I will be your presentation moderator today. I've been involved in the management of small cell lung cancer now for more than 20 years, and during that time I had the privilege to witness some major changes in the management of this disease, leading to improvements in outcome. Clearly, some of these improvements relate to better systemic treatment. However, better integration of radiotherapy and systemic therapy has also played a major role. Importantly, progress has been made thanks to the participation of patients in clinical trials, and it is a plea to all of you to offer trials to your patients. So I have a few housekeeping items to share with you before we start the presentation. So this activity has been planned and implemented in accordance with the accreditation requirements and policies of the ACCME, and the ISLC is accredited by the ACCME to provide continuing medical education for physicians. The ISLC designates the live format for this education activity for a maximum of one Category 1 credit. All faculty, planners and reviewers for this webinar have disclosed their conflicts of interest, which you can see on this slide. So this shows you the learning objective for this webinar. So clearly some areas of treatment are clearly very controversial at present, such as PCI for all stages of disease, thoracic radiotherapy in extensive stage small cell lung cancer, and generally the role of radiotherapy in the immunotherapy era. So our speakers will present the latest evidence on these topics. We're now going to move on to the first talk. So Dr. Higgins is going to share her slides. So Dr. Higgins is a professor and vice chair for clinical research at the Winship Cancer Institute of Emory University, and I'm actually delighted to announce that she became a professor just only a few days ago. So congratulations to you, Kristin. All right. Well, thank you everyone for joining us today. Let's start off with limited stage small cell lung cancer and understand where we are right now. What is the current evidence for what we do each day? For our patients right now, the standard of care is platen and atopocyte chemotherapy with thoracic radiation followed by prophylactic cranial irradiation. The dosing that we use right now is 45 grade twice daily or 66 grade to 70 grade daily, along with four cycles of chemotherapy, typically beginning radiation at the time of chemotherapy or with the second cycle of chemotherapy. We know that with this approach, five-year survival is between 25 to 30 percent. There are barriers to patients receiving the best standard of care therapies. We know right now in the United States that just over half of patients are even receiving curative therapy when they're diagnosed with limited stage small cell lung cancer. So I think despite the improvements in technologies and radiation and systemic therapies, we still have major issues to tackle when it comes to patients having the option for standard of care treatment and even getting referred to oncology teams. But that being said, how can we as thoracic oncologists improve outcomes for limited stage small cell lung cancer? And I want to go over the current data. So of course, our moderator, Dr. Fadre-Finn, conducted this very well-known trial in Europe, the CONVERT phase three trial. And this trial was really the trial to determine the optimal radiation fractionation for patients with limited stage small cell lung cancer. The study was designed to determine if once daily radiation to 66 gray was better than the current standard, which was 45 gray twice daily. You can see here that there was no statistically significant difference in the treatment arms. However, numerically, the twice daily arm did do a little bit better. If you look at toxicity, and I think this is a really important point, high grade esophagitis was 19% in both arms and pneumonitis was really quite low in both arms, 3% for BID versus 2% for Q day. And these were a lot lower than what we had been quoting historically. And I think this is showing us that over time, our radiation technologies have improved and it's getting easier to deliver these curative therapy for our patients. Importantly for patients in this study, they were eligible if they had a performance status of ECOG zero to one or two, if it was secondary to disease related symptoms and had adequate pulmonary function. It was a large trial, over 500 patients and again, I think it really kind of set and confirmed the standard of care, which I interpret as continuing to be 45 gray twice daily with concurrent chemotherapy. Now there was a similar trial to the convert trial that was conducted in North America. And this trial recently was presented at ASCO a couple years ago and did come out in the JCO in 2023. And it compared the 45 gray twice daily approach versus 70 gray once daily, again, with concurrent chemotherapy, CIS or CARBO, anatopicide, very similar inclusion criteria. Again, the primary objective was determined whether 70 gray would improve overall survival compared with twice daily 45 gray. This trial accrued much slower than the convert trial. It did recruit over 600 patients, but it spanned the course of 11 years. And this, I think was a challenge that it took so long to recruit these patients, but nonetheless, the results are very similar to what we see in the convert trial. Again, sort of confirming the dose fractionation of 45 gray twice daily. I think many people also interpret these two trials as also sort of allowing us to give once daily fractionation at a dose of either 66 or 70 gray. Now, what about hyperfractionated accelerated radiation and limited stage small cell lung cancer? I want to spend a little bit of time on a trial that was recently published in Lancet Oncology by Gronberg and colleagues. And this was a randomized phase two trial that recruited patients between 2014 and 2018, similar inclusion criteria, ECOG zero through two, randomized patients one-to-one to 45 gray twice daily versus 60 gray twice daily. Radiation started with the second cycle of chemotherapy and the stratified variables included performance status, AJCC stage and presence of pleural effusion. And you can see here the baseline patient characteristics were relatively well balanced. Just to go into the nuances of how patients were staged and treated, all patients received a PET CT and brain MRI. They did have a PFT cutoff of 30% predicted for FEV1 and DLCO. They did do simulation after the first cycle of chemotherapy. 