Okay, so you're going to hear my biased opinions as a person who does a little bit of transplant and a little bit of IP, because obviously this is kind of my role in our program is to deal with these complex decisions about how to approach nodules in patients who are being considered for transplant or in patients after their thoracic transplant. So I'm going to talk about the approach to nodules in potential transplant candidates, the incidence of lung cancer in transplant, the outcomes in our transplant patients, how we approach medical management, and then I'm also going to talk about lung transplantation for lung cancer. And I think it's important that when we talk about this, we talk about how many transplants we do, because obviously we are talking about a small population. And so when we look at data, these data is often coming from small series and small studies. So these are not coming from series of thousands and thousands of patients when we're talking about the number of transplants we do per year being in the four thousands, we just don't have that many patients with lung cancer to base this data upon. And when we think about the risk for these issues, we really have to look at the primary diseases that we're transplanting patients for. And this is a little bit older data, so this number has actually changed. That 16% for CF, we aren't transplanting young cystic fibrosis patients as much anymore. We're transplanting a lot of COPD, emphysema, a lot of IPF, patients who have risk factors for lung cancer because of their smoking history and their occupation. And why do we care about this? So obviously when I transplant a patient, I want to get them the longest survival possible. So I'm trying to mitigate risk for chronic rejection. I'm trying to mitigate risk for infection. But if we look at the solid blue line there, what we're looking at is that blue plus green is that risk of malignancy. And so we're talking about solid organ, so solid tumors and hematologic malignancies. I'm gonna sort of use this within a framework of three cases. And I want you to think about how you would approach these individual cases. The first case is a 70 year old gentleman. He has a history of IPF, started on supplemental oxygen in March of 2020. He's currently using four liters of oxygen at rest and five to six liters with exertion, completed pulmonary rehab this year. He's got a history of pulmonary nodules. He used to live in the Midwest and he actually had a right posterior thoracotomy in 2005. He smoked for 30 years, two to three packs per day and was a former railroad employee during his military service. He was in the military police. And then this is his CT of his chest. And so in his left lung, we can see that we have this new opacity. It's about 1.3 centimeters in size and the left lower lobe, and then some plural nodularity as well at the superior segment of the left lower lobe. So how would we approach this gentleman and his risk for lung cancer as he's being considered for candidacy for lung transplant? And then the second case is a 69 year old male. He has a history of COPD. He's on seven liters at rest, 10 with exertion and 15 in pulmonary rehab. He quit smoking years ago, but he did have a 70 pack year history of smoking. And he's had surveillance CTs over time. He's had bilateral nodules, but now he's got some new nodules, including that one more large nodule in the right upper lobe. And then the last case is a 50 year old male. He has a history of pulmonary hypertension. He is on sildenafil, macetantin, remodulin and three diuretics. He has a remote history of methamphetamine use. He also has a smoking history with a 20 pack year history. And he underwent transplant evaluation and was considered for a bilateral lung transplant considering his history of pulmonary hypertension. His CT of his chest during his transplant was pretty consistent with what you would see from pulmonary arterial hypertension. He had a few non-suspicious three millimeter pulmonary nodules. He goes to transplant though, and his explant pathology has incidental multifocal microscopic adenocarcinoma in situ. So when we talk about the clinical presentation in lung transplant, the reason I go through these cases because we see a lot of different presentations. It could be lung cancer in the native lung after transplant. It could be incidental detection of lung cancer in the explanted diseased lung. You could get lung cancer development in the allograft. So donor transmitted or de novo malignancy, or you can get recurrence in a patient who was transplanted for the primary indication of lung cancer. And our patients are at increased risk. So their incidence, if we think about the incidence of lung cancer in these patients, cancer represents the second most common cause of death in lung transplant recipients. This is three to four fold increase in all immunosuppressed organ allograft recipients. And the lung cancer data, like I said, is limited because it's case series. It's a small patient population. But if you look at one recent study, they compared rates to Nelson. And the overall incidence of lung cancer was 10.4 cases per 1,000 patient years compared to the 5.58 in Nelson. And if we break that down to just COPD, the rate is still higher, 21.1 per 1,000 patient years compared to 16.7. And then this is another study that looked at patients with cancer and then broke it down into native lung cancer and then donor lung cancer. And so you can see these are small numbers, but we are seeing a prevalence of lung cancer in these 19 studies of 184 cases out of about 7,000 patients. And the incidence is going to be impacted by the transplant type. So our single