Good morning, good afternoon, and good evening, everyone, depending where you are in the world. Welcome to the IASLC webinar, 2023 Radiation Oncology Updates. I'll be your moderator today. My name is Alex Louie. I'm a radiation oncologist and clinician scientist at Sunnybrook Hospital in Toronto, Canada. I'm very happy to be hosting this webinar on behalf of the IASLC Education as well as the Advanced Radiation Technology Committees. We have a few housekeeping items that we'd like to review. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for CME, ACCME. The IASLC is accredited by ACCME to provide continuing medical education for physicians. The IASLC designates the live format for this educational activity for a maximum of one AMA PRA Category 1 credit. Physicians should only claim credit that is commensurate with the extent of their participation in this particular activity. In addition, these are the financial disclosures that have been compiled for the presenters today and all faculty planners and reviewers for today's webinars have disclosed their COIs and the information is provided here. I'd first like to introduce our first speaker, who is Dr. Huda Bahig. Dr. Bahig is a radiation oncologist and clinician scientist at SHUM in Montreal. She specializes in the treatment of lung cancer and head and neck cancers with a special interest in the development of pragmatic clinical trials in new technologies within radiation oncology. With that, I'd like to have Huda present and begin our webinar. Thank you. Thank you very much, Alex. I'll start by covering some of the recent abstracts that were presented this year in the space of early stage non-small cell lung cancer. I've chosen to go over four important ones. We'll have to go quickly over them, but potentially have some time to discuss at the end of the session. The first one would be the i-SABR trial, evaluating the role of immunotherapy in early stage or isolated non-small cell lung cancer. We'll go over ASPIRE as well, which is the first prospective trial assessing the role of SBRD in ILD. We'll discuss and we'll have the two last studies, which will be presented very close together, which is the secondary analysis from the LUSTER trial, focusing on the toxicity in ultracentral stage 1 non-small cell lung cancer and the results of the LUNG-TEC trial that was presented at ASTRO this year. The first trial, which was very pertinent for our field and potentially a practice changing very soon, is the i-SABR study, which was a trial of SBRD with or without immunotherapy, nivolumab, in early stage non-small cell lung cancer. It was a phase 2 randomized trial that was presented at World Lung this year and already published in the Lancet for reference. In this trial, patients with biopsy-confirmed non-small cell lung cancer, stage 1a to 2b, and allowed also the inclusion of isolated lung parenchymal recurrent or persistent non-small cell lung cancer. Very large tumors were excluded, seven centimeters or more, ultracentrals and any lesion not suitable for SBRD, as well as metastatic lesions. And 140 patients were randomized to SBRD only, to a dose of 50 gray in four fraction or 70 gray in 10 versus a course of i-SABR, which involved nivolumab starting the same day with treatment for a total of four doses and the same dose of SBRD, 50 gray in 5 or 70 gray in 10. And the primary endpoint was four-year event-free survival. The patient characteristics for the two groups can be seen in detail in the Lancet publication, but the most relevant information here is that the two groups are rather comparable, included mostly small lesions with a median size of 1.7 centimeter. The majority were newly diagnosed, but there was about a quarter of lesions that were recurrent. And it was interesting to see that a majority of patients were able to receive, 83 percent were able to receive more than two cycles of nivolumab, only 17 percent received less than two. And also interesting to see that there was a good proportion of patients that had a PD-L1 status of less than 1 percent, about 40 percent of patients, and there was a good proportion, but a third, that had an unknown PD-L1 status. So the trial results, in a nutshell, shows that there was a significantly increase in event-free survival in patients that received immunotherapy, 77 percent in the iSABER group versus 53 percent in the SABER-only group. In the SABER-only group, there were no grade 3 and more toxicity. In the iSABER group, there was 15 percent grade 3 immunological AE related to nivolumab. There was no grade 3 pneumonitis and no grade 4 and more toxicity. And if we look at the pattern of failure, it's really almost at every level that there was a reduction in recurrent failure, including second primary lung cancer, local failure, regional failure was a bit less, distant failures, and any recurrence or death events were much lower in the iSABER group. So in a nutshell, this is what this trial had shown. And this is, again, it's a phase 2 randomized, but we're awaiting results from phase 3 trials that are ongoing, but certainly something quite promising in the field. The other trial, which I think is of high interest, is the ASPIRE-ILD. So we know that patients with interstitial lung disease from increasing literature are at higher risk of toxicity from SBRT and from radiotherapy in general. And this is the first prospective study in this space assessing SBRT in patients with a concomitant diagnosis of ILD and with a diagnosis of T1, T2, and 0 lung cancer. Patients were in this study stratified by the severity of their ILD with a rigorous assessment by a respirologist at baseline as well as during follow-up and were treated to 50 grade 5 fraction. And the purpose of the cohorts were really to have a de-escalation protocol should we see too many toxicities in one of the cohorts. So the inclusions for this trial included patients with T1, T2 lung cancer in the setting of fibrotic ILD. And the pathological diagnosis of non-small cell lung cancer was strongly recommended, but not mandatory as is often the case with SBRT. The primary endpoint for this phase 2 single arm trial was overall survival, and it was pre-specified that SBRT would be worthwhile if the median overall survival would be more than one year post-SBRT with the underlying data that patients with untreated non-small cell lung cancer have a diagnosis of less than one year, but also had to have a rate of grade 3 to 4 toxicity of less than 35% and grade 5 toxicity of 15% or less. And so if we look at the patient's characteristics from this trial, which involved 39 patients, a majority, 80% had a stage T1 disease. What's interesting to see is that about a quarter of patients, 20% had a diagnosis of IPF, idiopathic