Lung SBRT Dose Optimization [2022]: Overcoming Size & SUV?
When Was Lung SBRT (stereotactic body radiation therapy) Treatment Developed?
Lung SBRT (treatment) started in the late, 1990s, early 2000s. It was initially adapted in Japan, when radiation technology (using radiation beams) became, sophisticated enough to, instead of having one or two or three beams, coming from just a couple of directions aimed by an x-ray with a big giant rectangular target in the. As soon as the technology adapted the CT planning and controlling for tumor motion and allowing many beam angles so that you could shape the size of the high dose target very precisely that allowed for the implementation of (Lung) SBRT (stereotactic body radiation therapy), and the treatment of really tiny targets to really high ablative doses.
So lung cancer was one of the first sites treated. It’s one of the technically easier sites. Back in, 99, 2000. So it has about a 20 year track record. It’s moved into other sites of radiation oncology. So spine is an area that has about, 10 to 15 years of experience.
Liver SBRT has been around for about 10 years. We also treat metastases in different sites of the body, such as adrenal metastases or abdominal metastases. Kidney cancer is something that is relatively favorably targetable with SBRT (stereotactic body radiation therapy) so there’s a growing track record for that site as well.
And Gamma Knife for brain tumors has around, been around for, for substantially longer than SBRT (stereotactic body radiation therapy) as applies to the same concept. So it’s really just, essentially using extremely targeted radiation therapy from a huge number of beams. So that all of the beams don’t really contribute significantly to dose except at the one spot where they all cross and you very carefully control the area where they cross. Just has required enough technology to be able to aim those beams to the appropriate body site and feel confident that they’re delivered correctly.
4 Key Takeaways: Lung SBRT
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Studies that look backwards imply that growing tumor size, PET avidity, and squamous histology all have a negative impact on the likelihood of a patient experiencing local failure (LF) after lung SBRT.
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We were able to identify 1,573 consecutive patients who were treated with definite intent SBRT for stage I NSCLC (non-small cell lung cancer) between the years 2003 and 2020 by using an institutional prospective registry that had been approved by the IRB.
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PET SUV 7.5 and 2.2 cm in median tumor size. Adenocarcinoma (30.6%), squamous cell (27.8%), NSCLC (non-small cell lung cancer) NOS (7.3%), non-diagnostic (9.7%), and unbiopsied (24.3%) were the histological findings. 52.3% of patients were female, and 5% had never smoked, 72.7% had quit, and 22.3% were still doing so. 93.9 percent were medically inoperable, and 64% finished mediastinal staging.
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On multivariate analysis, only squamous histology and SBRT dose were significant correlates with LF. Squamous histology drives LF independently. Higher SBRT dosage (54-60 Gy/3fx, 34 Gy/1fx, BED >149) may overcome other LF correlations (size, SUV), but these remain the biggest correlates of distant recurrence.
Standard of Care for Medically Inoperable Lung Metastases in Non-small Cell Lung Cancer Patients
So it is SBRT (stereotactic body radiation therapy) for non-small cell lung cancer is particularly relevant to stage one because it’s a really small focused target. So it’s really only the stage one population that have isolated sites of disease that, that we’re typically targeting with SBRT. Those patients the typical standard of care for stage 1 non-small cell lung cancer is surgery. Though because of the comorbidities of lung cancer patients, it often include smoking or other medical illness, other medically comorbid conditions. Many of them are not ideal candidates for surgery.
So SBRT has been the standard of care for medically inoperable non-small cell lung cancer. Since its inception, 20 years ago, it has provided local control that looks very close to surgery, right? It doesn’t quite reach the levels of control that you would get in surgery patients, but it appears to be within a few percent at far less morbidity or something that’s far more tolerable for patients with medical comorbidities.
So it’s certainly the standard of care for medically inoperable stage I non-small cell lung cancer. There’s a group of patients that are high risk for surgery or that would be able to consider both surgery and (conventional) radiation therapy for non-small cell lung cancer. That’s a group of patients that meet with both thoracic surgeons and radiation oncologists and come to a careful decision as to whether they should be fully aggressive in their care with a surgical resection but have to potentially handle the morbidity of that.
Versus, go for an approach with SBRT that offers a much lower morbidity approach. But then, the question is, how close is the control rate of SBRT to the control rate of surgery? That kind of gets at what we were looking into, right? So our, study is a retrospective review. We looked at our experience at the Cleveland Clinic with Lung SBRT. We have a different range of doses and fractionation schedules that we’ve given over time. So some patients receive 50 Gy and 5 fractions of 10 grade refraction times 5. Other patients received 18 Gy times three or 54 Gy and three fractions.
More recently, we’ve also offered single fraction radiation. So with 30 or 34 Gy in 1 fraction, the main purpose of our particular study was just to compare the outcomes of those different regimens. Because we know that, I think as we’re comparing it to surgery, we want to make sure that we’re optimizing local control. We want to make sure that we’re offering, the right patient the right regimen. I think most of the (radiation) oncologists will know, but I think the treatment in general is remarkable in that about a third of the patients will have some fatigue versus, that lasts for a week or a month.
Not terrible fatigue, but mild fatigue, like they woke up an hour or two early every day, but nothing terrible. Two-thirds will have almost nothing. Only about 2 or 3% say that they have any breathing changes or symptoms that are different from their baseline respiratory function, even in patients on oxygen when they’re treated. And then, the other potential risk is that occasionally, when the tumor is next to a rib or chest wall, you can create, nerve irritation or a rib fracture. But that’s only in a small percentage of patients, compared to, surgery or other aggressive treatments that are going to have a 100 percent rate of chest wall pain when you do a resection, through the chest wall. So you’re right; I think that’s the remarkable thing about this treatment: you get excellent local control, not quite as good as surgery but close, with a very low risk of morbidity.