lung transplant recipients have a higher risk of lung cancer than our double lung transplant recipients. This study looked at 131 consecutive single lung transplants and compared it with 131 successive double lung transplants matched by native disease. And they saw that nine single lung transplant recipients developed primary lung cancer in their native lung. And there was no lung cancer in the matched double lung transplant cohort. And this is largely driven by the cancer risk of the disease and the native lung that's left behind. So in IPF, we have telomere instability, and in COPD, we're dealing with inflammation and maladaptive responses. And the challenge is that screening wasn't developed within a framework of lung transplant. It wasn't developed in a framework of immunosuppression. So if we look at the current criteria, we either are screening patients age 50 to 80 with a 20-pack year history of smoking, currently smoking or quit in the last 15 years. We might capture more with the broader screening criteria by going to 40 years or older with a 10-pack year history, current or former smokers. But I don't always know my patient's donor history as I move forward through the transplant process. I know that history at the time of transplant, but it's not carried forward. And I'll talk about this later on, but we are taking more and more donors with a significant smoking history. If we apply this just to the recipient criteria, looking at one retrospective study, less than 50% meets criteria, older study, higher age. So not the 50, the 55. And then 67% met when you drop that age to 40 and then 10-pack year history of smoking. And so given the fact that we don't have clear screening guidelines for lung transplant, we're oftentimes diagnosing cases at an advanced stage. And I think transplant centers across the US are accepting more extended criteria donor. So this means we're taking donors who are over 55, and we're also taking donors with a smoking history of more than 20-pack years. Both things that we know are going to increase their risk of lung cancer. And both things we know potentially actually impact our recipient survival. So this is the trend and extended criteria donors across the United States, all the way back to 2005 through 2018. You can see a steady rise in all centers and especially in high volume centers. And so taking these higher risk donors does potentially impact our recipients, but it also does increase that donor pool. And then all patients are obviously in this tight rope of balancing immunosuppression to prevent rejection, to protect them from infection and protect them from cancer. And so ideally, when we're talking about patients with cancer, we're trying to reduce that immunosuppression to a level that lets them have an immune response, but protects them from rejection. So oftentimes we're decreasing our anti-metabolite or our calcineurin inhibitor doses. And then we might potentially be adding on an mTOR for anti-neoplastic properties, recognizing that that does typically work better in skin cancers, but doesn't harm in these cases. And then the treatment's determined by stage. So obviously with all patients, early stage is better. And especially when we're talking about these single lung transplant recipients, their pulmonary reserve is often going to preclude surgery if we find it early. And then the immune checkpoint inhibitors are tricky because they enhance the anti-tumor immune effect, but there's also cases of increased alloreactivity and then accelerated graft loss in patients who receive these meds. So again, it's a balancing act, reducing immunosuppression for infection, malignancy, and drug tolerance, and then protecting patients from active rejection. And not surprisingly, when we talk about survival, you will see that red line that has a pretty precipitous drop. Lung transplant patients with lung cancer typically do not do well. So they do not have the same survival as that lung transplant cohort without cancer. And if we look at the survival of these patients, early stage here is defined as stage one and stage two. So these are patients who had explanted lungs with incidentally identified non-small cell lung cancers. And so the overall survival at one year was 60%. At five years, it was 23%. And in our patients, even if you had an early stage lung cancer at five years, one in three were alive. And then we're gonna talk a little bit about transplant after malignancy and transplant with malignancy. And so this is complicated. We're thinking about organ failure factors. We're thinking about patient factors and their quality of life. We're thinking about our need for immunosuppression. And then we're thinking about their cancer and their cancer risk. And so we do have some guidelines that help us with this, which is beneficial. So if a patient has a prior history of non-small cell lung cancer, there are some publications that suggest that waiting period. So if it's an early stage, it's a stage one, we ideally are gonna wait at least three years. But I think that you're gonna see that most centers are waiting five years for our patients with stage two and then stage one C lung cancers. But there are transplants done for early stage lung cancers. So these were patients who had cancer that was diagnosed at the time of their transplant between 1987 and 2010. So these were patients who had what was called then BAC. And it was 29 patients out of 21,000. The BAC patients that were transplanted in this cohort had a better FEV1 and less time on the waiting list. The explant pathology, 52% were pure BAC, 41% had some degree of tumor invasion, and 7% had pure adenocarcinoma. You look at the mortality, the 