pulmonary fibrosis, which is associated with very adverse prognosis in terms of their lung disease. And about 50% had unclassifiable fibrotic ILD. There was a fair distribution with the majority of patients having mild to moderate ILD. Actually, the majority, about 60%, had moderate ILD as scored using the ILD gap index. And most patients were symptomatic at baseline with dyspnea. About 70% of patients had presented dyspnea before their treatment. And so again, in a nutshell, the results from this trial, so we can see from the graph that the overall survival was way above what was expected. The one-year overall survival was 79% at a median follow-up of 19 months. The median OS was 25 months. And the interesting part was that there was about 8% risk of grade 5 toxicity, all due to respiratory deterioration. Two of the events happened at around four months per treatment. And one event happened at 13 months post-SABR. And these were rated in a very conservative way. So any event that could be associated with radiation, any deterioration in respiration was attributed to SABR potentially. And so it's important to keep in mind that for some of these patients, it may also be secondary to the course of their ILD disease. Two of these patients that had grade 5 had a connective tissue disease associated ILD, and one had IPF. And there were four patients with grade 3 events. So in summary, these patients, the rate of grade 5 were way below what we expect from the literature. It's still not benign. There are severe toxicities, including the risk of death that is approximately 8%. But compared to the retrospective literature that we have, where we expect about 20 or even 25% risk of death, this is a lot more acceptable. Still, there is an effort to reduce further the toxicity. The group is continuing with a future phase 2 trial that is about to open that will assess the role of SBRT or radiation in locally advanced lung cancer with fibrotic ILD with an attempt to reduce toxicity by using either N-acetylcysteine as an antioxidant or corticosteroid. And so stay tuned for the follow-up trial that will be coming next. Next is the LUSTER secondary analysis trial focusing on ultracentral stage 1 non-small cell lung cancer. So for those of you who are not familiar with the LUSTER trial, which was presented last year, it was a trial assessing SBRT versus conventional radiotherapy in a peripheral or central non-small cell lung cancer at a dose of 48 grade 4 or 60 grade 8 for central lesions versus a conformal radiation of 60 grade in 15 fractions. The trial had a sample size target of 324 patients, but closed early due to slow accrual. There were 233 patients that were accrued across 16 Canadian centers. And essentially, the trial showed that there seemed to be an improved local control, which was the primary endpoint with SBRT, but was underpowered to demonstrate that it was statistically significant. The trial had low rates of acute and late toxicity, about 1% acute toxicity and about 2 to 5% late toxicity. And about 27% of patients had central tumors. But looking at the data more closely, what the authors noticed is that there seemed to be, as we can expect, a numerically higher rate of late toxicity in the SBRT group, particularly for the central tumors. And they went ahead and conducted a retrospective analysis on the clinical and toxicity data from patients with ultra-central tumors, which they defined here as a PTV overlapping the proximal bronchial tree. And the primary endpoint of the secondary analysis was grade 3 and more toxicity happening at 3 to 36 months after radiation. The results, so if we look at the patient population, it's pretty standard for what we expect. It included 29 patients that had ultra-central tumors by the definition that was stated. And what we see when we compare the two cohorts, so they had 21 patients that had SBRT and six that had conventional radiotherapy. There were no grade 3 or more late toxicity in patients that were treated with conventional radiation. However, there was a 19% rate of toxicity, grade 3 or more in patients treated with SBRT. And if we look more specifically at these toxicities in the grade 3, we have bronchial strictures, chest pain, atelectasis, and one case of hemorrhage for a grade 5 patient that died from his treatment. If we look at the three-year local control or overall survival, it's actually quite similar to the rest of the cohort, where, as you saw, the local control at three years was about 87% for the whole cohort. So it wasn't significantly different from the rest of the cohort. Interestingly, what came up, and was also highlighted by other retrospective analysis at Estro this year, is that looking at the point dose, the DMAX, to the proximal bronchial tree did not seem to be the most predictive factor for toxicity. So they looked at patients that developed grade 3 or more toxicity and those that did not. And if you look at the DMAX to the proximal bronchial tree, it's actually quite similar, a bit of a difference, but not that major. But really, the major differences were more in terms of volumetric doses. If you look at the 0.2 cc, the D4 cc, they were significantly higher in patients that had grade 3 or more toxicity. So the conclusion here was that certainly for ultracentral tumor, we seem to see more toxicity as we can expect, with a 19% rate of grade 3 or more toxicity, late toxicity, one grade 5. And in this patient with grade 5, the dose to the DMAX to the proximal bronchial tree was actually close to the median, but it was the patient with the highest D5 and V100 gray to the proximal bronchial tree. So something to keep in mind, there were no late toxicities with the 60 grade 15 fraction, but certainly food for thought for considering volumetric dose to the proximal bronchial tree, potentially more importantly than the point dose. And I'll finish with the Lung Tech trial, which is a nice follow-up continuity with what I just presented, the LUSTER trial. So the Lung Tech trial was long awaited. It was kind of the equivalent of the RTOG trial for centrally located non-small cell lung cancer on the European side, a plan at least for a much larger trial that had to include 150 patients to be treated with SBRT. The primary endpoint was three-year freedom from local progression, and it was not a randomized trial, but a single arm trial. They had 13 participating centers. It accrued from 2015 to 2017. And the trial closed prematurely after 33 patients, mostly due to the trial was halted twice due to safety concerns for two events. And that led to a slow accrual and a decision finally to close the trial. And so what was presented at ESTRA this year was a result for the 33 patients that were enrolled in the trial. And if we