40 CT was highly encouraged. They used, I think, pretty standard margins of five millimeter CTV margin and no PTB, excuse me, the CTV margin was cropped if it was extending into an OAR that was not involved by direct tumor extension. No elective nodal radiation was allowed. And the dose constraints were very similar to what we use in our standard practice. And they're shown here. Interestingly, if a patient was on the dose escalated arm of the study, if the constraints were not met, they could reduce down to either 54 gray. And if still not met, they could go down to the standard of 45 gray twice daily. So this trial showed improvements into your overall survival. There was a trend towards improvement in progression-free survival. The curious thing is that there was no difference in local control and also no difference in high grade esophagitis or pneumonitis. And I think many radiation oncologists certainly would say, well, how can you dose escalate to 60 gray twice daily and not get higher rates of esophagitis? Because we know that would be a side effect. I think perhaps there could be underlying differences in the volume of tumors in patients on this trial. They were stratified by stage, but not tumor volume or sort of anatomic lymph node regions that were involved. That could be one explanation. But nonetheless, this is a phase two trial. I do want to point out that we certainly have had positive dose escalation trials in radiation oncology that were phase two, but did not result in successful phase three trials, especially in the setting of dose escalation. We know this from RTOG 0617 in the non-small cell lung cancer setting, for example. There is a phase three Chinese trial of 45 gray twice daily versus, excuse me, 54 gray twice daily versus 45 gray BID. And this has completed a cool. This phase three trial will be presented, I think, very soon. And that will be interesting to look at some phase three data with this approach. And also I would say that the follow-up on this trial is short. So I will need to look at longer follow-up. There was no radiation quality assurance, and that could also perhaps be an issue. And then I mentioned the imbalance in tumor volumes that could possibly be explaining differences in toxicity. But I think ultimately for limited stage small cell, we really need strategies to reduce distant metastasis. This is a major problem for these patients that many times will progress to metastatic disease. And so how can we address that problem? But before we get there, I did want to mention just a point on moderate hypofractionation. There are many studies that have looked at giving anywhere between 2.5 to 3 gray per day as a different approach. I'm showing some of the data here. There has been phase two data that we've seen. The results look similar to 45 gray twice daily. We don't have any phase three data for this moderate hypofractionation approach. So what about radiation fractionation in the real world? What is actually happening in clinics across the United States and the world? We have one paper that was published in Clinical Lung Cancer recently in 2023, and this was a National Cancer Database retrospective study looking at patients getting thoracic radiation for limited stage small cell in the United States. And they just looked at trends and fractionation, and it was a large cohort of patients over 17,000. And they saw that 60 gray once daily was the most common fractionation regimen. And overall, 28% of patients received twice daily treatment, but it was decreasing over time. And I think we could probably chalk this up to a multitude of reasons, but I think some would say that it's due to logistical challenges of patients coming in twice a day for radiation. So what are the guidelines for the dose that we should give when delivering thoracic radiation in limited stage? There have been ASTRO guidelines that have been put forth that 45 gray BID is the optimal dose schedule for patients with limited stage small cell, but that 60 to 70 gray once daily is acceptable. If you look at the NCCN guidelines, they will list 45 gray twice daily or 66 gray to 70 gray once daily. Again, my bias is to try to do twice daily for every patient that I can. I do run across patients that say they just can't come twice daily if they're still working or if they live several hours away and can only make it one time a day for treatment. And for those patients, I will generally try to give 66 gray daily. I'm not overly enthusiastic of giving 60 gray just because I think that the data in limited stage small cell, if you're going to give once daily treatment would be either 66 gray or 70. So I want to talk about immunotherapy. Immunotherapy has, I think, changed what we do in extensive stage small cell lung cancer. Our frontline systemic therapy is now a combination of chemotherapy and immunotherapy as seen from these phase three trials, both the Caspian and the Empower 133 trials that were industry sponsored trials. And this again led to a change in the standard of care with atezolizumab and chemotherapy