30 day and the five year was similar. It was not statistically significant difference between those two cohorts. However, we have to pay attention to the cancer types that they were transplanting and the stage of cancer and those patients. There are centers that are now transplanting for advanced malignancy. Two cases to date. The first one was done September 25th of 2021. So a 54 year old patient who was transplanted with stage four lung cancer. And then about one year later, they also transplanted a 64 year old female who was also transplanted with stage four lung cancer. These patients are now part of a DREAM study. So it's an ongoing study looking at transplant for advanced malignancy. And then in the interest of time, I'm gonna go through the follow-up on those cases pretty quickly. That first case actually had positive serologies for COX-E. So made our job easy. We started on fluconazole and then followed on CT. Had migrating nodules on CT, but had improvement over time as we did surveillance imaging on high dose fluke. They went to a left single lung transplant. You'll remember that nodule was in the left lower lobe and they had features that were characteristic of UIP and then had necrotizing granulomas and the left lower lobe consistent with COX-E. And they are currently on posaconazole with a plan to keep them on for lifelong therapy. The second case is that gentleman with severe COPD who has these migrating nodules. One in the right upper lobe looking a little bit more concerning. We did serology. It was pan-negative. Sputum culture was negative. We did proteomic risk stratification, which actually showed that they were reduced risk. We did a three-month CT, which showed scattered new nodules and variable changes in size of the prior. And so that individual is now listed for a bilateral lung transplant. And oftentimes these patients are high risk for bronc. So these might be patients that you're trying to avoid taking for biopsy. And so I will use these proteomic risk stratifiers in these patients to see if I can confidently reduce their risk. And so what these tests do is they're going to give you a blood-based autoantibody assay, and they're gonna tell you, am I high risk? And if you are not, then it's gonna be integrated into the secondary classifier that potentially reduces your risk. And so in our patient, you can see, we reduced our risk down to 1%. And then the last case is that patient with pulmonary hypertension who had incidental findings on his explant. He had Q3-month CTs for his first year, had no evidence of recurrence. He has a donor-derived calcified granuloma that's been stable on serial imaging. We've kept him on our usual three-drug regimen. We did discuss transitioning him to an mTOR, but he's done really well, so we've left things as they are. And that is it. Okay. That's the summary. So I'll be reviewing diagnostic and therapeutic dilemmas with specifically with interstitial lung disease and lung cancer. My name is Tejas Sinha. I'm the Interventional Pulmonary Fellow at Ohio State. No disclosures. So the objectives, briefly I'd like to review the risk of complications with biopsy of peripheral pulmonary lesions in patients with lung cancer and IPF and ILD, and then to describe the risks of chemotherapy, targeted therapy, immunotherapy, and surgery in patients with lung cancer and IPF or ILD. So a brief bit of background. We do know that there's an increased incidence of lung cancer across all subtypes of ILD. Specific subtypes of no would be connective tissue ILD. We know that patients that have systemic sclerosis, rheumatoid arthritis, polymyositis, and dermatomyositis all actually have an increased risk of developing malignancy. One study looking at CTILD versus ILD patients actually found an increased risk of malignancy in patients under the age of 60. However, most of the seminal work in this field has been done with patients with idiopathic pulmonary fibrosis. One meta-analysis of 35 studies found a 13% incidence of lung cancer in IPF patients. Fairly staggering. The most common subtypes would be squamous cell carcinoma, adeno, and then small cell. And as far as specific risk factors, we know that lung cancer is nine times more common in men and in smokers who have IPF. Most commonly, it presents in lower lobe and peripheral regions adjacent to those zones of fibrosis. This has been described as the scar carcinoma, first described actually in 1939. Since then, there's been a lot of basic science research done to validate this model. And I'm not a molecular biologist, but essentially we know that lung cancer and fibrosis share a lot of the same pro-inflammatory mediators. Those inflammatory mediators can cause impaired wound healing in response to injury to the alveolar epithelium. And then that perpetuates a cycle where myofibroblasts deposit excess extracellular matrix and then create a stroma that provides a substrate for these abnormal cells to proliferate and thrive and then cause subsequent tissue damage. We do know that genetics and environmental factors may also play a role in this as well. Why is this important? Similar to what Dr. Fry presented, lung cancer has a profound impact on survival in IPF. This retrospective study done in 2015 by Tomasetti et al, published in CHESS at a single center in Italy, looked at IPF patients with lung cancer and IPF patients alone. They also found a 13% prevalence of malignancy, also found that malignancy was more common in smokers and those with emphysema. And patients with lung cancer in IPF had a much shorter median survival and the hazard ratio was 5.0. So as far as diagnostic dilemmas, really the fundamental diagnostic dilemma is the risk of