look at the patient characteristic, again, pretty standard, mostly stage T1 to T2, adenocarcinoma and squamous cell carcinoma, nothing really unexpected there. I mean, of course, it was only 33 patients, but the freedom from local progression at three years was 79%, which failed the primary objective of failure from local recurrence of more than 80%. So that primary objective was not met, but again, it was a trial that was closed early, important to keep in mind. And if you look at the pattern of recurrence, there was about 16% local and regional and about 35% distant, which is again, the numbers that we expect. Now, the part that is of interest here is that long toxicity, the incidence of acute and late toxicity. If we look at the grade five toxicity, there was one event of acute grade five toxicity, which was one of the events where the accrual was halted. And there was also one grade five event in the late toxicity. So the acute event, the acute grade five was actually a pneumonitis and the late grade five was a case of hemoptysis. The two toxicities happened in what we would define as ultracentral lesions. The hemoptysis happened actually in a patient that had a gross tumor volume abutting the proximal bronchial tree, patient on anticoagulant, and that had a biopsy a few days before. And the patient with a grade five acute toxicity had a PTV touching the proximal bronchial tree. And then in terms of grade three or more toxicities, mostly lung, acutely, mostly respiratory at 6.5%, which we can expect for central tumors in general. And the late toxicity, it was actually quite high. And I think this is maybe one of the elements to keep in mind is that for those central tumors following these patients and leading to grade three or higher toxicity at three years of up to 24%. So it's really not just the acute toxicity, but the long-term toxicity in patients with central tumors that matters. This is the survival data, three-year survival is 61%. And the pattern of recurrence and death with toxicity, as I mentioned, two events of grade five toxicity. And this is pretty much it. And so just quick take home messages from the trial I presented. So in terms of ASPIRE for the patients with interstitial lung disease, I think we see that the toxicity is reassuring, but not entirely benign. It's important to keep in mind that the context of the co-management by respirology, a lower dose of radiation and very strict lung dosimetry probably contributed to having less toxicity compared to what we know from the literature. The ice saber, definitely something quite encouraging from a short course of Iowa and SBRT. And I think this is where the future is heading and we have ongoing phase three trials. And finally, for the result of Lustre and Lung Tech, I think the take-home is that the safety of dose-adapted SBRT for ultracentral tumors is still unclear. The result of the SUNSET trial focused on ultracentral tumors, phase two, will be presented this year. Certainly important to start considering volumetric dose to the proximal bronchial tree. And we have a lot more to learn about the dose toxicity effect in these tumors. Thank you. Great. Thank you so much, Dr. Pahik. Next, we have Dr. Fiona McDonald. She will be speaking on the topic of locally advanced as well as oligometastatic cancers. Dr. McDonald is a consultant thoracic radiation oncologist and clinical oncologist rather at the Royal Marsden. And she is also the PI of the HALT trial and she is also the past chair of the Advanced Radiotherapy Committee at the IASLC. Thank you very much, Alex. The first study I'm going to go through, I've got two studies in the locally advanced space from World Lung this year. And then we're going to touch on oligoprogression from a study in ASTRO. So firstly, we all know the RTOG0617 study presented a number of years ago now comparing 60 gray to 74 gray in locally advanced non-small cell lung cancer that unfortunately showed the higher dose was associated with worse median survival and that the cardiac doses correlated with that poor survival. At World Lung, we had a secondary analysis that had been pre-planned in this study comparing the outcomes of the IMRT population to those that had conventional 3D conformal radiotherapy. Because at the time this study was recruiting widespread use of IMRT was not available partly due to labor intensity and also cost. But the hypothesis was that IMRT would achieve superior longer-term outcomes compared to conformal radiotherapy. So in this study, they had a good balance between patients having conformal radiotherapy and IMRT in both the 60 and 74 gray arms. And then with a median follow-up of just over five years, they've been looking at this comparison. So looking at survival, progression pre-survival, late toxicity and development of secondary malignancies. So the baseline characteristics were in general fairly well-balanced. Other than the fact you'll see importantly here, the PTV median was much greater in the IMRT arm. So the deck of cards is stacked against IMRT from the beginning treating larger volumes. And on average, this was 59 milliliters. And Stephen Chung pointed out this was equivalent to median increase of a double shot glass. The other thing that was significant is despite having larger PTV volumes overall, we had a lower median V40 for the heart in the IMRT volume. So the outcomes by radiation technique, you can see whether we look at overall survival, progression pre-survival or distant met pre-survival and even the occurrence of secondary malignancies, they were similar regardless of which of the two modalities were used. However, the advantage we see with the IMRT is a massive reduction in the pneumonitis risk. So this is reported as grade three or above pneumonitis, only 3.5% in the IMRT arm, and that's more than doubled at 8.2% in the 3D conformal radiotherapy arm. The esophagitis, weight loss, cardiovascular, neurological and hematological was similar across both techniques. And then this comes back to the overall survival multivariate analysis, again, highlighting the importance of the V40 for the cardiac dose. So the significant difference, if we keep the cardiac V40 under 20%, patients do better than if this is over 20%. And then as we previously knew radiation dose, the 74 gray arm did worse than the 60 gray arm. And I guess not unexpectedly, those with a larger PTV volume as a continuous variable did worse, but there was no difference, no significant difference in the overall survival dependent on the lung V5 as a constraint and also not separated by age. So the conclusions from this pre-planned subgroup analysis is the strongest evidence that we have to date and are likely ever to get for the use of IMRT in locally advanced