becoming an FDA approved regimen in 2019 and chemotherapy and drivalimab becoming an FDA approved regimen in 2020, both in the setting of extensive stage small cell lung cancer. And we as investigators in small cell lung cancer have been looking for strategies to improve survival for our limited stage patients. And we began designing this trial NRG-LU005 in 2016 with the goal, again, of reducing distant metastasis and trying to cure more patients building on Dr. Fabry-Finn's trial, confirming our dose fractionation, and then looking for some additional systemic therapy. And this is a phase two, three trial that began enrolling patients in 2019. The patient population is shown here. Any patient with limited stage small cell lung cancer that did not have any underlying autoimmune disease. We included PS 0 through 2. They're stratified by the radiation schedule that the investigator put forth. They could either receive twice daily radiation or once daily radiation to a dose of 66 gray, but it had to be predetermined. They could have received chemotherapy with CIS or carboplatin, and they were also stratified by sex. And then they were treated with one cycle of chemotherapy that was pre-registration. And this allowed us to really capture those patients that got diagnosed in the hospital setting, would get a cycle of chemotherapy, and then would get discharged and meet with their oncologist and would still want to participate in a clinical trial. So by making the registration after the first cycle of chemo, it allowed us to really capture those patients. And in this trial, also patients could get their staging PET CT after that first cycle of chemo, knowing that that's what happens a lot of times in the United States in the staging of these patients. And that really helped us capture more patients. And then they were either randomized to the standard of care, again, which was platinum toposide chemotherapy for four cycles with thoracic radiation, or that same chemo radiation treatment with atezolizumab at the start of radiation given every three weeks for a total of one year. In this trial, PCI was recommended for patients that achieved a complete or near complete response, but it wasn't mandated. The trial completed a crawl in June of 2022, 506 patients were enrolled. It actually is still enrolling patients in Japan. The Japanese patients are, Japan is trying to recruit 10% of the trial population so that if the trial is positive, they could potentially get an indication in their country. If you look at the statistics, the trial was initially designed as a phase two, three, which most cooperative group trials in the United States are designed in that fashion, with the phase two endpoint being PFS and the phase three endpoint being overall survival. However, during the trial, we accrued patients very rapidly, and we were looking at having to stop accrual in order to perform this phase two analysis, but we hadn't had the number of events that were necessary, so we were going to have to hold accrual for probably at least a year or more. But we were able to go back to the NCI and essentially revise the statistical design so that it could be a straight phase three trial, which it is now with the primary endpoint of overall survival. We hypothesized that median overall survival will improve from 27 to 38 months with the addition of atezolizumab. I do want to discuss another trial combining immunotherapy with radiation and chemotherapy, and this is the Adriatic trial. This is a trial sponsored by AstraZeneca that has also met accrual. The eligibility criteria is very similar. However, it only allows ECOG PS 0 to 1. Patients received treatment for their limited-stage small cell lung cancer with chemoradiation plus or minus PCI, and after that treatment was completed, they would then go into the study protocol and be registered to one of three arms, either durvalumab plus placebo, durva plus tremie, or straight placebo. They're stratified by stage and whether or not PCI would be given. And this trial, again, has met accrual and I think should read out very soon also. And it's a little bit of a different treatment regimen, being that the immunotherapy is given in the maintenance setting, so sort of more similar to a Pacific regimen from the non-small cell way. And I can just compare and contrast more of these trials. Inclusion criteria-wise, LU005 does include PS 2 and Adriatic does not, so perhaps there could be a slightly more fit patient population. LU005 gives concurrent immunotherapy and the Adriatic trial begins immunotherapy after the CRT is complete and patients do not progress, so anybody that progresses after chemoradiation would not be eligible for Adriatic. For LU005, the protocol therapy is one year. And for the Adriatic study, it's two plus years. The immunotherapy in Adriatic is continued for 24 months. And also, you know, patients did complete the chemo radiation beforehand. So it's a little bit more than two years of total therapy, which is probably, I think, the major difference here for patients. Certainly the drugs are different. We have a dual immunotherapy strategy for one of the arms in Adriatic. And the stratified variables are also slightly different. But again, I think it'll be exciting to see the results of both of these trials. We could potentially have multiple ways to incorporate immunotherapy into the treatment paradigm for limited stage small cell lung cancer. And I think we're all awaiting the results of these trials anxiously. So what about the role of thoracic radiation in extensive stage small cell lung cancer? So the CREST trial was an important trial conducted by Dr. Ben Slotman in Europe. And this introduced thoracic radiation after chemotherapy. It randomized patients to thoracic