Welcome to the ISLC webinar Case-Based Controversies in Locally Advanced Non-Small Cell Lung Cancer, a Radiation Oncology Update. I'm Dr. Stephen Chun, and I'm a radiation oncologist at the MD Anderson Cancer Center in Houston. I'm going to be the moderator of the presentation today, and we want to start this activity off with some brief housekeeping items. After the presentations have concluded, you may ask any questions by using the Q&A button feature located on your video screen. We invite you to ask these questions, which we'll address after the three-speaker presentations as time permits. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education, or the ACGME. The International Association for the Study of Lung Cancer is accredited by the ACGME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates the live format for this educational activity for a maximum of one AMA PRA credit, category one credits. Physicians should only claim credit commensurate with the extent of their participation in this activity. All faculty, planners, and reviewers for the webinar today have disclosed their conflicts of interest. And so to get started off today, I'd like to welcome our panelist, Dr. Andrea Filippi. He is a radiation oncologist at the University of Milan in Italy. We also are joined by Dr. Pamela Sampson from Washington University in St. Louis, where she specializes in thoracic radiation oncology. We've already gone over the accreditation statement, and these are our financial disclosures. And so we'll start off with Dr. Filippi's presentation on stage three locally advanced non-small cell clinical trials in 2024. Stephen, I thank you so much for the invitation to join this very interesting webinar. So I'm going to share my screen and start the presentation. In these 10 minutes, I'm going to talk about the results of trials that has been presented in 2024 with combining drugs with radiation therapy for stage three RSF-Clobosomal cell lung cancer. And the first one was a negative trial that you probably all know. It's called Pacific II. It was implemented by Dr. Bradley in European Lung Cancer Conference in early 2024. The randomization here was 2-to-1 to a regimen of chemotherapy plus durvalumab given concurrently and durvalumab maintenance versus a standard control arm that at that time did not include immunotherapy maintenance, but standard of care. At that time, chemotherapy alone. The trial was negative, both for PFS and OS, and the results have been discussed a lot. We will maybe have time to discuss a bit on that, but for sure it means that giving concurrently immune checkpoint inhibitors with recurrent chemo radiation in lung cancer, as in many other form of solid tumors, is not the right strategy to pursue. In the best scenario of ongoing trials trying to break the Pacific ceiling and try to improve the results of Pacific trial, we also had a press release regarding the failure of Checkmate 73L, which was a similar trial comparing chemo radiation, concurrent chemo radiation with the integration of nivolumab, followed by either nivolumab or epidimolar plus nivolumab versus Pacific. And again, it was negative, so it's the second negative trial with concurrent chemo radiation plus checkpoint inhibitors. We still have open two trials in this field. One is Killing-012 and Equiviral-06, one with pembrolol-laparib and the other one with pembrolol-glucosolone, which is an anti-TG agent. But we also have many trials ongoing in the consolidation maintenance field, so not including immunotherapy in chemo radiation. For example, Pacific-8, Pacific-9, the ADVANCE and SCARPET-03 trials. I'm going to talk a little bit more about the induction-IO-containing trial, because three of them have been presented this year, and then briefly also the dual trial, which is limited to patients eligible for chemotherapy. We also have positive news, because in Phase 2, KINAT-1799 trial, which is the basis of the Killing-012, for example, trial, we had an update in 2024 for both cohort A and cohort B, and here chemo radiation was given together with PEMBRO plus maintenance Pembrolizumab, and in this Phase 2 trial, the 12-month PFS is 77.3, which is very good, and also we had for the first time the molecular data, and at Cycle 7 from Baseland, many patients were able to obtain ctRNA clearance, they got molecular response, and as you can see here, the PFS for patients reaching molecular response, it's very, very good, and this is, to me, a very nice signal. We also have an update regarding the COAST study, which was a Phase 2 study comparing Durvalumab in maintenance phase after chemo radiation to the combination of either Durvalumab plus oleicumab or Durvalumab plus monolizumab, and in the update, still these two experiment alarms were superior in terms of PFS with respect to Durvalumab alone, so we are still very positive, and we eagerly await the results of PACEV9, which is the consultee Phase 3 trial. But also in 2024, for the first time, results have been reported regarding the approach of induction immunotherapy. The first one trial I would like to talk about is the FT16 Alliance Foundation trial, which was testing atezolizumab for four cycles in BDL1 positive patients with stage 3 A and B unacceptable disease, and then chemo radiation, and then atezomaintenance. In this trial, there were many patients that did not reach radiation therapy, because only 44 out of 62 actually received the plan of the chemo radiation, but if you can see, I didn't intention to treat curve or the curve in patients receiving radiation therapy, where the patient-free survival measures since the end of chemo radiation, you can see very encouraging results, and especially the overall survival data in this trial is very good, because at 24 months, we have more than 75 patients alive, which is a very significant result, and probably these trials need to be implemented, need to be a bit, let's say, refined, but