non-small cell lung cancer because a randomized comparison is unlikely to happen. The IMRT was associated with a significant reduction in severe pneumonitis. It's highlighted the importance of the cardiac dose and the conformality that can be achieved with IMRT and that we should look at this heart constraint seriously, trying to optimize the cardiac V40 to less than 20% where possible. Previously, there had been concerns about the lung V5, the low dose bath, but this doesn't seem to be associated with any increase in lung toxicity or increase in development of secondary malignancies. So this data does not support the use of a V5 constraint which could degrade the conformality elsewhere. Age in itself is not a contraindication and we conclude that the IMRT should now be standard of care for locally advanced non-small cell lung cancer. We also had an update of the PACIFIC-R study, which the real world analysis at World Lung. So just as a reminder, the parent study was the PACIFIC trial and the latest data we have from that is the five-year overall survival of 43% with the addition of adjuvant divalumab after concurrent chemo radiotherapy for locally advanced disease. As a reminder, earlier this year, we had a JTO publication on the very small subset of patients who had known EGFR mutation positivity in the PACIFIC, the parent PACIFIC trial. So 35 patients and looking at the progression-free survival and overall survival didn't appear to be any difference with the addition of adjuvant divalumab. So just back to the PACIFIC-R real world data that was presented at World Lung. So PACIFIC-R is a retrospective review of the case notes in the patients that were entered into the PACIFIC early access program. So patients receiving divalumab after PACIFIC closed and the results were known. So they entered the study between September, 2017 and December, 2018. And the time point we're looking at now is the data extraction, the three-year overall survival time point. And the full set comprises of over 1,150 patients from 10 countries. Looking at the three-year overall survival time point and the investigator assessed progression-free survival, we see a three-year overall survival of nearly 64%, which is comparable to the three-year overall survival in the parent PACIFIC study, which was 57%. And again, similar with the regression-free survival. So in the real world setting, reassuring to see that rollout of this is giving roughly equivalent results to the initial parent study, despite all the caveats of real world data and allowing both concurrent or sequential chemo radiotherapy in this study. But what they've also done is gone and looked at the EGFR mutation positive population and they presented that data also at World Lung. So they had 466 patients who had EGFR status known and of those only 44 were positive for an EGFR mutation. So it's 9.4% of those with a result. And we do see, if we look at progression-free survival, that there appears to be worse survival in this small subgroup for those with mutation positivity. Whereas the overall survival curves you see there are overlapping. So the conclusions from this study is that, albeit with small numbers, we've got a real world PFS lower in the EGFR mutated non-small cell lung cancer patients compared to those that are wild type. And although it's small numbers in both studies and they're not directly comparable, it does appear to be consistent with the parent PACIFIC trial that divalumab might not be beneficial for this particular population or subgroup of the locally advanced non-small cell cancer patients. But what we really want to do is wait for the LORA trial, the phase three study to report, and we're hopefully going to get some initial results of that next year. So just as a reminder about the LORA trial. So in this trial, locally advanced and non-small cell lung cancer, so stage three A, B and C patients with an EGFR mutation can either at investigator's discretion be given concurrent chemo radiotherapy or sequential chemo radiotherapy. And then following that, they're randomized two to one to receiving osimertinib or placebo. They're stratified for whether they had concurrent or sequential chemo rad. They're stratified into stage three A versus B and C, and also the Chinese population versus the non-Chinese population. And then the osimertinib can be continued within the study until progression by resist, but there is an option in both arms to continue with post-progression osimertinib, either if the clinician feels they're benefiting from it in those that were on osimertinib or to switch over for those that were in the placebo group. So really looking forward to those results to hopefully get a better outcome, better treatment for the patients who have underlying EGFR mutation. And then we're moving out of curative disease now. There's just one abstract I wanted to touch on in the metastatic non-small cell lung cancer setting, and that's the STOP trial presented at ASTRO. Just a bit of background to that. So this is looking at the role of stereotactic radiotherapy for patients with oligoprogressive disease. And we've had the first study presented two years ago at ASTRO, the CURB study that looked at patients with either advanced non-small cell lung cancer or breast cancer. And at the point of disease progression, if they had a pattern of oligoprogression, they were randomized to the additional knot of stereotactic radiotherapy to their systemic anti-cancer therapy with the primary endpoint being progression-free survival. If you look at the non-small cell lung cancer population here, there were 58 patients. Only 14% were driving mutation positive. So the vast majority were not. But if you look at their progression-free survival, there was a significant difference with benefit demonstrated for the addition of stereotactic radiotherapy, 10 months versus two months with reasonable toxicity as we've come to associate with these studies. But separating out the breast cancer population, there was no median progression-free survival advantage in that subgroup. So this, although it was presented two years ago, ASTRO is due out in the Lancet any day now as a full publication. I encourage you all to look out for that. This is the second study to be presented at ASTRO this year, which is the STOP study. So the STOP study took patients with any, well, initially started as just non-small cell lung cancer, metastatic with oligoprogression, but then due to poorer crawl, opened out more similar to the studies we know like COMET to be any histology. And patients could have up to five oligoprogressing lesions, but no more than three oligoprogressive lesions in any one organ. Brain mets were treated a bit differently. They could be treated