radiation and PCI or PCI alone. And there was an improvement in two-year overall survival. Now, the primary endpoint of this study was one-year overall survival, at which point there was no significant difference. So this trial, I think, is interpreted differently depending on which side of the fence you sit. In the US, I think many oncologists saw these results and said, well, it's a negative trial. And we didn't really see thoracic radiation incorporated that frequently into the treatment paradigm for extensive stage small cell. I think in Europe, more patients probably received this treatment regimen. And I think just globally speaking for extensive stage small cell, especially pre-immunotherapy, there were so few advances in this disease. So why not use all the tools possible that we can have for these patients? But nonetheless, I would just say that the way it was incorporated into treatment would, I think, be variable depending on where you were in the world when this data was published and when these data became disseminated. But I would say now there's more excitement to incorporate radiation into extensive stage small cell lung cancer because, again, our systemic therapy backbone is now chemoimmunotherapy followed by maintenance immunotherapy, and there could be a potential to leverage the synergy of immunotherapy and radiation. And so there has been a phase one trial of consolidative immunotherapy and thoracic radiation that was published by Jim Welsh and MD Anderson. This trial was a phase one design. Patients were receiving pembrolizumab and then received 45 gray and 15 fractions to their thoracic disease with IMRT technique. There were 33 patients in this study. You can see in the middle, the toxicity looked very favorable. There were no grade three or four toxicities and survival I think looks somewhat favorable shown here. And that trial was really the preliminary data that was needed to justify a larger phase two, three trial in this space. And that trial is NRGLU007. And this trial is now open here in the United States. Patients are eligible if they have extensive stage small cell lung cancer and have had stable disease or a partial response to chemo immunotherapy. They then get randomized to either maintenance immunotherapy alone or radiation to the chest and to their extra thoracic sites plus maintenance atezolizumab. This study did activate during COVID and it has accrued somewhat slowly, I would say, but it is ongoing. And I hope that you would consider opening this and putting patients on this trial because I think it's a really important trial for our field. In this study, PCI is optional, but co-enrollment in SWOG S1827 is allowed, which is a study of MR surveillance. And then I did want to touch on biomarkers in small cell lung cancer. This is the Holy Grail for small cell lung cancer for which right now we have not and are not using any biomarkers to change our therapy, but there has been exciting new data that has been published looking at transcriptional subtypes of small cell lung cancer. And they have been retrospectively analyzed in the EMPOWER-133 trial. And there is a suggestion that the inflamed subtype of small cell lung cancer may drive more of a response to or more of a benefit to immunotherapy and that's, I think, exciting for patients and for researchers in the small cell lung cancer space to potentially have biomarkers to drive therapy. And in NRG LU005, we hope to go back and potentially look at these transcriptional subtypes and part of our correlative science approach. And so I wanted to end with a case. This is a 66-year-old male who presented to the ER with worsening shortness of breath and cough. He had a 10-pack-year history of tobacco use, but quit many years ago. No other significant past medical history. His physical exam did show facial swelling and right upper extremity edema. And he had a CT in the ER that showed a large mediastinal mass with compression of the SVC as well as a right upper lobe mass. He had an EBOS and biopsy with pathology showing small cell carcinoma. He did receive staging with a CT chest, abdomen, and pelvis that were negative for distant metastatic disease, as well as a brain MRI. I was consulted around that point. And after a discussion with my medical oncologist that also treats small cell lung cancer, we agreed that we would hold off on radiation because we really didn't know if this patient was limited or extensive stage, there's the chance that we could deliver curative therapy. And so we decided to treat the SVC with a stent and also one cycle of chemotherapy in the hospital. The patient received that chemotherapy and had significant reduction in symptoms, also received steroids and the SVC symptoms went away. He was then discharged and had a complete staging workup with a PET CT shown here. He was staged as T4N3M0. He was recommended to undergo concurrent chemo radiation and we would start with the second cycle of chemotherapy. We actually have a clinical trial open at our institution that is studying the feasibility of intensity modulated proton therapy in small cell lung cancer. And he opted to enroll in this study. On this study, the dose is kind of, you can range, it has to be daily treatment, 66 to 70 gray is the ideal dose. However, we weren't able to meet constraints with 66 gray. So we had to back down to 60 gray, at which point we were able to meet our lung constraint, which was the primary constraint that was really difficult. Even with proton therapy, you can see here, he has an elevated diaphragm making his lung volume smaller, but he was able to complete radiation and chemotherapy and is pending his restaging with a plan for PCI, assuming he does not develop progressive disease. And I like this case because I think it