complication with pursuing a biopsy. Stuff like proteomics and risk stratification really is gonna help with that coming forward in the future, but the most feared complication is that of an acute exacerbation following biopsy, as this can be fatal. Some studies have quoted mortality as high as 50 to 80% with acute exacerbation and a median survival of three to four months. Research can be a little bit problematic in this field due to variable definitions of acute exacerbations, both for IPF and ILD alone, as well as variable definitions for IPF and ILD over the past few decades. However, exacerbations can happen with even seemingly benign procedures. BALs have actually shown a 2% risk of developing, patients with ILD who undergo BAL have shown a 2% risk of developing acute exacerbation. Cryobiopsy done for the diagnosis of ILD, there's three studies which showed about a 2% risk of developing acute exacerbation. Interestingly, acute exacerbations have been reported also in non-pulmonary procedures on patients undergoing CABG, total knee replacement, in one case, a patient undergoing total hip replacement that wasn't even intubated and had spinal anesthesia, they had acute exacerbation. This just shows the kind of the classic histology of an acute exacerbation. Panel A shows the temporal and spatial heterogeneity of fibrosis seen in UIP with the fibroblastic foci shown with a clear arrow. Panel B shows the transition. So the area underneath the dotted line is background fibrosis and the area above the dotted line shows the acute exacerbation evolving. Panel C shows a pattern of diffuse alveolar damage with highland membranes forming and the exudated phase acute lung injury and panel D shows the fibro-polaroporative phase of acute lung injury. So as far as biopsies themselves for peripheral pulmonary lesions, a quick transthoracic needle aspirations are still done quite frequently for peripheral pulmonary lesions despite the proliferation of navigational and guided bronchoscopy. One study looking at the risk of complications and diagnostic yield in ILD patients with suspected lung cancer reported a fairly decent diagnostic actually about 89%. They actually had 34% of their cases were non-diagnostic. Risk factors for a non-diagnostic biopsy were lesion size, less than three centimeters and a high risk of heart failure. Less than three centimeters and a needle tip outside the target. However, what's really most interesting about the study is the complication rate. In a study of 91 patients, they reported a complication rate of 51%. They divide their complications into major and minor complications. Minor complications included pneumothorax without needing a chest tube and transient hemoptysis, which is fairly high. The major complication rates included acute exacerbation of IPF and the pneumothorax requiring a chest tube. You can see the pneumothorax requiring a chest tube was 9%. Acute exacerbation occurred 2% of the time. This is in contrast to the prior studies we know about transthoracic needle aspiration. In patients without ILD, where the incidence of requiring a chest tube is probably about four to 6%. So nearly double the complication rate in patients that have ILD that require a biopsy. The predominant risk factor for complication is the presence of honeycombing along the path of the needle with an odd duration of 11.2. So navigational bronchoscopy for lung cancer and interstitial lung disease. Obviously a hot topic and a growing field. Unfortunately, we don't really have published data on diagnostic yield or complications for patients with lung cancer and interstitial lung disease. Can presume that's probably likely the same as the complication rate for other forms of peripheral bronchoscopy. A quick note, PET can be really useful for pre-procedural planning in these cases and really with helping to delineate areas between areas from fibrosis and malignancy. So when you're doing your case planning, you know really where you can hone in on your target here. One study showed a sensitivity of PET of 98%. So since we don't really have data on navigational bronchoscopy, you can look at data that we do have about radial EBUS and the biopsy of peripheral pulmonary lesions for interstitial lung disease. This study by Lee et al looked at the safety of radial EBUS transbronchial lung biopsy in patients with IPF. They divide patients into those that had UIP, probable UIP, and non-interstitial lung disease. They showed a diagnostic yield that was much lower in the UIP group than the non-ILD group, 62% versus 76%. That was statistically significant. A quick note that the diagnostic yield is actually relatively high overall for all these studies. You know, other studies for radial EBUS have shown a diagnostic yield closer to 50 percent. So it may be taking a little bit of grain salt, but at least you can see a strong comparison between the groups. Odds of having a successful procedure were determined by the mean diameter of the lesion, positive bronchus sign, and having a good signal on the radial E-bus. And the UIP pattern was actually independently associated with having a non-diagnostic procedure. This study actually didn't report a very high complication rate. It was only between zero and three percent, and none of the groups had a statistically significant difference in complications. Another paper published just a year ago about radial E-bus interstitial lung disease looked at radial E-bus with guide sheath, transbronchial lung biopsy in patients with and without interstitial lung disease. Again, showed a lower diagnostic yield for patients with interstitial lung disease as compared to those without. As far as factors that impacted