radically in either arm of the study, but had to be counted, if they were progressing, they had to be counted in the total of the five progressing lesions. As far as the systemic anti-cancer therapy, physicians were asked to pre-specify whether they were planning to switch, continue, or discontinue systemic anti-cancer therapy. And oral agents were discontinued 48 hours before any stereotactic radiotherapy. Immunotherapy had to be stopped a minimum of five days before radiotherapy and hormone therapies were continued. So these patients with this oligoprogressive pattern were randomized two to one. So for every two that were randomized for addition of SABOR, one just received their pre-specified plan of systemic anti-cancer therapy. And the primary endpoint was progression pre-survival. So you can see from the baseline characteristics here that the most common histology, partly because we had a headstart because it was only lung to begin with, but most common primary histology was lung cancer. As with many of these studies, the most common irradiated site was lung lesions. And again, as with other SABOR oligo studies, even though we were allowed to put in patients with up to five oligoprogressive lesions, the vast majority were one or two lesions. So you can see here, both the progression pre-survival headline and the overall survival headline, that there was no significant difference between the control arm and the addition of SABOR in this population of patients. But part of the problem, trying to work out exactly what's going on, is the high degree of crossover and access to non-SABOR ablative treatments in the control arm and accessing late SABOR in the control arm. So kind of early versus late. So they've divided the control arm here in an exploratory way to look at the control arm who didn't receive ablative treatment, kind of as intended, and those that did receive ablative treatment, either early or crossover late. And you can see, although they all overlap in the progression pre-survival curve, if you take out the control arm that did have ablative treatment, and you just compare the SABOR arm to the control arm without ablative treatment, there does appear to be a bit of separation of the curves for the overall survival. So the conclusions from this study is that there wasn't a significant observed difference in PFS or overall survival in this basket histology trial, using SABOR to treat oligoprogressive disease. But the caveat being, there was a substantial use of higher radiation doses, SABOR and radiofrequency ablation in the non-ablative standard of care arm, as well as significant withdrawals from the study after randomization to standard of care. But unlike the CURB study, we didn't see a histology specific response. And therefore they conclude that what we really need is more larger studies, histology specific trials, including phase threes. So just to shamelessly plug the HALT study, so the HALT study is specific to advanced non-small cell lung cancer and specific to patients with mutation positive disease who have oligoprogression on tyrosine kinase inhibitor. So just to highlight, this study is now fortunately fully recruited across Europe and we're hoping to get results of this study in 2024. Thank you very much. We will move on to Dr. Mahindra's content. Dr. Mahindra is a radiation oncologist and vice chair of operations at Case Western Department of Radiation Oncology. He's also currently the chair of the ISLC education committee. Thanks Alex. We'll continue the conversation on the locally advanced non-small cell lung cancer and look at the updates from the ASTRO meeting just earlier this year. So we know from the slide just presented and from before radiation associated cardiac toxicity is relevant in lung cancer. In the RTOGO617 study, the original analysis showed V5 and V30 gray had impact on survival with incidence of cardiac events being around 7% between the both arms. But as we saw from this updated analysis presented at World Lung, the V40 gray parameter is probably a good OAR constraint to look for. We also know that these cardiac effects can be seen within the two to five years post radiation and it's no longer something that's only relevant for late toxicity. And so studies have started looking at cardiac and cardiac substructure dose as predictive factors. And the parameters that have come up significant include atria, D45%, pericardium and ventricle, the minimum dose to the hottest region of 55 and 5%. There's still limited data on the impact of consolidation immunotherapy on the cardiac events and we'll probably learn that in future as more data comes from specific or specific R and such efforts. So the study that we'll talk about is this very large institutional cohort of locally advanced non-small cell lung cancer from University of Pennsylvania, where patients were treated with concurrent chemo radiation over a 10 year period. Nearly half of these patients were treated with introduction of strict cardiac constraints and in the dervalumab era. So these were labeled as a immune checkpoint inhibitor era cohort. The end points they looked at were post radiation cardiac events, major adverse cardiac events or MACE and grade three plus events, including AFib, AFlutter and they did a competing risk analysis. They also looked at grade four lymphopenia and survival of course. What was interesting in their analysis is when they looked at their own cohorts, median heart dose and the dose to the LAD V15 grade, it was relatively lower than the analysis published from 0617 and other studies. And it just signifies the impact of good treatment planning that is relevant for these patients. Partly they had about 57% of their patients getting IMRT and 38% getting protons with a very small cohort getting 3D CRTs, which resulted in lower cardiac doses. And with this approach, the overall incidence of major adverse cardiac events was about 12.5% ranging from 8% in patients without risk factors was coronary heart disease and 18% for those with existing baseline risk factors. And so when they completed the analysis, the cardiac dose was associated with lymphopenia and survival, but it was not associated with major cardiac events. What this means was they could not find a dosimetric parameter that would directly predict the risk of cardiac events, even though the dose itself was associated with lymphopenia and survival. They further analyzed that lymphopenia was a poor prognostic factor, and this may be even more relevant as we see in this figure in the immune checkpoint era where patients with grade four lymphopenia tend to have much inferior survival than those without. I think the bottom line summary that this study is leading towards is we need to be mindful