drives home the point that many times small cell lung cancer patients are so symptomatic at diagnosis, as radiation oncologists, we're meeting them in the hospital. You know, I think it's very easy to say, oh, let's just do palliative treatment, you know, 30 gray and 10 fractions or 20 gray and five fractions. But I would advise that we kind of step back and see if we can make symptoms better. Patients are very responsive to chemotherapy and then complete the staging workup, see if the patient is eligible for a clinical trial and really make sure that we're not depriving any limited stage patient of curative therapy. And I think in conclusion, our small cell lung cancer team is becoming much more of a multidisciplinary team approach. I think our paradigms are evolving. It's not so much now that a radiation oncologist is making a treatment decision in isolation. I think it's much more of a multidiscipline and a tumor board approach to really every patient with limited stage small cell lung cancer. I think the decision-making is certainly getting more nuanced, particularly around the radiation fractionation and the timing of when to initiate treatment. And we look forward to the data that will come out soon in terms of the role of immunotherapy in limited stage disease. And I think as a field, we just need to keep pushing forward for better treatment options for our patients. And that is all. And I'll be happy to answer questions, but I will hand it off to my colleague, Dr. Levy now. Thanks very much, Kerstin, for an excellent talk. So Antonin is now going to share his slides. So Antonin is an associate professor at the Institut Gustave Brossy in Paris, and he's going to talk to us about prophylactic cranial irradiation and brain stereotactic radiosurgery. Please continue sending your questions in the Q&A. Kerstin may try to answer some of them whilst Antonin is talking. To you, Antonin. Thanks, Corinne. So this is the outline of my talk. I will review the current knowledge on PCI in limited stage. So stage one, two, three. Extensive stage, so metastatic patients without brain meds. What is the current data on hippocampal avoidance and the possible influence of immune checkpoint blockers. Then we look on patients with brain meds, the role of stereotactic radiosurgery, and then some concluding remarks. So first, what about PCI? As you know, brain meds is frequent during the natural history of small cell lung cancer. 15% diagnosis and more than half patients will develop brain meds that have been described are diffuse and multiple. So to reduce this incidence, PCI has been developed. So I will talk to you about a case vignette. So it's a 61-year-old female smoker with a chronic cough, no other specific symptoms, and a CT scan. Then a PET-CT showed a thoracic and mediastinal lesion. The first brain MRI showed no lesion. The biopsy by IBUS showed a small cell lung cancer, classified CT for N2M0. This patient is receiving the standard of care in thoracic chemotherapy, and the restaging showed partial response on the thoracic part with no lesion at the brain MRI. So the question there is what would you do? MRI surveillance, immunotherapy consolidation, brain stereotactic surgery, PCI, or inclusion in a clinical trial. And I will show you what I would propose after some literature evidence. So what do we know? So you all know the large individual patient meta-analysis from Gustave Roussi, including thousands of patients that were randomized in seven trials to PCI or no PCI. In this meta-analysis, it was shown that PCI can lead to 50% brain mass incidence reduction and increase in 5% survival. So this meta-analysis has now 20 years and patient at this time did not receive brain imaging and PCI dose varied quite substantially. So it's not a bit criticized. From the secondary analysis of the convert trial on PCI patient, 80% of patient at PCI, but only 20% at brain MRI. And what was showed is the thoracic tumor volume is associated with the occurrence of brain meds. So this confirmed that PCI generally should be delivered to larger stage patient and that stage one patient are not good candidate. From the guideline, you can see here a summary of ASTRO and ISMO guideline. PCI remained the standard of care in stage two and three small cell lung cancer following response to concurrent chemo radiotherapy, thoracic chemo radiotherapy, and no other progression. But in the extensive stage disease, there are more debate. You know, the ERTC trial that was published in the New England Journal of Medicine 15 years ago. At this time, extensive stage patient receive PCI or no PCI after chemotherapy, no immunotherapy in such trial. And this trial showed again, brain meds incidence prediction, but also survival benefit. It should be emphasized that at this time, brain imaging was not done at baseline. It was done only in case of symptoms. So the more recent Japanese trial assessed the role of PCI in patients receiving baseline brain MRI and then MR surveillance. At the opposite of the ERTC trial, this Japanese trial showed no survival benefit in such patient. However, there was again, a 50% brain meds incidence prediction. These two trials are really different, much more selected patients in the Japanese trial. Access to MRI is much more easy in Japan and all patients receive four to six line of chemo and brain irradiation in the Japanese trial. However, since this trial, there are more and more debate on the role of PCI. And it is even more important because you all know that there are some possible toxicity with brain irradiation. And it wasn't showed in many trial that PCI can decrease short-term quality of life in a decline in memory. There are very nice data from Cecile Le Pechot on this topic. So hippocampal avoidance IMRT was developed