yield, the presence of ILD decreased yield, not surprisingly, and then being in the lesion, having a solid lesion, stuff that normally increases yield also was associated with having more likely to get a diagnosis. This study did show a difference in complication rate between patients that had ILD and those that didn't have ILD. There's a six percent complication rate for ILD patients as opposed to four percent overall complication rate, and that difference was driven really by pneumothorax as being the primary mitigator. So there's a four percent incidence of pneumothorax in the ILD group versus 0.6 in the non-ILD group. So some therapeutic dilemmas. Chemotherapy. So chemotherapy has been known to induce pulmonary toxicity. Diagnosis requires a history of exposure and exclusion of other etiologies. Clinical presentation can vary anywhere from bronchospasm to having more severe reactions like ARDS, alveolar hemorrhage. The primary chemotherapy agent that really everyone should know about are the taxanes. The platinum therapy really doesn't cause a lot of pulmonary toxicity, and the reason for the taxanes causing toxicity is their source. They're derived from the Yew tree, which is organic, and that can cause a hypersensitivity pneumonitis reaction, which can be fairly severe and clinically devastating for some patients. Treatment. Drug discontinuation, steroids, sometimes diuretic therapy. Another phenomenon that we'll discuss a little bit more with immunotherapy is the incidence of recall radiation pneumonitis. So essentially patients develop inflammatory reactions, pneumonitis in areas where they previously received radiation. This can happen with immunotherapy, but also with chemotherapy. The other most common chemotherapy associated with pulmonary toxicity is gemcitabine, classically a second-line agent for cancer. However, it can cause a lot of toxicity and pneumonitis, and that toxicity is actually increased when combined with taxanes. Targeted therapy. Less is known about targeted therapy and interstitial lung disease and pneumonitis. We do know that EGFR inhibitors and specifically can cause pneumonitis, and that incidence is increased specifically in Japanese and Asian patients. One study that was a multicenter retrospective study looking at osimertinib and the incidence of pneumonitis actually reported an 18% incidence of pneumonitis per patients. Another prospective study in Japan that was done in 2008 compared the incidence of pneumonitis in gefetinib, a TKI versus chemotherapy, and noted that gefetinib actually also had an increased risk of pneumonitis. What's where the data is missing really is what is the risk of pneumonitis in patients that already have ILD. We do know that the patients in the gefetinib study, if they had pre-existing ILD, they were more likely to develop pneumonitis, but there's more work to be done there. The incidence of pneumonitis is lower in ALK inhibitors. One meta-analysis found an incidence of only about 2%. Immunotherapy and ILD. So risk factors are combination immunotherapy with PD-L1 and CTLA-4 inhibition, prior radiation to the chest, interstitial lung disease, COPD, asthma. Again, immunotherapy can cause radiation recall pneumonitis. It's really a poorly understood inflammatory reaction within previously radiated fields. This can actually be a potential mimic of disease progression or pneumonia. So it can be tough to delineate what's actually happening. It can happen weeks to years after radiation. But the real question is, should we really be treating patients that have severe interstitial lung disease with immunotherapy, given that they can have pneumonitis, which can be a life-threatening and fatal complication? I tried to do some extensive searching for this, and there's no real clear guidelines about whether or not we should. One of the parameters that we should be looking at as far as pulmonary function tests in just making this decision, it really probably requires multidisciplinary evaluation and monitoring and close monitoring of pulmonary function tests, specifically with a focus on the DLCO. Another issue that can happen with immunotherapy in interstitial lung disease patients is sarcoid-like reactions. So this can often present as patients that have new PET-avid nodules for lymphadenopathy after starting therapy, and it can happen weeks to years after initiation. It likely is more common in patients being treated both with CTLA-4 and PD-L1 inhibition. And so this image from this paper published by Ramby et al., panel B, you see some lymphadenopathy in the mediastinum as well as some nodularity stuff to see here in the upper lobes. They did a biopsy, found non-necrotizing granulomas consistent with sarcoid, and they actually made the decision to discontinue therapy, and they actually had subsequent resolution of the upper lobe nodularity with stable lymphadenopathy eight months after. So again, what to do about these patients, it's kind of unclear. In some cases, if they're tolerating it and they're asymptomatic, you can probably continue the drug, but in some cases, you may want to just pause it for a little bit and see how they do. Surgery section can be very tricky in interstitial lung disease. Typically, the more you resect, the greater the risk of developing pneumonitis afterwards. As compared to a wedge resection, you can see that the more you resect, the greater odds that you develop an acute exacerbation. So as an odds ratio of 6.9 with a pneumonectomy. It's unclear whether it's the resection itself that's causing that risk of exacerbation or if those are just sicker patients that already have more parenchyma involved. However, as far as deciding who to do surgical