it's promising. And another study tested the induction immunotherapy, but this time plus immunotherapy, like the neo-durant approach we have with surgery, and the main investigator was Mariano Provencio from Madrid, and they tested the analysis phase two non-randomized trial, the chemoatezo, plus concurrent chemo radiation, and maintenance atezodizumab, and if you use the same landmark for estimating PFS as for Pacific trial, they call it PFS Pacific-related, they obtain 68.9% of 12-month radiation-free survival, which is, again, superior to Pacific and very promising. Another study that has been reported in San Diego at the ASLC World Cancer Event was the phase two Pacific Brazil. Here we have induction chemo IOE DERVA, then concurrent chemo IO, and then consolidation DERVA. The primary was a 12-month progression-free survival. For the first time, the results have been presented, and the study is positive for the primary endpoint, because the progression-free survival, again, is very similar to the previous study, 68.1%, which is approximately 15% more than Pacific. Obviously, it is only a phase two non-randomized study, so these data need to be confirmed, but again, they are promising. Then we have, for the first time, the presentation of the trial, that is a trial randomizing two to one patients with stage three non-acceptable EGFR mutated normal cell lung cancer, and patients were randomized after chemo radiation, like in Pacific, if they were responding to either ozometinib up to progression discontinuation, or placebo. As you can see, there is a huge benefit in PFS for ozometinib given after chemo radiation, and the control group did perform very badly. Many of these patients were probably already stage four. In any case, the benefit of ozometinib is very good for all subgroups and all certifications, and also the overall survival is very good, because there was a high fraction of patients receiving ozometinib progression, and at the end, the results for overall survival is good also for the control arm, because many patients were saved at the time of projection with 81% of crossover. The adverse events that profile the toxicity profile were very acceptable. At the very beginning, we had some concerns regarding this aspect, especially the incidence of pulmonary arthritis, but it's not confirmed, so the incidence of pulmonary arthritis is slightly higher, but not in grade three, only grade one, two, so it's very manageable. And another trial confirmed the benefit of a targeted approach in the GFR-mutated patients using amilartin in the Polestar phase three trial, where again, patients were randomized one-to-one to chemo radiation plus amilartin or placebo, and again, the results were very positive and have been presented again at the World Lung Cancer Conference in San Diego. Finally, we had the opportunity to present a TASMO-2024 in Barcelona, and the results of our study, the dual study, which is a study for patients ineligible to chemo radiation certified in two cohorts independently on the dose they received before entering the study, either palliative or more radical intent, and these two groups were approximately very similar. We previously reported the results in Thermo-PFS and OS, and for the first time here, we are reporting the molecular data. As you can see, quite a huge number of patients were able to collect samples from blood at cycle one, cycle two, and cycle seven in both cohorts, and in approximately 91% of the intention three population. And similar to the keynote 1799 here, we are showing that patients are able to obtain cDNA clearance after radiation therapy, and especially during maintenance, and there is a huge difference in progression for subava between infection reaching molecular response in comparison with those not reaching molecular response independently of the dose they receive. So the combination of radiation therapy and immunotherapy is very active also in patients treated with a non-radical dose of radiation. So, closing, I would like to say that concurrent CR-TIO is probably not the right strategy for improving calming with two negative trials. Sequential CTIO followed by chemo radiation and DIO appears to be a promising sequence. TKI administered after chemo radiation on congenital tendency provided superior progression for survival for sure, and this was proven with two agents in a randomized trial. And cDNA clearance for the first time has been proven to be useful also in patients treated with chemo radiation. We only had the retrospective data from Stanford, but this data comes from prospective studies, phase two prospective study, but they are very promising because they will allow us probably in the future to de-intensify or intensify maintenance therapy because they are strongly associated to PFS. And thank you very much for your attention. Well, thank you so much Dr. Filippi for bringing us up to date with some very important clinical trials that were reported in 2024. And next we'll have Dr. Pamela Sampson talk to us about some very challenging controversies that we're seeing in radiation oncology as a result of many of these clinical trials and innovations in technology we've seen. Dr. Sampson. Thank you for this opportunity. So in the same spirit of discussing case controversies in radiation therapy for non-small cell lung cancer, the topic I'll be talking about today is re-irradiation therapy for recurrent early stage or locally advanced non-small cell lung cancer. What I'll be going through is some historical data supporting re-treatment, recent consensus guidelines and experiences, a decision flow chart that can help in the clinical setting, and a very brief case review to go over some of the salient points in this presentation. So one of the largest re-treatment series we have in the literature is an MD Anderson series from 2004 to 2014. And in this they examined over 900 patients that were treated for