of the cardiac dose as an overall parameter and use modern technology, including IMRT and our proton therapy to try and reduce dose to the cardiac silhouette, which helps reduce risk of lymphopenia. And then again, as we see in the figure, fewer patients with grade four lymphopenia get immune checkpoint inhibitors, and hence it's a relevant parameter. Another study that was just published, and I'll just show a screenshot here, was looking at a secondary analysis of the RTOGO617, but they performed in voxel-based analysis for various structures within the heart, and they basically identified this area in the base of heart as a region of significance. And when this factor was included into the multivariate analysis, it actually removed the significance of the radiation dose level. And roughly as we see from these axial figures, it almost correlates with the origin of the coronaries. And so I think the significance of the suggestion from this is, again, overall cardiac dose and being especially mindful to the base of the heart is relevant. And when we do that with modern radiation planning, we potentially can achieve higher radiation doses with relative safety. So moving on to the second study, I was looking at the impact of nodal target volumes. So historically the radiation fields used to be relatively large, but then over time they have evolved into this approach of not doing any elective nodal irradiation and relying on imaging such as PET-CT scan to guide what to irradiate within the mediastinum or hilum. With increasing use of PET-CT scan, the sensitivity to detect N2 diseases reported to some beings high 70 to 80 percent. So it's not perfect and therein comes the role for EBUS or endobronchial ultrasound as an approach for direct mediastinal staging of lymph node stations and again studies have shown that it identifies about more than 10 to 15 percent patients with PET occult disease. So the CSMIC trial was basically impact of systematic mediastinal staging via endobronchial ultrasound for patients with locally advanced lung cancer. This was a prospective non-randomized multi-institutional study spanning continents and the aim was to assess utility of systematic EBUS prior to curative intent chemo radiation in patients with stage 3 and they looked at proportion of patients upstaged or downstaged and the dosimetric impact of that change. So what they found was the PET-EBUS discordance was about 37 percent which is a significant number. EBUS resulted in upstaging in about 12 percent of patients for all of whom the radiation treatment plan or the overall treatment plan changed. EBUS downstage treatment or the stage for about 25 percent patients of which almost half of the patients had a change in their treatment plan including use of surgery etc. So again I think what this signify signifies is systematic EBUS is relevant even in addition to PET-CT for these patients. So what they then did is looked at the subgroup in which there was was under staging by PET and EBUS upstage these patients and looking at the example here that they showed in the presentation some nodes that were in the mediastinal region were not originally included in the PET target volume and so what they looked at is what impact does radiation planning have on these lymph nodes and in the entire that subgroup they basically found that the GTV for the lymph nodes was undercover in almost 86 percent patients and near minimum dose less than 50 percent was seen in about 71 percent so significant underdosing and then similar changes noted for the V95 of the PTV itself with the mean doses dropping down. So really the message there was EBUS upstaging can identify those lymph nodes which otherwise would be undercovered. And so moving on to the final study is our journey on dose escalation in locally advanced non-small cell lung cancer. I think there's still belief that there is role historical like control rates for local disease was about 40 to 50 percent in our own prior analysis when we looked at PATH-CR at primary tumor post-chemo radiation it was in about 48 percent even though the mediastinal response rates were much higher. RTOGO 617 study showed that with 60 grade the local control was about 60 percent was slightly lower with 74 which was difficult to explain and then again in pacific study the local only control was about 64 showing that there's still significant room for improvement of local control. Whenever attempting dose escalation cardiopulmonary and esophageal toxicity are dose limiting and hence the question comes through is whether SPRT can play a role. Local control as we know for stage one is superior with SBRT as against conventional chemo radiation for well-selected peripheral tumors as we saw from the CHISL study of 69 percent versus 86 percent with SBRT. So using this hypothesis this was a phase two trial of primary tumor SBRT followed by concurrent mediastinal and hyaluronic chemo radiation and adjuvant immunotherapy for locally advanced non-small cell lung cancer. So it's a single arm 61 patients with stage 2-3 disease primary tumor was expected to be less than seven centimeters in size. They did allow central and peripheral tumors both and if central tumors they had to be at least two centimeters separation from the nodal disease to basically allow a separate SBRT plan and a chemo radiation IMRT plan. SBRT doses used were standard for three to five fraction regimens. Mediastinal chemo radiation was also standard 60 grade which was then followed by drivalumab. The primary endpoint was PFS at 12 months also looking at pulmonary and cardiac toxicity and what they noticed was their overall incidence of grade two plus or grade three plus pneumonitis was very good lower than the pacific reports again recognizing that all these patients were treated with IMRT to mediastinum. Median PFS was 26 months which is also extremely impressive higher than what was achieved in the pacific. The local failure was only two percent and regional failure was about six percent. So while this is a small phase two single arm study these results are impressive and of course it was exciting enough to to spur the NRGLU008 study which is now a phase three prospective randomized trial using this approach of SBRT followed by concurrent mediastinal chemo radiation for locally advanced non-small cell lung cancer. Dr. Simone and Dr. Heinzerling being the co-PIs. So with that I guess I will summarize the key updates for locally advanced from ASTRO that cardiac events are still significant and even with modern treatments even though the overall dose to heart is lower but that lower dose of heart is relevant because it predicts lymphopenia which then has bearing on the risk for immune checkpoint inhibitors and survival. The