SABR and Hypofractionated Chemoradiation Improves Lung Cancer Outcomes

Percy Lee, MD

The landscape of radiation therapy for locally advanced non–small cell lung cancer (NSCLC) is evolving, and recent research is focusing on enhancing the efficacy of treatments while reducing the duration and adverse effects.

Emerging studies, including one done by Percy Lee, MD, et al, are exploring the potential of high-dose ablative radiation when delivered over a shorter timeframe. This approach is known as stereotactic ablative radiotherapy (SABR), which aims to deliver high doses of radiation in fewer sessions to potentially offer better benefits and reduced toxicity.

In a recent early-phase, dose-escalation, nonrandomized controlled trial published in JAMA Oncology, this regimen of concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy was shown to be safe and effective when used in patients with locally advanced, unresectable NSCLC. Though toxicity challenges remain, these advancements point towards a more personalized approach to cancer treatment.

In an interview with Targeted Oncology^TM, Lee, medical director of Orange County & Coastal Region Radiation Oncology, City of Hope Orange County, and vice chair of clinical research, Department of Radiation Oncology, City of Hope, further discussed the findings from this study.

Targeted Oncology: Can you explain the concepts of accelerated hypofractionated chemoradiation and SABR in the treatment of NSCLC?

Lee: The concept we envisioned was to shorten the treatment course of standard chemo-radiation, which is typically delivered over 6 weeks at a lower dose per day. We [aimed] to adopt this approach of SBRT, or stereotactic body radiation therapy, in these more locally advanced cases. [This approach] leverages the advancements in precision radiotherapy technology and potentially offers some biological benefits by giving radiation in 10 to 15 sessions at higher doses [that are] perhaps more immunogenic and more effective in combination with chemotherapy or immunotherapy. [However], the study was designed prior to the immunotherapy era, so we cannot claim an interaction with immunotherapy, but the concept was that a higher dose per day may [trigger a] more effective immune response to the treatment.

Microscopic image of non-small cell lung cancer - Generated with Google Gemini AI

Could you provide an overview of the design of the study?

The design was a phase 2, dose-finding trial. Prior to this, a number of studies looked at how we can shorten the treatment course of radiation. Frankly, there were some that were met with toxicity. This was done when radiation was not as focused or advanced. We decided to give every patient a regimen of 10 treatments of 4 Gy with concurrent chemotherapy. Then, we were going to repeat a PET scan around treatment number 7 or 8 to assess the response. Then, we would do what is called adaptive radiotherapy and use that new PET scan to see if there was some tumor shrinkage or less active areas and we then shrink the last portions of the treatment into 5 sessions of stereotactic boosts. [This allowed us to] accelerate this treatment course to a total of 15 sessions.

We designed it as a toxicity-finding, dose-finding trial. If the first cohort of patients at a lower boost dose—where the boost was 5 Gy times 5 sessions after the initial 40 Gy in 5 sessions—tolerated the treatment, we would advance to the higher boost dose level of 6 Gy times 5 sessions. If that dose was also tolerable based on prespecified toxicity end points, we would proceed to the highest dose level of 7 Gy times 5 sessions, on top of the initial 40 Gy in 5 sessions. The idea was to use the PET scan to customize treatments so that they are not only more aggressive but also safer.

For example, if a lymph node in the mediastinum was active but became less avid after the 40 Gy, the treating physician had the discretion not to give an additional dose to that area, as further doses could cause more tracheal or esophageal toxicity. The rationale for the 40 Gy was that it might be sufficient to sterilize responsive areas of disease. So, this approach was more customized and personalized, rather than a one-size-fits-all method.

The end points we were looking at included 90-day cardiac, pulmonary, and esophageal toxicities. We had specified criteria that, if a certain number of patients exceeded the treatment's tolerance as defined by CTCAE criteria, we would stop the trial early. Fortunately, we did not meet the maximum tolerated dose threshold, so we were able to complete the full study with the full dose of 75 Gy in 15 treatments.

What were the criteria used when selecting patients for the trial?

These studies were intended for locally advanced non–small cell lung cancer, typically stage III patients who have the mediastinal nodal involvement. They needed to be assessed by a thoracic surgeon to determine if they were nonresectable or not good surgical candidates. Standard exclusion criteria, as far as prior thoracic radiation and secondary malignancies, were also included in the eligibility criteria. I should add that the study did not directly address the primary end point, [which] was toxicity. The primary end point was to determine the maximum tolerable dose using this 15-treatment approach with the built-in adaptive PET-guided radiation boosts with SBRT.

How did the efficacy of this approach compare with other treatment regimens for locally advanced NSCLC?