early stage non-small cell lung cancer with SBRT. And according to the flow chart listed here, they identified patients that after SBRT either had isolated local recurrence or had isolated regional recurrence. And they divided the patients out retrospectively to see was re-irradiation possible or chemo RT for regional recurrence, and then went down this pathway of either radiation, repeat radiation therapy or surgical resection. If neither radiation or surgery was an option, was other techniques such as thermal ablation possible. And what we saw in this group was that for the patients with isolated local recurrence, the majority of patients, the largest group received repeat SBRT followed by surgical resection. So one in four patients that got SBRT were able to get salvage surgery for their recurrence. And a not insignificant proportion received thermal ablation or systemic therapy alone. For patients with infield regional recurrence or isolated regional recurrence, the majority did receive a chemo radiotherapy with a smaller proportions receiving RT alone or systemic therapy alone. And this found three major findings among this group. So the first major conclusion from this series was that patients with either isolated local or regional recurrence that received salvage therapy did live longer than those patients that had recurrence that did not receive salvage. So this was not a surprise, but it was important to establish that salvage therapy after recurrence did extend overall survival. The second finding was that patients with isolated local recurrence that received salvage therapy had similar survival compared to those patients that never had an isolated local recurrence. So those patients that went on to get SBRT again or surgery had a similar survival to those patients that never had a recurrence. The third finding though, was that patients without isolated regional recurrence had improved overall survival compared to those that did have a regional recurrence, even with salvage treatment. So unfortunately for patients with a regional recurrence, even though their survival would be improved compared to no treatment, it didn't quite catch up to those patients that had no recurrence at all. When spotlighting those patients that received re-irradiation therapy, this is a different cohort of patients. This was patients that had received definitive intent concurrent chemo radiation therapy for locally advanced non-small cell lung cancer with their first course of radiation being everything from 2D, 3D, IMRT, and proton. When they experienced a recurrence, they then went on to receive re-treatment with either IMRT or proton therapy. So in this series, there was 102 patients with a median first course dose of 70 gray. The median interval to re-irradiation therapy was 17 months and the median re-irradiation dose was 60 gray. And what they saw in this series was low and acceptable rates of grade three or greater esophageal and pulmonary toxicity. However, there were some important caveats in this population. So they saw that patients receiving definitive intent re-irradiation therapy had better outcomes if they received concurrent chemotherapy, if they had an adenocarcinoma histology rather than squamous, if the re-irradiation volume was a GTV was small, if the time to retreatment was greater than six months out from the conclusion of the previous treatment, and if they had an excellent performance status with an ECOG of zero. So over the years, although there have not yet to date been any randomized re-irradiation trials with a definitive setting, studies like these from MD Anderson have led to some consensus statements about how we go about selecting which patients could benefit from definitive intent re-irradiation therapy. And some of the consensus that were reached here, you'll see the percentages off to the right-hand side with the degree of consensus among this expert panel, was that surgery should be considered in all appropriate patients. Complete re-staging should be done before re-irradiation therapy with PET and brain MRI. Patients should have an ECOG status of zero to two. Re-irradiation therapy should be avoided in patients with a history of interstitial lung disease or interstitial pulmonary fibrosis. And attempt at biopsy should be done if anatomically and physiologically possible. If the patient's PD-L1 score is greater than 50 percent or if there's an actionable mutation, immunotherapy or targeted therapy respectively may be preferable to high-risk radical re-irradiation. In regards to the treatment approach, this consensus guideline had some statements as well that re-irradiation should be done with highly conformal techniques such as VMAT. When fusing the original plan to the CT simulation to combine the new plan with the old plan, either rigid or deformable registration should be used. There will be more on this in a future slide. Protons may have a role, but further evaluation is needed. And in my clinical opinion, I will often create a proton comparison plan, but depending on the anatomic location of the recurrence in the lung, proton retreatment plans do not always win from a dosimetric perspective. But I will usually compare a VMAT plan and a proton plan to see which is preferred. SBRT is the preferred re-irradiation strategy when the tumor volume is small and there's minimal overlap with the organs at risk and the target is not considered central or ultra-central. In regards to treatment planning, they describe that the desirable cumulative maximum point dose to the esophagus, EQD2 of 75 gray, for the spinal cord, 60 gray, the brachial plexus, 80 gray, and to the aorta, great vessels, 115 gray, and the pulmonary artery, 100 gray. So this flowchart is adapted from one that Dr. Dan Gomez has made, kind of bringing together some of these recommendations that for a local regional failure for a patient that is not a candidate for surgery, if