seismic trial demonstrated that EBUS has significant value in addition to PET-CT because there can be significant discordance both upstaging and downstaging and in upstaged patients the radiation plan is significantly suboptimal under covering the target volumes. And then we potentially have yet another strategy for dose escalation for SBRT to primary and we'll see the results for NRGLU008 if you have access to this study would definitely encourage opening that. So with that I would sign off here and over to you Dr. Louie and Dr. McDonald. Thank you Dr. Mahindra. So that concludes the presentations. We do have some time to start our discussion. Maybe I'll begin off in the stage one space and the question for Dr. Baheek or the rest of the panelists is what are your thoughts on ILD in general with lung radiotherapy in that I did see a social media post in the past couple of months that one individual raised whether it should actually be considered an absolute contraindication and the results that we see from Aspire it is a small sample size you know do suggest that there are still some real risk but perhaps not as high as what some of the initial studies have suggested so I'd be interested in the team's thoughts on that. Perhaps I'll start and the others can comment as well. I think you sort of stated what the current status is. I don't think it should be considered an absolute contraindication because these patients don't have any other good option. But they're most of the time not surgical candidates. Systemic treatment including immunotherapy is also associated with high toxicity so they have limited option. I think that the important thing at the moment is really to have a discussion with the patients and discuss the risk and in I think Aspire is very reassuring. It's showing yes eight percent risk of grade five toxicity but this is a risk that we see sometimes in some surgical settings. I think after a careful discussion and also in the context of and I insist on that because I think this can really change things. A close follow-up by respirology and awareness of the potential risk and following these patients very closely and also using very strict lung dose constraints are very important things that we can do to reduce toxicity. But I think there are situations where patients don't want to take the risk and prefer to be followed and that can be fair but it's really an informed discussion that we should have with them. Knowing that they don't have many other options it's something that can be considered and I think that could be acceptable. What I would add is we certainly evaluate such cases in the tumor board. These cases are also sometimes unrealized that they may have ILD and you're proceeding with radiotherapy and when you're reviewing at quality assurance rounds the radiation oncologist becoming a bit more familiar of how to diagnose ILD and when it may be a potential cause for concern and also considering whether or not there may be other options whether it's RFA cryotherapy depending on the availability at your center. We have a number of questions from the QA specifically on locally advanced lung cancer and this was touched on a little bit Dr. Mahindra about dose escalation in the context of adding on SBRT. I'm interested if on your thoughts or even on you know the mechanism of how the North American team did deliver the SBRT in a somewhat sequential fashion or in other ways it could be done. Yeah I think this is again an evolving area so I guess if you just go by NCCN guidelines as a frame of reference it allows the dose from 60 to 70 gray right so anything in that spectrum may be acceptable. I think increasingly the common practice is just to stay with 60 gray with many folks at least in the in the U.S. will oftentimes consider 66 gray as a means of slight dose escalation. The way I have personally approached this to some degree is guided by the degree of the nodal stations involved in the mediastinum. For instance if someone with multistation N2 disease even N3 diseases those patients I try to stay at 60 gray as as an approach oftentimes because the lung and the cardiac doses can be limiting but for those that have bulky primary tumors and relatively less nodal involvement 66 gray is potentially an approach that I land up defaulting to at least in my own practice and again the recent RTOG 1308 study for protons and photons use 70 gray as a starting point so I think anywhere in that range is okay. We should use the OAR constraints as our guiding factor to see what can be safely administered. There's a question as well about how you know the SBRT in that particular clinical trial is is delivered and I do believe that there is a recent publication as well as the protocol of course as guiding how to do so because there are some questions that if you're delivering the SBRT and the conventional separately let's say to the metastatic nodes and then to the peripheral tumor dose calculation reconstruction dosimetry evaluation you know image guidance etc etc. Yeah again I think that's why the the protocol document actually would be a handy resource to consider. There are some treatment planning systems that have the ability to create a cumulative plan incorporating EQD2 calculations so if you have access to those which we do at my current center I think that's one approach as well. Again the study had a built-in safety parameter of having at least a two centimeter distance between the tumor primary tumor and the nodes to allow for that dose gap so I think there is bound to be some overlap in the low dose regions and simple EQD2 calculations would be a good starting point but at least trying to minimize the overlap would be a good approach. But that's where again I think this is a real world study and we would learn from these experiences as to what's a safe way to do this. Just as I switch to stage three a number of stage one questions trickled in specifically on ultracentral and one question is about you know when it's indicated and another is discussing you know 60 and 8 in that in the United States it would not be categorized as SBRT by nature of the fact that it is greater than five fractions and so how to best decide and or separate you know SBRT versus hypofractionation and any comments from the group? I can comment briefly. I think it's a space where we still don't know very well what to do and I think what's coming out of the data is that the dose to organs at risk is really a priority so for ultracentral tumors it does happen that we sometimes we were treating them under protocol strictly when the protocol was open. Now that it's not open we do consider it in some instances and when we do we would always prioritize organs at risk and really accept