resection on, I think you kind of have to lean on the well-known risk factors for developing a resection and those that probably won't do well with surgery. So patients with lower FVC, TLC, DLCO, six-minute walk, comorbid pH and hypoxia, likely all have an increased incidence of acute exacerbation with interstitial lung disease. So in summary, lung cancer and interstitial lung disease share common pathophysiology and are often comorbid. Diagnostic procedures in ILD patients carry an increased risk of complication, most notably acute exacerbation and pneumothorax. Be wary of taxanes and gemcitabine in patients with interstitial lung disease. More work is really needed to define the role of immunotherapy in patients with lung cancer and interstitial lung disease. And beyond immunotherapy, even patients that have interstitial lung abnormalities without truly diagnosed in ILD have noted to have an increased incidence of pneumonitis. And finally, surgical resection can be challenging in patients with lung cancer and patient selection, as always, is critical. Thank you. Brief acknowledgement, I'd like to thank my mentor, Dr. Nicholas Pastis, who's done a lot of work in this field and helped me with this presentation. Dr. Kreiner, who was my mentor at Temple before I came to Ohio State and helped with the session development. Obviously, my awesome speakers as well, Dr. Kreiner and Dr. Spears. I'll hand it off to Dr. Spears. So my name is Christina Spears. I'm a radiation oncologist at Cancer Center of Hawaii. I have nothing to disclose. Today, I'll be talking to you about the role of radiation therapy in lung cancer. I'll give a brief discussion on radiation pneumonitis as a sequela of radiation treatment, and finally discuss how we may or may not modify treatment in those with IPF and post-transplant. So the use of radiation therapy in cancer treatment is predominantly through indirect DNA damage that occurs through free radical generation. And it is dependent on the use of a favorable therapeutic ratio. So if you see here in the X-axis is cumulative dose and the Y-axis shows percent of tissue damage, with a favorable therapeutic ratio, less of a dose is needed for tumor control than normal tissue toxicity. However, with unfavorable therapeutic ratios, the same dose would lead to normal tissue damage and tumor ablation, either leading to underdosing of the cancer or excessive normal tissue toxicity. Radiation can be targeted geometrically using beam design, going to one specific part of the body. I'll talk more about treatment planning later. And patients can be sensitized to radiation through the use of immunotherapy, chemotherapy, and molecularly targeted therapy, as Dr. Sinhai described. So the use of radiation for lung cancer patients is dependent on intent of treatment. So on the left, you have definitive treatment, consolidated treatment, treatment for local control, and palliative treatment, as well as stage. So for stage one and two patients, we use stereotactic body radiation therapy, or SBRT, or S-B-R-T, and that's going to high doses in five or fewer fractions. If we cannot treat with SBRT due to proximity to organs at risk, such as the heart, lung, bronchus, et cetera, then we will increase the number of fractions to eight to 15 fractions. And these volumes are generally larger because there's more motion from day to day. For definitive, meaning definitive, curative, preoperative, postoperative treatment, we'll go to over six weeks of treatment because often we're treating the mediastinum and those tissues are a lot more sensitive to radiation therapy. In oligometastatic patients, we will sometimes treat high, like stage one or two patients, to ablative doses in five or fewer fractions. But this is where knowing whether this is going to give the patient a benefit and then first do no harm, assessing whether the organs at risk can accommodate that dose is super important. For stage four patients, we treat for symptoms. Generally, it's an adjunct to systemic therapy, and we are trying to prevent future issues such as spinal cord compression. So limiting radiation side effects in the lung begins before consultation. As we already discussed, biopsies are difficult in patients who have pulmonary comorbidities, and so multidisciplinary discussion, making sure there's been a comprehensive diagnostic evaluation and tumor board discussion is key. We wanna make sure that if there are non-radiation options that can be given to the patient, such as observation or short-term imaging, that these are discussed, or is neoadjuvant chemotherapy or surgical therapy a preference? And it's super important to discuss with patients the risks of treatment. There's about a 5% pneumonitis risk per Timmerman et al with SBRT, but this can go up to 13% with stage three non-small cell lung cancer patients, and this has only been complicated by the use of systemic therapy and immunotherapy in modern eras. And this can be further elevated with comorbidities, and as I said, other systemic therapies. Radiation treatment begins after the consult with CT simulation, where a CT scan is performed with the patient in the treatment position using a device that can communicate with our treatment planning system. The patient is immobilized in order to maximize safety, comfort, and consistency of treatment. Patients then have this image set used to develop a treatment plan alongside our physicists and dosimetrist counterparts. And then while we treat patients, we will see them weekly to assess for acute side effects as well as long-term side effects in the future. Evaluation of radiation pneumonitis, it's something that you can limit with excellent planning. So in