they are a possible candidate for SBRT, they should proceed down that pathway appropriately. And with a five-fraction regimen, we could again expect local control rates of 80 to 90%. If it is a mediastinal recurrence or there's large volume disease, based on the performance status of the patient, you may consider palliative intent versus definitive intent. For those definitive intent patients, though, something we do in our practice is if the patient is not a candidate for chemotherapy and the dosimetry of the prior plan allows, we will consider an altered fractionation of 60 gray over 15 fractions, especially with a conformal plan. If they are a candidate for chemo, we will do a concurrent chemo RT. This RULAC paper also gives some important guidelines regarding what different series have reported for their dose constraints for re-irradiation cases. So this is a handy slide to have on hand when you're evaluating these patients in clinic as these cases are increasing in frequency. We're certainly seeing more now than we ever have. So there are obviously some challenges in evaluating the composite dose. The first and most obvious problem is the one that we all learn about as radiation oncology residents in our first couple of years and that's that we cannot simply add a dose among cases that have received a different fractionation regimen. So we always have to get out our EQD2 calculator. The second problem is that we can certainly do a global max dose from two different plans and that can be the safest approach, but it is not necessarily accurate. So if I simply look at the Dmax from my two plans that's listed out in my plan dose symmetry, I may get a spuriously high dose and EQD2 if the parts of the esophagus that were treated that saw that max point dose were in different anatomic locations. So an option to this would be creating a sum plan, but only as much as I trust my registration and the anatomy, that the anatomy hasn't significantly changed. So instead of looking at my global max, I'm looking at what my max was in that area. So where my max is for my new plan and going back and looking at what my esophageal max was just in that anatomic area where there would be overlap. So what I'll do is I'll just present a very quick example of how we would use some of these guidelines and recommendations for a repeat SBRT case. So this was a patient with a central tumor that had received 50 gray over five fractions. His previous dose symmetry values are listed here. He was found to have a mediastinal recurrence that was biopsy proven by EVS TBNA. And what we selected for this patient was concurrent chemo radiation therapy, 60 gray over 30 fractions, IMRT approach, conventional simulation like we would do with a 4D CT. Our primary images were the simulation CT. We then fused it with the prior SBRT plan, his PET CT and the 4D images. You always wanna make sure as auto-contouring becomes more and more popular to always do a close examination of your auto-contours, especially on these retreatment cases. I find in particular that I often have to touch up or edit the auto-contours for great vessels and esophagus in particular. It usually does a pretty good job with the bronchial tree, but I do always check that as well. And something that I will make to help the optimization programs is to make a high dose isodose line structure. So to take in my previous 50 gray, 30 gray isodose lines and make that as a independent structure in my current CT simulation plan. So I can evaluate that as I'm designing my treatment plan. Our volumes were a GTV, an ITV, a CTV of five millimeters with no elective nodal volume and a PTV expansion of five millimeters. And those contours are shown here. Now we have a decision point to make in this case, and that's whether we perform rigid registration where the CT simulation is registered with the previous plan based on anatomy such as the bony anatomy. But what you can see here is over time, scar tissue from the lung, the heart, the great vessels, the bronchial tree can be in significantly different positions. And you see that here with the amount of pink and green shadowing showing the difference between these two plans. So how much can I trust my max dose when these structures look that different? So a common application that has come about is what we call deformable registration. Where basically the algorithms in our treatment planning system will stretch and bend the differences between the two plans to make them more equal, to make them look more similar. And it's always important though that when deformable registration is being used that either the physicist or yourself check the amount of stretching, so to speak, to make sure that this anatomy is not being overworked and stretched or changed in a way that would make it inaccurate, okay? So what we saw for this plan interestingly was that for the esophagus and the bronchial max in particular, if we had just used the EQD2 global max sum, we would have exceeded both our intended esophageal composite max and our bronchial composite max. And this plan would have been deemed unsafe and unable to be delivered. However, when we actually used the raw sum using just those anatomical areas that saw dose last time in the neighborhood, so to speak, of that organ at risk, we actually saw that the esophageal max and the bronchial max were within our retreatment limits for this patient. So what I say is that probably the truth is somewhere in the middle, probably closer to the plan sum side than the global max side, but I shouldn't necessarily assume, especially if deformable registration is being used, that the raw sum technique is perfect. Interestingly, for the future directions in retreatment planning, one thing Brooks and Joe Chang and group are working on is rather than creating plans that, composite plans that show you a composite dose, that the algorithms are actually able to show you a composite