under dosing to try to reduce toxicity. When it's feasible I think with the data that we have at the moment conventional fractionation is probably the the safest approach for strict ultracentral tumors as they find this tumor touching the proximal bronchial tree and the safest approach I think still remains as we can see from the data to treat them with a conformal approach. I don't know what the others experiences. The only thing that I would add is even though I don't practice in the U.S. we do in our group often favor a five fraction approach and in a scenario where we are significantly concerned about the OIR dose even though it is sometimes difficult to actually pinpoint what is the actual constraint that you want to optimize to whether it's for the esophagus or for the airway that you cannot do one of two things either you decrease the overall total dose if it's let's say an oligomet and you want to prioritize safety rather than potential decrease a couple percentage points on local control or you still go ahead with your you know RTOG approved 50 gray dose but you would have it much like you do in SPRT spine where you highly optimize and prioritize your OIR to a particular number of what you think that the group consensus might be. There is a question as well on the seismic study and this is actually a very interesting question and that is the scenario whereby you have a lymph node that is positive based on your biopsy and let's say negative on your PET or in the inverse where you actually have something that's clearly PET avid but your nodes are negative and so if you have something that's very very hot on PET but your ebus suggests it's negative do you still have an inkling of potentially including it or not and you know this is something that I think would be challenging potentially to decide and so interested in what the group has to think about that. So the investigators I can at least give their perspective from what was available to us on their slide. So they did look at the subgroup to see what would be the benefit of just purely going by ebus and there would be some benefits in dosimetric structures especially for esophageal doses but I think they generally felt that the benefit that might be seen is may not be worth the risk in these cases so there will always have to be some clinical judgment involved. I think a little bit of it is relying on and the trust you have built up with your interventional pulmonology team or the surgical team that does ebus and what resources you have in terms of their comfort levels to be able to get accurate ebus. So I think this is a question that definitely each one should keep looking at in their own teams what their ebus false negative rates are and then again whenever safely possible to include those nodes I think most of us would land up including them if at least one of the techniques PET or ebus is positive. And then I think finally the PET avidity can also guide if you have a two centimeter node that's barely PET avid when the primary tumor is significantly much more avid then you're like maybe that is a reactive node right so I think there's potentially multiple factors of lymph node size avidity of the primary and other lymph nodes that go into that decision making. And what I would add to that I think that a discussion in a scenario where there could be you know some discordance is potentially warranted with the individual who did the procedure in that there may be additional information whether on the report or even just on a quick phone call or email to gauge what the endoscopist thoughts were but also to scrutinize the pathology report because you can take a look at the sample and there's a difference between something being negative, negative with lymphocytes which you'd probably be a bit more confident if it's normal lymphocytes, or if it's negative but then you actually read it and it says non-diagnostic so that you may not necessarily include in your denominator of something that that is a true sample. Dr. Diego just brought up of whether or not to kind of go another step that you have your ebus you have a PET there's a discrepancy should we actually go another step and do a mediastinoscopy. Again I think it's a it's a balance at which point do you draw the line and so it really comes back to what would be the dosimetric gains if you really were to prove. Again I think some of those level 5-6 lymph nodes are always a bit difficult to judge and if the tumor is in proximity and they look reasonable in size I think many of us will land up including them in the volumes. Curious what rest of the panel members do about it. I 100% agree. I mean it's very rare now dosimetrically that we're not able to cover these nodes and so when there's a discrepancy my tendency would be to to cover it. Yeah I think we do the same but it is very much case dependent if it's the difference between radically incompatible or not you've got to get that decision right as opposed to shall we just include an extra node and I think increasingly with the neoadjuvant you know is it operable and resectable again if it's the difference between two different modalities it's a big difference then we would go down the route of suggesting mediastinoscopy to answer the question but if it's more nuanced you know is it one additional node we might not delay the patient to put them through another technique and when it can simply be included. And what I would say is that I think this study very much highlights the importance of multidisciplinary teamwork and that I think that you know this from the Peter Mack group is a potentially practice changing study wherein previously if we just wanted a diagnosis is this locally advanced or not there is clearly value you know beyond surgical patients but also in radon patients of benefit of potentially decreasing toxicity but also potentially as well increasing control of the cancer. So it looks like we are out of time. I would like to thank the panelists, the presentations as well as the ISLC education and our teams for helping to put together today's webinar. There are many other additional learning tools and webinars available at the ISLC. You may have noted that we did not include anything on small cell today and that's because we recently had a webinar on small cell that is available on the website and so stay tuned from our group that we're hoping to host this at least twice a year as updates from conferences as well as provide other educational tools to our members and again we'd like to thank everyone for their participation as well as their attention.

IASLC

webinar

Radiation Oncology Updates

immunotherapy

SABR

adverse events

SBRT

oligoprogressive disease

cardiac toxicity

lung cancer treatment