to decrease this neurocognitive toxic effects. What do we know? We have now two published randomized trial, one from the NKI in Dutchland and one from Spain. Two, these two randomized trial include many limited stage patients and did not use the same neurocognitive tests. Interestingly, there was opposite result from the two trial. So the Dutch trial was negative, no difference with the addition of hippocampal avoidance technique, but the Spanish trial showed that were less neurocognitive decline with the use of hippocampal avoidance. So we need more data and more mature data from this trial, longer term data. And there are also other ongoing trial in this setting. So did the immunotherapy change the game? So you have here a table of main trial with limited stage SCLC patient receiving immunotherapy. So as it was shown by Christine, there are many ongoing trial and especially the NRG LU005, Adriatic, Keling and others. From the stimuli trial, that was the first published trial, consolidation, nivolumab, ipilimumab after concurrent thoracic chemo radiotherapy, there was no PFS difference with the addition of immunotherapy and all patients receive PCI. From the smaller single arm phase 1, 1, 2 trial, there was fewer brain mets relapse in patients receiving PCI and also possible increased survival, even if there are possible selection bias because it was not done to ask this question and brain imaging was not standardized. Now in the extensive stage, you know the EM Power 133 and Caspian trial evaluating the addition of immunotherapy to chemotherapy. In such trial, a very limited number of patients receive PCI, 10% per group. And in the Caspian trial, PCI was not permitted in the immunotherapy group. We have secondary analysis of intracranial relapse in these two trial. And what was showed is that patients receiving immunotherapy had delayed time to intracranial progression, suggesting that immunotherapy can act in preventing brain mets. However, in these two trial, brain MRI was performed only if clinically indicated and not mandating at screening and during treatment. So we need more data and evidence is still limited. So to come back to our clinical case, my proposition would be to include such patient in the hippocampal avoidance PCI trial versus no PCI trial in patient that will have baseline and brain MR surveillance. The other option would be PCI or MR surveillance as a third option. So you know that there are large group trial evaluating this question. In Europe, there is the ERTC 19-01 trial, primal lung, evaluating in limited stage and extensive stage, PCI or no PCI, all patients will have baseline brain MRI after standard of care and follow up with MRI. Hippocampal sparing is allowed, and there will be stratification with immunotherapy. There is a parallel sister trial in the US, the SWOG 18-27, the MAVRIC trial that will assess the same question. So what do we know about patients with brain mets? What is the role of stereotactic radiosurgery and possible immunotherapy influence? So if we come back to our case, the patient was included in the ERTC 19-01 trial and received brain MRI surveillance and no PCI. Six months afterwards, she developed one brain lesion. There was no active extracellular disease and no symptoms of asthenia or so on. So what would be the management in such case? Brain surgery, brain stereotactic radiosurgery or one brain radiotherapy. So I'm sure you would discuss brain stereotactic radiosurgery in this case, and that's what we've done. So what is the data about that? So first we need, and there are some prognostic tools that should be used. And according to the lung GPA, this patient has good survival, median survival of 23 months because ECOG PSC is good, younger age, only one brain mets and no active extracellular disease. So this tool should be used for discussion. So the current data is mainly retrospective. There is this recent literature-based meta-analysis on a retrospective report, more than 1000 patients. And in this analysis, the median oral survival after radiosurgery was nine months and longer than much patient that received one brain radiotherapy. However, it should be interpreted with caution given heterogeneity between reports and possible selection bias in patients receiving one brain radiotherapy, more symptoms or more tumor volume in the brain. The first prospective cohort that are coming, very nice work from Chad Ristovan in the FHIR SCLC cohort, 710 patients, including 100 patients from the prospective Japanese cohort about brain radiosurgery. In this analysis, median overall survival and time to intracranial progression were eight months. And as compared with matched world brain radiotherapy patients, SRS led to higher overall survival, but lower intracranial control. And again, it should be interpreted with caution given possible selection bias. There's also the recent CROSSFIRE study just published in the GNCI, almost 900 patients, median overall survival 10.5 months. And it was this time compared to non-small cell lung cancer patients. And in this analysis, small cell lung cancer patients had similar time to cranial progression, similar neurological mortality, and similar number of lesions at CNS progression. So this suggests that SRS can be used in such patients and that this diffuse and multiple progression is not always the case. There are ongoing randomized trials in this setting, and especially the NRG CC009 phase three trial of stereotactic radiosurgery versus world brain radiotherapy for patients with less than 10 brain mets. It's a larger and unique trial assessing this question in extensive stage small cell lung cancer. So can we expect brain response in patients with brain mets? So unfortunately, generally, small cell lung cancer patients with