BED on your plan for evaluation. So I think this is a particularly interesting and useful direction for plan evaluation that could help us make sure these retreatment plans are safe moving forward. So in conclusion, historic data supports the use of re-irradiation therapy for very carefully selected patients. I would say probably the biggest ones that we see time and time again would be that they are more than six months out from their original treatment, that they have an excellent performance status and that they are on the side, especially if it is in field for smaller volume. Current guidelines shown here do provide guidance on patient selection, treatment planning and treatment delivery. However, we should acknowledge that a major gap is how these toxicity and efficacy rates may be different in the age of immunotherapy. And evolving approaches for creating composite plans will help us tailor retreatment plans to unique patient anatomy and high risk areas and make sure these treatments are safe moving forward. Thank you. Well, thank you again, Dr. Sampson for going over re-irradiation, which is always very controversial from an academic perspective as well as just a practical tumor board perspective. With the emergence of immunotherapy targeted therapy, patients are living longer and longer with the chance to develop local recurrence. Whereas I think the attitude before was, these patients will never live long enough to have a local recurrence and won't live long enough to have a radiation toxicity. But now with the majority of patients making it to long-term survivorship, this is very much a topic that we've got to figure out as a field. And thank you so much for giving us a great framework how to approach these cases. So for the final part of this webinar, we're going to quickly go through some cases that represent some of the controversy that's emerged, particularly as a result of recent studies for locally advanced non-small cell lung cancer. And so for our first case, we have a 65 year old female incidentally found to have a lung mass in the right apex, no significant medical history or social history, certainly no history of smoking, just really minor car accident, they did trauma scans. Dr. Sampson and I both did surgical internships, so we are very familiar with trauma scans. And so the patient underwent this CT guided biopsy showing an adenocarcinoma consistent with a non-small cell primary. It was TTF1 positive, P40 positive, and PDL1 30% by immunohistochemistry. Interestingly, the tumor was negative for a activating EGFR mutation, also negative for the EML4 ELK translocation, but there was a met exon 14 skipping mutation. Further workup was done showing no distant metastases. Pulmonary function tests were done and they showed excellent pulmonary function as would be expected because this patient has no history of smoking or any other lung disease. And so in line with the theme of this webinar, I wanted to briefly go over another important trial that was published in 2024 in Lancet Respiratory Medicine. This was the seismic trial, which evaluated the role of bronchoscopy and EBIS in patients who had already undergone rigorous staging workup with a PET scan. And Dr. Phillippe, Dr. Sampson, I want to just ask the two of you, so for a patient who has undergone a PET scan and there are no significant nodes identified, are you routinely seeing that bronchoscopy and EBIS is being used in your practice? Well, I can answer first, Pam, if you're okay. We are starting discussing all these cases in our multidisciplinary team and if we have a completely negative CT and PET scan and patients, let's say, are elderly or with comorbidities, so we tend not to perform systematic endoscopy staging. While for all other patients, we are now, even if they already have a biopsy or they already perform a bronchoscopy EBIS, we perform systematic endoscopy staging to be sure regarding the mediastinal staging and as this trial pointed out, this is not only important for accurately defining the clinical stage, but it's also very useful for us as a radiation oncology if the patients will finally be addressed to radiation therapy. Yeah, and just to add to that, we tend to look at the whole clinical picture, especially in the U.S. where patients may already have had delay of care, certainly ordering an EBIS may add additional time until they can get to their treatment, so we have to take that into consideration, but the things that will make me say, no, we absolutely need an EBIS, even if the PET is negative, for me would be if the patient has a tumor with a central or ultra central location, the T-stage of the tumor, things that I think will increase their risk of N2 nodal involvement or N1 involvement over that 10% estimate that we typically think of for stage one lung cancer. So as their risk factors go up, my willingness to do an EBIS goes up. I'll also look at how old the PET scan is. In the U.S. typically we can't order another PET scan if it hasn't been three months yet, but I can order an EBIS. Right, these are great perspectives, and I think the two important points from the seismic trial was that roughly 15% of patients, they found a different nodal stage than was represented on the PET scan, which led to a clinically meaningful difference in the radiation treatment volumes, obviously. But I think the second important finding of this trial was that there wasn't really a downside of doing the bronchoscopy and EBIS. They saw no serious adverse offense. So I think an EBIS, particularly in the hands of a skilled interventional pulmonologist, I tend to always favor getting the little bit of additional information. And I would say I have been surprised roughly 10 to 15% of the time, as is represented in the seismic trial. And so this patient underwent bronchoscopy and EBIS. Indeed, there were no lymph nodes involved, so it was a T1CN0M0. But this patient, she was healthy. This