increased risk for toxicity.

Is there any insight into which patients may be less likely to develop toxicities like pneumonitis?

In general, if you’re thinking just about the risk of pneumonitis from radiation, we know that the smaller the tumor, the smaller the amount of lung exposed to the radiation; this certainly goes along with pneumonitis risk. When planning radiation, we look at, for example, the volume of normal lung tissue exposed to 20 Gy. If that is 20%, as opposed to 30%, we know there is less risk.

In terms of biomarkers, we don’t have any good ones [to understand who is at increased risk of certain toxicities]. Certain patients, in general, are at increased risk of developing pneumonitis, such as those with interstitial lung disease; however, this represents a minority of the overall population. Unlike the metastatic setting, we also don’t have a great biomarker for response, such as PD-L1 expression. The ongoing trials have not limited patients based on PD-L1 expression. When considering patients for these studies, our main question is: Is the [care] plan going to put them at a high risk of developing pneumonitis? That would give us pause.

How is the use of radiation expanding in patients with oligometastatic disease?

Historically, patients with oligometastatic disease were defined as those who had 1 metastatic site and a stage I tumor; however, the definition has since broadened. It’s an ongoing debate as to who would most benefit from aggressive local treatments. For example, the SABR- COMET study [NCT01446744] showed really impressive PFS and OS benefit in patients who received SBRT to all sites of metastases along with systemic therapy. Certainly, AEs were associated with aggressive local therapies; thus, collaboration among the specialties and careful patient selection is critical. However, this is an area where we are seeing very encouraging results and we’re seeing outcomes improve. [We need to consider] all the potential options for patients, even if they have metastatic disease.

Reference

1. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697