brain mets are not included in a trial. And in a recent report from various histology with a tumor with brain metastasis, published in the nature of medicine a few months ago, only two patients had small cell lung cancer. Also, one burning question is brain mets biomarker in non-small cell lung cancer patients. It was shown that 50% of analyzed brain mets differed from primary in terms of oncogen driver or histological type. Also, it was shown that there were no brain response to immunotherapy if PD-L1 was less than 1%. So can we expect future perspective from liquid biopsy? A caveat is that if you have isolated CNS progression, CTDNA is generally negative. So we'll need data on that topic. And there are work and perspective in MR virtual biopsy by imaging features. So to finish with some perspective and conclusion. So liquid biopsy is fastly developing in various tumor type and in extensive stage small cell lung cancer. It was shown recently in the clinical cancer research journal that cell-free tumor load could be of high interest and may be used to select and propose various treatment to patients. And possibly it could be used in patients who could benefit or not from PCI given that patients without circulating disease could be at less risk of developing further brain metastasis. Another perspective is the development of newer drugs and association. So now it's mainly in the extensive stage. So there are the TIGIT. There are the PARP inhibitor. There are also some fucozygm-1 monoclonal antibody. And you saw also that there are strategy with more ablative radiotherapy in patients with a limited number of lesion. So all this will ideally lead to clinical benefit in patients. So what are my main messages is that in patients without brain metastasis, PCI at a dose of 25 gray in 10 fraction is still standard of care after any response to concurrent thoracic chemoradiotherapy. In extensive stage, there is a debate with possible surveillance with MRI, but PCI can still be considered. Hippocampal avoidance is an option. We are awaiting more data from further trials. There are ongoing trial assessing the role of PCI versus MRI surveillance only in the era of immunotherapy. And we should include patients in such large academic trial. In patients with brain metastasis, stereotactic radiosurgery can be discussed. There are also ongoing randomized trials that will show or not a benefit of such strategy. And finally, there are nice perspective on liquid biopsy, newer drug, local radical treatment and association. So with this, I thank you for your attention. That's great. Thanks very much, Antoine, for an excellent talk. So we have a lot of questions in the Q&A. Thanks for your questions. So Christine and I have already answered some of them. So please have a look at the answered section. But some questions we are going to answer live. So the first one in the limited stage setting. So someone has asked about the Canadian regimen, so-called Murray fractionation of 40 grain 15 fractions. So it is indeed used in Canada, but also in parts of the UK. I understand. So is this something that we should consider? What's your view on that, Christine? Yeah, so I mean, I think that there is certainly retrospective and phase two data supporting this approach. And it looks, I think, fairly good. And it was also a great potential regimen to look at during COVID when we were trying to reduce the number of times that patients needed to come back and that sort of thing. It's not something that I tend to use in my patient population because I think, again, the phase three data supports twice daily approaches. So I'm generally giving 45 gray twice daily. I'm not giving 60 gray right now because there's no phase three data. So I really, in my practice, like to use what's been tried and true with validated phase three data. So, well, I think it's an option. It's not something that I routinely use here in my practice. Yes, same in Manchester. Just wanted to add that at the time when we were designing the convert trial, there was a big discussion about having a free arm trial with the Canadian regimen. But when we worked out the calculations in terms of number of patients, it was just not going to be achievable. But it's a shame because I think that would have been a really nice question to ask. So we don't really know the answer, but I think it's used, but in a limited fashion. So, Christine, again, in the trial that you've been running with the addition of immunotherapy to chemotherapy, have you seen any, have you had any issues with pneumonitis? Yeah, so I think with the concurrent immunotherapy approach, we do actually have published data for the non-small cell lung cancer setting, which does show slightly heightened rates of pneumonitis around 8%. So I think we would expect that we would be getting, I think, slightly higher pneumonitis rates. But what we've seen is that it's been manageable. I can't give exact toxicity rates right now as the study is still ongoing. But I think if I had to hazard a guess, I think it'll look similar to the toxicity that we see in Keynote 799, for example, which is Pembrolizumab given concurrently for chemoradiation for non-small cell lung cancer. I think we'll probably see something similar. Mm-hmm. Thank you. And then before we turn to Antonin, what are your thoughts about the use of stereotactic radiotherapy in the oligometastatic small cell setting? So I think it's an interesting question. I think in times past, having a limited disease burden was not something that we saw often because most of our extensive stage patients had more widely metastatic disease. But I think we are seeing now it's widespread PET-CT for staging and some patients getting diagnosed from lung cancer screening, for example, and