This study was designed and implemented before the era of immunotherapy and prior to the PACIFIC trial [NCT02125461]. Out of the entire cohort, only 1 patient out of the 28 or so patients received adjuvant or consolidated durvalumab [Imfinzi]. To evaluate efficacy, we were looking at locoregional disease control. Did the areas we eradicated recur, and if so, when? Historically, the recurrence rates with standard chemoradiation without immunotherapy would be around 30% to 40% at some point in their life expectancy. I would argue that as patients have lived longer with the PACIFIC regimen, that number may increase, and we have seen that in follow-up studies of patients treated in this manner, where they may have a locoregional recurrence despite standard chemoradiation. That is the main problem.

That said, the results were encouraging. We saw locoregional control rates in the upper 80% to the low 90% range, compared with historical rates, which were more in the 60% to 70% range with standard chemoradiation. I think that is because the biological effective dose of this regimen is much higher than the 60 Gy given in 30 treatments. That being said, I would caution people that in the highest dose cohort, we did see more toxicity, and then in the lower dose cohort, we did see more locoregional failure–[both of which] are explainable by the concept of biological effectiveness.

Our conclusion in the paper was that if one were to use this regimen, we would recommend settling on the intermediate dose level of 40 Gy in 10 treatments, followed by a 6 Gy times 5 boost, while also cautioning about the risk of complications, especially when treating bulky mediastinal lymph nodes near critical structures such as the esophagus, trachea, bronchial tree, and the heart.

What were the most critical adverse effects experienced by patients undergoing this treatment?

The big picture regarding toxicity was very similar to what one would expect after chemoradiation. Patients experienced fatigue, cough, short-term cough, and shortness of breath. Most of these symptoms were short-lived and resolved over time. There was some incidence of radiation pneumonitis, but I think those rates were comparable with standard chemoradiation. Unfortunately, there were a couple of grade 5 toxicities, which led to death. One case was attributed to pulmonary lung failure after treatment, and another was due to severe tracheal-esophageal stenosis. These are significant outcomes, especially considering the small size of the study. However, severe toxicity is something we expect in patients treated with chemoradiation for stage III lung cancer, given the generally sicker populations we treat.

That said, I’m not certain if these numbers are specific to the aggressive nature of our treatment. A larger study would be beneficial to further explore this, especially in the era of immunotherapy, from both an efficacy and toxicity standpoint.

How do you envision this treatment regimen being integrated into current clinical practice?

As we learn more about higher-dose ablative radiation, especially in the era of immunotherapy, we’re optimistic about the potential synergy between the right radiation regimen and combining it with current immunotherapy and future targeted or immunotherapy drugs. I was on a different call just before this, and we were actually highlighting this idea of using SBRT to the primary tumor, along with standard chemoradiation for the mediastinum, which is a similar concept to our treatment—more of an abbreviated hypofractionation for the entire disease course.

My hope and vision are that we won’t need to offer the standard 6 weeks of chemoradiotherapy in the near future. By shortening these treatments, it’s not only more patient-centered and easier for patients, improving access so they do not have to come to a center for 6 weeks, but there may also be a biological benefit. As I mentioned before, ablative radiation may be more stimulatory to the immune system, and in combination with immune checkpoint inhibitors and other drugs, it may elicit a stronger effect that helps with further disease control in distant sites that are not visible on scans. It is exciting to consider combining this with immunotherapy to see if there is an overall survival benefit, as our study was done mostly without immunotherapy.

The rationale, again, is that by doing shorter treatments, we cause less lymphopenia. When we target a smaller field, we cause less damage, and we know that these factors are negative prognostic indicators in patients receiving chemoradiation for locally advanced non–small cell lung cancer. All this to say that with advanced technology and precision oncology in radiation therapy, we’re aiming to be more precise and accurate with our treatments. By doing so, we can enhance the patient experience while also achieving the biological benefits of this treatment, all while ensuring safety, which has always been a concern. It was never about efficacy; we just have not been able to do this safely until more recently.

I would say that more personalization is the future, leveraging biomarkers—both in the blood, tissue, and imaging scans—during chemoradiation. For example, using [circulating tumor DNA] to understand which patients need more aggressive therapy vs those who do not, and perhaps exploring beyond PET/CT, which has been around for a long time. Are there other radiomics or biomarkers that we can look at during chemoradiation to boost more specific areas that are resistant, or just to do something even more personalized than what we did with our study? I should also mention that this work was done while I was at UCLA. I want to thank the institution, my department chair back then, and the department’s support for this trial. It would not have been possible without their financial and overall support.

REFERENCE:

Wu TC, Luterstein E, Neilsen BK, et al. Accelerated hypofractionated chemoradiation followed by stereotactic ablative radiotherapy boost for locally advanced, unresectable non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol. 2024;10(3):352-359. doi:10.1001/jamaoncol.2023.6033