addition to immobilization, where you try to move the organs at risk as far away from the actual tumor target as possible, we'll use PET-CT and MRI imaging to carefully delineate the treatment target as well as the organs at risk. And we use 4D-CTs to limit respiratory motion or to account for respiratory motion in our treatment target. Planning includes evaluation of target coverage as well as target conformality, looking at the gradient of high dose to low dose, both inside and outside of the target. And we use dose volume histograms shown here on the right to assess organ at risk constraints. So obviously for a tumor target, we want a high dose, which is on the x-axis and normalized volume, which is on the y-axis. We want that ratio to be high. So GTV is gross target volume. PTV is planning target volume, which tends to be bigger because that includes microscopic disease inclusion as well as planning target motion from day to day. And we want the organs at risk to have a low dose to volume ratio. So this includes in this image heart, spinal cord and total lung. But we also look at the trachea, large bronchus, small bronchus, brachial plexus, rib, et cetera. It's important to remark here that there is data suggesting a linkage, which is not surprising to any of you, between the heart and the lung for late injury, meaning that if we damage the lungs, we can cause increased cardiac toxicity and vice versa. So this has to be accounted for. And during treatment delivery, we will actually use the 4DCT, which is binned according to either respiratory phase or amplitude. If there is excessive motion of the tumor target, say something over one centimeter during the respiratory cycle, we may actually choose to do a gated treatment, where we treat during a subset of the respiratory cycle to decrease the respiratory motion and decrease uninvolved lung exposure. So radiation pneumonitis evaluation is an important part of the follow-up. At the top here, we have the CTCAE guidelines, grade one being asymptomatic disease, grade two to three being symptomatic disease that requires increasing medical intervention, and obviously grade four and five being life-threatening disease or disease causing death. Generally, we do see these symptoms within one month to a year after radiation, so it's a big part of our follow-up with the patient and intake with the patient. Patients often present with dyspnea on exertion and nonproductive cough, and they may or may not have RALs on exam. Radiographically, we use high-resolution CT. Dr. Sinha talked about PET-CT, which is essential to rule out malignancy. There's low-level evidence suggesting it may have some benefit in IPF rule out, but most of the time we're looking at malignancy as being on the differential diagnosis. Treatment is usually done with steroids, usually oral. However, there is some data on inhaled steroids over a longer period of time if patients are contraindicated for PO steroids. And there's discussion of other therapies that have impact with the patient, such as immunotherapy, because this can often, as Dr. Sinha mentioned, happen at the same time. So let's say with our Stage 3 patients, if they're on Dervalumab, which can also cause immunotherapy pneumonitis, there's often an attempt to give the patient the benefit of the doubt and perhaps observe or treat them as if they have radiation pneumonitis so that they don't have to discontinue their immunotherapy. So to step back and talk about radiation effects and long-term sequelae, I just want to mention that radiation toxicity is the outcome of treatment and patient characteristics. And so basically, the outcome is often fibrosis due to radiation injury and pro-inflammatory cascades. The participants are tissue-dependent. It depends on the tissue in which you're speaking of. So early-responding tissues include the skin and GI. Late-responding tissues include heart and CNS. And lung tissue is in between. In this really beautiful review paper by Torkhan et al., they talk about direct DNA damage and, as I mentioned, indirect DNA damage in the lungs leading to AEC apoptosis, depletion, type 2 AEC hyperplasia, oxidative stress, pro-inflammatory gene expression, chemokine secretion leading to increased permeability, blood cell leakage, inflammatory cell infiltration, and then alveolar and interstitial edema. Radiation pneumonitis has both short-term and long-term impact. This is a Hallmark textbook from 1968. That's why the images are kind of wibbly-wobbly because it's a Xerox. But this is by Rubin and Kasseret. And this basically shows clinical manifestations we no longer see because, at this time, there were much higher doses and volumes given with radiation. But in patients that have radiation injury where there is radiation pneumonitis diagnosed, they're treated with cortical steroids. And over time, decreased oxygen diffusion, interstitial fibrosis, and even corpulmonality have been described. And subclinically, you can have segmental fibrosis and septal thickening. What was described in this book was decreasing lung volumes over time after radiation injury. IPF patients are thought to have elevated risk of radiation pneumonitis, which makes a lot of sense. The data is still fairly sparse, which is a theme here. So radiographic screening by Kim et al. suggested that those that had diffuse interstitial changes prior to radiation therapy on high-resolution CT had elevated risk of grade four, or excuse me, grade five radiation pneumonitis seen in four out of five patients. And serology and inflammatory markers such as IL-6, TGF-beta, surfactant protein A and D have been described. But it's important to know that these are not routinely used. So