things like that. We do see patients that have limited metastatic disease. Right now in my practice in the United States, we're trying to put all these patients on LU007 to, again, really understand the role of thoracic radiation. I'd be interested to see any data looking at SBRT in the oligometastatic setting for small cell. I just haven't seen much. But I think it would be a good research question. We should pull our data and see if there is any conclusions that we could draw with that approach. It's not something that I do very much in my practice right now, but there could be other centers that are using it. I actually don't know what the practice patterns are. I'm curious what they are in England and in France, if you guys are using. Yeah, so we certainly are not routinely in the oligometastatic setting for small cell lung cancer. But Antoine, how about you? Yeah, I fully agree. We have a few cases of patients that have oligoprogression or oligorecurrence. And sometimes it's before, let's say, the polymetastatic occurrence. And we discuss at the multidisciplinary tumor board such case. And sometimes we try to deliver some more radical treatment, but it's really rare. Yeah, and so you're exactly right. That's where I'm using it the most is for patients that are on maintenance atezo or drivalumab and then progress in one area. And I'm using it like an adrenal gland and I'll do adrenal asperity. Those are the situations where I'm finding that I'm using it the most is for that oligoprogression. And then patients can stay on their maintenance immunotherapy for longer because we know once you go to second line therapies in small cell, their response rates aren't great. Second line treatments aren't, they're not that great. So if we can use asperity as a tool for oligoprogression, I think that there could be some potential there. And I'd love to see some data with that approach. Yeah, absolutely. So the answer is please enter patients in clinical trials if you have the trials open in your center. So now turning to Antonin regarding brain metastasis and prevention of brain metastasis. So is age a factor that has a big influence when you decide to give PCI? Well, so we all know that generally older patients have more neurotoxic effect of PCI. So we don't know the exact threshold of age. So it's debated according to centers. But what is generally discussed and showed in the guidelines is the 70 years old age. So this should be included in the discussion. However, as Corinne said, I would encourage to include patients in trials and in the SWOG and in the ERTC trial, there is no specific limitation on that. Yes, absolutely. And we need to learn more on that because of course the European trial run by Ben Slotman at an age cutoff of 75. But, you know, it's really important that we include patients of all ages in our trials and learn from that. Similarly, you know, patients having I.O. or not having I.O. So there's a lot to learn. The question about mementin, but I'm not sure that you're using it Antonin and Gustave also. Perhaps Christine can answer that one. What type of toxicity do you see and how often do you see it? With mementin? Yeah. So it's actually for most patients it's very well tolerated and I give it to all of my patients that I give whole brain radiation to and I am also giving it to patients that receive PCI just so I can sort of maximally reduce any sort of neurocognitive sequelae. I have had some patients that have developed some dizziness and discontinued it and I've had some other patients that have just developed generalized malaise that they attribute to the mementin and then they just say they take themselves off of it and they don't want it anymore. But I would say that's rare. Most patients tolerate it, I think, very well. Yeah, thanks. Antonin, what relapse interval would you consider minimum before offering SRS in patients who had a prior diagnostic of limited stage disease and then relapse with brain metastasis? We don't really know about that, but we can see the tumour velocity during, there is some score in one year, the number of neural lesions in one year. I think that the first brain match should be considered anyway and then we repeat MRI and we discuss afterwards, but we can offer a chance. So in my end, I wouldn't exclude stereotactic radiotherapy based on the first occurrence. On the interval, yeah. And then would you give PCI with thoracic radiotherapy at the same time concurrently? Yeah, generally it's what we do when we deliver sequential thoracic radiotherapy. So we can also deliver PCI at the same time. With concurrent chemo radiotherapy, we don't generally do that. Yes, and it's very important never to give chemo at the same time as PCI. It's definitely a contraindication. Okay, we may have time for one more question. So Christine, do you expect your study LU05 to read out first or will it be adriatic? You know, that's a good question. Both studies are event-driven in terms of, you know, when the readout would take place. So I certainly will say the adriatic met accrual first. So we would probably expect to see the adriatic results first, potentially. But, you know, When you present your results, do you know that already? Um, so I think I hope sometime in the next two years. Okay, thank you. Right. So I think we're coming to the end of this webinar. A big thank you for joining us today. I hope you enjoyed it. So with that, I'd like to thank the two fabulous speakers and all of you for attending and for your questions. And we hope to see you in other ISLC webinars in the future. Thank you.

small cell lung cancer

treatment strategies

limited stage

extensive stage

radiotherapy

systemic therapy

platinum-etoposide chemotherapy

thoracic radiation

prophylactic cranial irradiation