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Please Tell Our Radiation Oncologist Viewers about the Clinical Trial Design For Patients With Non-small Cell Lung Cancer?
The use of SBRT is driven by the objective of reducing morbidity in the care of this group of patients (non-small cell lung cancer). Different clinical trials over time have told us which doses in fractionation regimens patients might be eligible for based on tumor size and tumor location and what Texas cities they might have with treatment. One thing we’ve noticed when we’ve looked at our database, as well as (randomized) clinical trials and other people’s databases, is that increasing tumor size is correlated with higher rates of local failure.
Maybe not surprisingly, there are more metabolically active lung tumors. So increasing PET SUV is also correlated with rates of local failure. And then, within these different SBRT dose regimens, some are slightly more aggressive, some are slightly less aggressive. We were curious to see whether different dose regimens altered those local failure patterns, and, while we were looking for that, another thing that has become apparent in the data is that there are two primary histologies: adrenal carcinoma and squamous cell carcinoma.
And this group of people with squamous cell carcinoma seems to have a higher chance of local failure as well. And so that’s what we were searching for in this trial or in this retrospective review: to see if the different dose regimens led to different rates of sensitivity for large versus small (lung) tumors, PET-avid versus non-avid (lung) tumors, and squamous cell carcinoma versus adrenal carcinoma.
Key Aspects of the Lung SBRT Clinical Trial In NSCLC (non-small cell lung cancer)
So this is actually a retrospective review of our experience. We’ve been very consistent about using those dose regimens. So we were able to go back and find our data—patients who received exactly those dose regimens. For stage I non-small cell lung cancer (therapy), specifically, 96% of the patients were medically inoperable. About 4% of them were technically medically operable when deciding between surgery and (conventional) radiation therapy.
But predominantly, this is a medically inoperable population, and then we were able to assess their rates of tumor control based on tumor size, PET SUV, histology, the kinds of known factors for local control, and then also the radiation dose that was used.
Lung SBRT Trial Results
What we found when we looked at the range of outcomes for the different dose regimens—the 50 Gy in 5 fractions—is that there’s a way of calculating the biologically equivalent dose in radiation oncology. And you know that, historically, they have looked for a threshold of this biologically equivalent dose to reach 100 Gy, or biologic radiation units. That 50 Gy in a 5 fraction regimen is exactly 100. So it meets the minimum threshold for the dose you would want to use in lung SBRT (stereotactic body radiotherapy). The single fraction regimen is 34 grains; one fraction is a little bit more aggressive and comes out to 149 radiation units by biologically equivalent dose.
The 3-fraction regimen is the most aggressive, and it comes out to between 150 and 180 radiation (treatment) units, depending on how you calculate them. So we did find when we looked back at our patients that tumor size and PET SUV, the known predictors of local recurrence, were still predictors of local recurrence. We also found that adrenal carcinoma versus squamous cell carcinoma was a strong predictor. In fact, it failed to mention that approximately one-third of our patients were not biopsied, so the patients treated based on an enlarging tumor with an SUV of or higher. A third of the patients had adrenal carcinoma.
A third of the patients have squamous cell carcinoma, and the patients with squamous cell were three times more likely to have a local recurrence than patients without tissue or with adenocarcinoma diagnoses. So that was a strong predictor of local control. However, when we looked at the dose in the two higher dose groups, the single fraction in a three-fraction group tumor size PET SUV, and histology, they were no longer statistically significant.
And only radiation dose was suggested; the suggestion is that when you have a large PET-avid resistant tumor, you may be able to overcome those risk factors for resistance by giving some of the higher dose radiation (treatment sessions) regimens, the single fraction (30, 34 grain, one fraction) or 54 grain, three fractions. Versus when you treat those larger, more aggressive tumors with the 50-g, five-fraction regimen, while the local control is reasonable at 80%, it’s not the 95% that we typically are able to get with Lung SBRT.
Final Thoughts On The Lung SBRT Clinical Trial
When we have small adrenal carcinomas that are not particularly PET-avid. They’re extremely well controlled by all SBRT (stereotactic body radiotherapy) regimens, whether it’s five fractions, three fractions, or one fraction, when we have larger PET-avid tumors and squamous cell carcinomas. Those are the risks associated with higher rates of local recurrence.
And it does appear that the more aggressive dose regimens—the single fraction, 30 to 34 Gy, the 54 to 60 Gy, and 3 fractions—may overcome those risk factors for local recurrence. If you can treat patients with the higher dose regimen, you can achieve excellent results in those patients. That’s, of course, limited by the risk of toxicity (severe toxicity) based on tumor location and other factors. So there was no significant toxicity.
We’re not saying that the higher, more aggressive (lung) dose regimens should be used to treat all patients. But overall, if you have a relatively fit and healthy patient with a tumor that’s at high risk for local recurrence based on size, PET avidity, and squamous cell carcinoma, we would advocate for more aggressive, higher dose regimens in those patients, provided that, based on location and other factors, the toxicity profile would remain favorable.
Kevin Stephans, MD – About The Author, Credentials, and Affiliations
Dr. Kevin Stephans, MD, a radiation oncologist in Cleveland, Ohio. He is currently employed by the Cleveland Clinic and is affiliated with the institution. He accepts multiple insurance policies. Dr. Stephans is radiation oncology board-certified. In 2004, Dr. Stephans graduated from the School of Medicine at Case Western Reserve University. In Cleveland, Ohio, he practices as an oncologist.