in Yamashita et al., after 2006, the group developed a paradigm and started using it to rule out patients for SBRT. What they found was that if you used a serum, Krebs-Vonden-Lungen or KL-6 and surfactant protein D levels, in addition to the presence of a slight, medium, or severe IP shadow, that they found improved rates of radiation pneumonitis in treated patients. It went from 18% down to 3%. So in the image on the right, this patient was scaled as having slight IP shadow. They were treated with SBRT. The plan is shown on the bottom. And you can see here the conformality index that I talked about as being a quantitative metric for radiation plans is this light blue, which is the 50% dose, and this dark blue is the 100% dose. This plan is a little atypical in that there appears to be no dose de-escalation or moving the target off of the heart, which usually has a lower constraint. However, after treatment, what's very clear is that you see these changes in the interstitial tissue, both inside the high and moderate dose, as well as in the low dose as well. At the moment, it's important to describe that there is no recommendation for dose modification in IPF patients. So I just wanted to go quickly through this beautiful figure from the same review paper, which draws parallels between IPF and radiation pneumonitis. So basically, IPF is in this reddish-orange color. It's associated with age-related changes, repetitive injury, and you notice aberrant AEC cell proliferation, or excuse me, activation, basement membrane disruption, and fibroblastic foci, whereas radiation pneumonitis, early changes include, obviously, the incidence of radiation pneumonitis is associated with radiation exposure, affiliated with patient-related factors, treatment-related factors, as I discussed, and is associated with Th1 and M1 activation and increased vascular permeability. And then later on, you get Tth2 and M2 activation, as well as further changes resulting in fibrosis. However, both result in Tt2 apoptosis after hyperplasia and proliferation, chemokine release, changes in the EMT, and fibrosis. So there are certain parallels that we can draw in between the two. I was asked to speak about proton therapy as another modality of radiation therapy. Protons have a different dose distribution than photon therapy. In the image shown on the right, where depth is shown in the x-axis and percent depth dose is in the y-axis, photons will result in exposure of the full thickness of the tissue. You can adjust where the percent depth dose occurs by beam hardening or by adjusting the energy of the beam, but you are going to see that deposition throughout. Whereas in photon, I mean protons, excuse me, you have a Bragg peak, past that point, you're not going to have radiation exposure. And again, that can be adjusted by working with the energy. But obviously, you have two very different dose depositions here. So do we use protons all the time? No. There's not a lot of data supporting its use as superior to photons, with the exception of chondrocycomas, chordomas, or pediatric patients with CNS disease, in which avoiding developing tissue may have huge impact on long-term side effects. There is scant data otherwise to show that a modality that sometimes causes, I mean costs five times as much and is more rarefied in terms of accessibility of disease centers is more beneficial. However, in this small study by Kim et al., they suggest an overall survival benefit with protons. They had 30 patients that they were evaluating. I will say that even though I think this is an interesting and hypothesis-generating study, that it did overlap with multiple treatment areas, including 3D, IMRT, SBRT, different fractionations, different volumes. And so I think that those factors themselves have prognostic implications. However, it's something that I would discuss with patients at the time of consult. Lastly, I just want to talk about post-transplant patients who can likely be safely treated with radiation with some caveats there. Obviously, it depends on the type of transplant. More commonly, we see patients following total body irradiation that previously happened that's used for conditioning. We see this less and less often now, where bone marrow transplant utilizes total body irradiation. More and more now we're seeing chemotherapy conditioning. However, this is an example on the right where you have a patient who has compensators placed over the lungs to limit the lung dose. Relative contraindications should be discussed in these patients, including connective tissue disease and ongoing immunosuppressants as they have implications as well on patient's outcomes. In this small study by Volok et al., they noted that three patients who had lung transplant and then lung radiation did not have any increase in expected adverse outcomes. However, all constraints were met in these patients, you know, which is so important to emphasize that whatever we can do at the front end to limit lung dose and volume exposure is very important. And with that, I'd like to summarize that patients with pretreatment pulmonary disease are best treated with thoughtful patient selection, detailed informed consent, no dose modification or serology prescreening at this time, but with careful treatment planning, and multidisciplinary management both before and after radiation therapy. And with that, I'd like to thank my session partners, especially Dr. Sinha for innovating and organizing this session, the chest organizers, and all of you for listening. Thank you.

radiation therapy

lung cancer

interstitial lung disease

lung transplant

nodules

transplant recipients

biopsy procedures

acute exacerbation