tumor, it was somewhat close to the vascular structures, and there's been the emergence of the neoadjuvant perioperative paradigm, whether it be CHECKMATE 816, whether it be AGEAN, whether it be the NADEME2 trial. And so this patient was treated in accordance to the CHECKMATE 816 paradigm with three cycles of cisplatin, paclitaxel, and nivolumab, and underwent a PET scan for restaging, which actually showed slight progression of the right upper lobe nodule, now measuring three centimeters. And so the patient was taken for surgical resection, right thoracotomy with right upper lobectomy, mediastinal nodal dissection. The mediastinal stations being dissected were negative, but this tumor having grown closer to the vascular structures, there ended up being a R1 microscopic positive margin at the resection margin. And so I wanted to ask our panel here, you know, especially in light of the LUNG-R trial, and, you know, with a R1 positive margin, you know, probably, and if you look at ISLC data, the recurrence rate is lower than you'd think. It's only about six to 10%. I mean, what are the postoperative indications now in the perioperative world of chemoimmunotherapy? This seems to be something that comes up in tumor boards, at least for me, quite often. Yeah, I mean, right now the answer I would, that comes to mind most readily is for either R1 or R2 resections where there's a positive margin. And we know now that just for the presence of positive lymph nodes and two nodes, as long as they were resected, there really isn't any benefit with postoperative radiation to those fields. So I am just doing it for positive margins now. Now, that being said, we are seeing in our tumor board and in our referrals, an increasing number of what looks like patients where induction therapy was used to make a inoperable or marginally operable case operable. And so now we are seeing things like retained N2 nodes, partially resected nodes, where the positive margin isn't the primary tumor, it's the node itself. And it's kind of a reminder that when people are using the neoadjuvant regimen, it really needs to be for patients whose tumor is operable from day one, before they get that first cycle of induction therapy. I think there are a lot of people that are trying to use big bulky tumors or big patients with multilevel bulky N2 disease and turn those into operable patients. And we're seeing the ramifications of that on the other side. Yeah, and I'd have to say, I totally agree. We've seen people kind of push the perioperative paradigm, but all of these perioperative trials were not intended to show, hey, we can convert these unresectable tumors to resectable. What these trials showed is that if you're going to do perioperative therapy, chemo-immunotherapy is better than chemotherapy. Yes, absolutely. And, but I agree what we're seeing is a lot of pushing the envelope outside of that inclusion criteria. You know, in terms of, I think perhaps another controversy is extra nodal extension. In fact, you know, the ISLC considers extra nodal extension as an R1 resection. How are you guys approaching extra nodal extension as a potential indication for postoperative radiation after perioperative chemo immunotherapy? I have to say that luckily we don't see so many patients with this kind of, let's say pathological reports with extra capsular extension of positive would say margin in the lymph nodes. But in the case we will be probably offering postoperative radiation therapy because this is completely outside of the LungArT trial in my mind. So we're not offering any more postoperative radiation therapy to all and to patients I do completely agree with Dr. Samson. And, but we are offering for this very selected cases of reciprocal disease, either the reciprocal disease is in the marginal bronchial, let's say, section or it is in the mediastinum. I would say that this is due to the, yes, to overall optimistic idea of chemo and surgery in patients with borderline or unacceptable tumor. So if you carefully select patients before, and as you all were agreeing on that you're using the same criteria, selection criteria that has been used in the clinical trials is very unusual to have a problem in the nodes. And for this particular case, I just want to highlight that probably with this kind of NGS finding, you know, the exon, the metaskippin mutation, we would probably not offer any immunotherapy combination in Italy and we would go either for neoadjuvant chemo or to direct resection and adjuvant chemo, but without any volume on, because even if we don't have data in very rare mutations, such as exoskippin mutations, the general feeling apart from KRAS is that if these tumors are all coagulated then the benefit of immunotherapy is not so evident. So it's probably, it's my experience in Milan, but you know, if you perform a lot of NGS in early stage, you're starting to see this a lot of rare mutation that are not only EGFR or ALK, but there are ROS1, BRAF, exoskippin mutation or NTRK or others. And at the end, it's very difficult to know what to do with these patients regarding immunotherapy use. Yeah, and just in regard to the ENE question, I will talk to my surgeon and my pathologist because often these nodes are resected in a packet. So they're resected sometimes depending on the location, instead of being plucked out, they're actually resected with the mediastinal fat around them. And if that's the case, that would make me less enthusiastic for port. Yeah, and I think one final thought that I'd like to talk about with this case is, you know, when we look at the lung art trial, actually for even multi, for, you know, N2 disease, there was a pretty dramatic reduction in local recurrence with postoperative radiation. It did not translate into a survival advantage. But I also wanna point out that majority, I think about 90% of those cases were treated with 3D conformal radiation, which by today's standards is a somewhat primitive technique that would degrade the therapeutic ratio, exposing the heart and lungs to unnecessary radiation dose. So I think this is a very, you know, hot topic right now. Ultimately the patient was treated 54 gray in 30 fractions with a simultaneous integrated boost to 60 greater the area positive margin, treating the entire operative bed as the CTV. And then the area I suspected a positive margin plus a centimeter, kind of like a head and neck plan actually, like something you'd see in RTOG 12-16. I've treated head and neck too. In any case, in the interest of time, I'm gonna move to the next case. This is a 75 year old, had a cough. You can see the X-ray that showed that tumor there. Further workup showed a right lower lobe mass, lots of mediastinal nodes. This was EGFR mutation positive. Multiple mediastinal nodal stations were positive, 10R, 4R, 7, 4L, and 2. And even the right supraclavicular region. And so again, you know, for a locally advanced case like this with EGFR mutation, I wanted to just kind of very quickly find people's general treatment strategy for this. Oh, please, Pam. Oh, you first. Okay. No, we are for sure the standard of care here is should be tumor radiation, if feasible. It is a very large volume, but I'm sure that with a very accurate planning strategy, you can do it. And then if the patient does not progress, follow up by osimertinib. However, in these particular cases, I would suggest, and I'm talking personal opinion and outside the evidence. And, but I think we will be moving in using a kind of a flower to combination like chemo and osie a couple of cycles before. And because we know that these patients are gonna respond very well, and then irradiate and go for with osimertinib maintenance. But this is, I know it's completely outside the standard of care, but it's very logical to me in case like this one. No, I like the thought process there. And actually we ultimately ended up pursuing the ALARA approach of chemo radiation with consolidative osimertinib, with a thought that if they, at restaging, if there was progression, then we convert to chemo and osimertinib. If there was no progression, just continuing on with the osimertinib. As you can see here, the mediastinal nodes were actually fairly close to the mediastinum. So it wasn't felt that induction immunotherapy was going to buy us much. And we ended up with somewhat reasonable DVH criteria. Lung V20 was 35%, the heart V40 was 17%. And so we ended up going with this plan. And again, just recapping a very big trial this year, the LARA trial showing a benefit of osimertinib, big benefit when given in the consolidative setting after chemo radiation, which is now the standard of care. I know these patients were included in the Pacific trial, but as we know from the ancillary analyses, you know, the hazard ratios for immunotherapy with an EGFR mutation, it's really not particularly effective. And so I think we only have time for two cases today because we do want to give the audience time to ask some questions. And looking through the panel here, I think we've got about five questions. Let's see, we have a question from Dr. Drew Mokonaki. The in-field failure rate after chemo radiation for stage three locally advanced non-small cell in prospective clinical trials is often confounded by progression-free survival definitions that include out-of-field relapses anywhere on the thorax. How do you navigate this issue and what do you think the in-field failure rate is after chemo radiation plus dervalumab? That's a great question because out-of-field failures can happen, out-of-field failures can happen a few ways. So I will be very careful to document in my note if I think, okay, we treated a locally advanced left upper lobe primary with some N2 disease, or out-of-field failures tend to be more clear like if it's one nodal station above where their previous field was. I am much more likely to say, obviously that's progression of disease. And I have to say that I'm certainly in agreement with the sentiment of Dr. Mokonaki that it's frustrating that a number of these trials report PFS without the actual pattern of failure, whether it's local or distant. This is not a problem specific to chemo radiation trials, but when you look at AGN, when you look at CHECKMATE 816, I mean, it's purely progression-free survival. They don't say, okay, it was a mediastinal node that has failed. I think where we're potentially gonna get a lot more information on specific local patterns of failure with chemo radiation plus derva specifically will probably come from RTOG 1308. Oh, that's a study of protons versus IMRT, where I know that they very specifically looked at local failure in a similar way to RTOG 0617. Anecdotally, perhaps, and I probably shouldn't give anecdotes, I would say local failure in field, probably my rough guess, at least in my practice, about a third. But again, a great question. Let's see, there's another question here. In a patient with clinical, from Dr. Arnald Almsor in T2N2, who received perioperative chemoimmunotherapy, who achieved a complete response radiologically, before offering surgery, what would you recommend for the next step? I guess this is kind of begging the, is it possible to just observe these? Because when we look at these perioperative trials, I think it's what, about 20% of patients have a PCR, and it's, in many other disease sites, rectal cancer, there's the OPRA trial. You can just observe esophageal cancer. We know that in squames, that you have a PCR 60% with the cross regimen. Yeah, what, I mean, this is kind of outside of the box, but what do people here think about potentially observing patients who have a radiographic complete response after chemoimmunotherapy? I think it's very rare, because complete responses, radiological complete response are very rare after three, four cycles of chemo. It can happen in patients with very low tumor burden. I would for sure do bronchoscopy, trying to do biopsies, try to confirm the presence or not of tumor cells. And then probably we'll, in any case, go for surgery, because this was the original plan, outside a clinical trial. We can also discuss with the patients the idea of offering an intensive follow-up. I would also couple with ctDNA if feasible, but it's not very easy in the clinic, outside the trial. So again, we are navigating an area where we don't have any data. So it's completely, let's say, outside the box. You were right, Stephen. So I don't know. You need to talk with the patients, but probably at the moment, we need to keep our original strategy, that in this case was probably surgery. We've got another question from Philip Blumenfeld. I think that would be well-answered by Dr. Sampson. When treating with infield re-irradiation, do you typically give a clinical treatment volume margin or CTV margin in conventional or hypofractionated radiotherapy? Our practice has been that if we're doing a hypofractionated regimen, a 60 and 15 approach, we do not do an elective CTV. However, if we're doing the more conventional fractionation, we do. And that's just to try to keep our safety margin as tight as possible. How about you, gentlemen? I similarly try to get as the best imaging I can, PET scan, even an MRI. And it's actually very important to collaborate with the radiologists. It's gotta be a cardiac gated MRI, or there can be incredible amounts of artifacts there. I try to delineate the tumor as accurately as I can. And then I feel that we have to trust the technology, be it an MR-LINAC or your cone beam. And I just do a PTV. I really, I'm not in the habit of doing CTVs on re-irradiation cases. Interestingly, actually, re-irradiation, what I've been doing for these cases at my institution, we have actually a re-irradiation trial where, and again, this is purely a trial. This is not something done, that should be done in just regular practice, but injecting the tumor with a novel radius sensitizer, and then treating to 45 gray and 15 fractions, a nanoparticle, which I'll be eager to see what the results are. Because I think doing radiation again, if it didn't work the first time, you kind of wonder, okay, how, I like the trial because it may or may not work, but it's trying to change the biology. Yeah. And I would say, no, it also depends, is it like smack dab right in the middle in field recurrence? In that situation, I probably wouldn't use a CTV, even if I am doing conventionally fractionated 60 and 30 again, or was it more of a marginal failure where I have kind of healthy lung around it? And everyone quotes the six month cutoff, has it been more than six months since the original treatment? I personally tend to use more than, like, has it been more than a year? Because I think if it's any sooner than a year after treatment, is it really a recurrence or is it just persistent disease at that point? In my enthusiasm, even though the MD Anderson data shows that beautiful split at six months, I really look for things other than radiation therapy if it's been less than a year, because I just don't think that's radiosensitive disease. I think we have time for another question. One final question from an anonymous attendee for locally advanced non-small cell cases that are upstaged after resection, kind of like the case we presented. When do you consider PORT instead of immediately initiating sequential systemic therapy? And I think that very much is a, I don't think there's actually a clear answer on that, because if you look at AGN, that continued for a year of dervalumab, regardless of whether the tumor was upstaged. And we know that about 15% of cases are gonna progress on chemoimmunotherapy. And so really, we have data for PORT with lung art, but that was prior to chemoimmunotherapy. It was also fairly primitive radiation, but yeah, Dr. Sampson, Dr. Filippi, somebody comes back, progression after perioperative chemo, and let's say multiple N2 nodes were resected. Maybe there's EC or something with progression. Do you, at that point, have thoughts on continuing with, let's say, a systemic regimen that didn't work, or do you try to change the game with radiation? I think this is an open question that nobody really knows the answer. Yeah, this is becoming an increasing scenario. We're seeing on our tumor boards as well, and our consensus with medical oncology has been to change the game and do chemo RT. So I think we're a little bit over on time, and there's so many great questions here in the chat box. I'm sorry we can't get to all of them, but I'm going to conclude this session. I really wanna thank everyone in the audience for tuning in. I hope that we've provided some pearls of wisdom that might be helpful in your practice to achieve better outcomes for our patients. And again, I think 2024 has been a great year for the field of lung cancer, especially in the locally advanced space, and we can offer patients real hope and of long-term survivorship in a way that we never could do even 10 years ago. So again, I wanna thank everyone for joining. Feel free to contact. I think, I don't wanna speak for everyone, but I think everyone would be welcome for you to contact us if you have any further questions or input. Thank you very much, Stephen, for your moderation, and thanks to Pam also for being a speaker, and to ISLC, Advanced Radiation Technology Committee for organizing. Also, and particularly Alex Lewis, and it's been a pleasure, really, for me. And I was open to being contacted from everyone, if you want. Yes, likewise. Well, thank you. And wherever you are in the world, we wanna wish you a good day and take care, everyone. Thank you, bye. Bye.

locally advanced NSCLC

radiation oncology

immunotherapy

chemotherapy

clinical trials

re-irradiation therapy

molecular responses

targeted therapies

advanced imaging

lung cancer management