(upbeat music) - Back to the recording studio. This is on "Cology" for the inquisitive mind featuring a Michael Fernando and you're one and only Melbourne host, Dr. Joshua Hurth. So just to update you on our lives, 'cause that's far more exciting, Michael. Well, actually it's not. It's what people come to hear about is the gossip, isn't it? - That's it. The gossip is this is now back to a trend state, an interstate podcast with Michael in sunny Queensland. It looks somewhat sunny, but it looks tropical, definitely. - Well, I'm sitting here in my new recording studio, as you said, the nine wearing t-shirts and shorts in winter, late winter. Josh is still very cold. - Yeah, I was gonna say that the other co-host here is somewhat still cold. - And no, Michael, today we are not doing a cold episode. We're doing what we call pretty hot episode, some interesting takes. - Do we call that Josh? Do we call those hot episodes, do we? - Well, we will, for the purposes of sunny Queensland. But essentially, we're gonna, Michael is gonna introduce the topic on Lancaster. Let's roll, small cell, Lancaster. - I was gonna say, I was gonna say, we've had a couple of episodes on non-small cell Lancaster and of course, for those of us listening who, I mean, we've known about the different streets, small cell and non-small cell for a long time, so perhaps our newer listeners begs a question, well, what is small cell? If they've got a bunch of non-small cells, what's small cell? And the answer to that is that small cell is a poorly differentiated neuroendocrine tumor, very, very nasty. I often tell patients that this is, along with maybe testicular cancer, the closest we get to dealing with something like a lymphoma. It is very aggressive, very, very rapid onset and despite good initial treatments, I think their response rate initially is about 50 to 70%, majority of patients still relapse, so it is one of those yo-yo cancers. It represents approximately 15% of all lung cancers, which is good because if it was any more common, lung cancer would be even worse than it was. And nearly all patients are current or former smokers, with only 2% being never smokers. No history of either passive or active smoking. Like other variants of neuroendocrine carcinoma, we've spoken about a couple of those on the podcast previously with gastrointestinal necks. Small cell lung cancer has a T67, which is a marker of the rough doubling rate, of greater than 50% usually, and sometimes it approaches 100%, which obviously is as high as it can go. And typically arises from the central airways, the central lobella. And so the usual presenting symptoms are things like cough, dysnear weight loss and general debility. Patients may also present with hemoptosis and post-abstructive pneumonia, though these are less common than when squamous cell cancers, which we know are very liable to bleed. Only 30% of patients present with limited stage disease. And this is another sort of quirk of small cell is the staging system. And this was originally introduced by the Veterans Affairs Lung Study Group, the ALSG in the late 1950s. So well before we started using TNMs and having this one size fits all sort of criteria. So there are two stages for small cell. It's nice and easy. There's limited stage where the tumour is confined to the Ipsilateral hemithorax and regional nodes. The way this has come about is that this means it's able to be included in a single tolerable radiotherapy field. And if we're converting this to TNM, it's TNM stages one to three B. And then the vast majority of people who present with a new diagnosis of small cell will present with what we call extensive stage, is anything beyond limited stage. And this commonly manifests as malignant plural or pericardial effusions or contralateral or distant involvement and distant involvement. Most frequently will involve the liver or will involve the brain. I've seen a number of patients I know Josh has to where a patient is presented with a completely different presenting complaint. One memorable patient that I met very early on should present with the fall. And she had a screening CT. And they found this big nasty thing in her brain and she unfortunately had lung cancer. Was it a screening CT or screening CT? 'Cause I had screaming, screaming. No, no, no, that's just the internal sound that I make almost constantly. No, screening CT to look for a bleed. Unlike non-small cell, there are also few therapeutic molecular targets. So there's no EGFRs, there's no K-RAS. In fact, the mutations here are very rare and they haven't been shown to portend any therapeutic benefit. Almost all small cell lung cancers have mutations in P53 or the retina blastoma 1 gene, RB1. But recently, and I won't spoil one of Josh's later studies, but their Delta-like ligand 3 or DLL3 has been identified as a targetable mutation and this is very promising. But we will come to that. But that's the background of small cell lung cancer sort of large Josh. Why don't we jump right in? We're gonna focus on two stays in the limited stage today and we'll go to one two extensive stage next time. So why don't you talk about a standard of care regiment with the Adriatic tribe? Yeah, look, Michael, thank you so much for that absolutely incredible introduction and the internet's working, so even better. When Michael moved, I'm like, you have to check your downloads being made 'cause otherwise this ain't gonna work. First thing, it wasn't, how was the move? Have you got all your stuff? It's what the internet's be. And do you have any hair left? So Michael covered most of the introduction apart from his little small ball spot, but we won't get into that today. As Michael said, absolutely, it's an aggressive cancer and he got the statistics right, it's 15%. And the starting current standard of care for a limited stage Michael is thoracic chemotherapy and platinum/etopicide for I guess this cohort of patients. And most patients will relapse within a couple of years. Overall survival despite this being limited stage is poor. Into devalue map and you might know devalue map from such great trials as the Pacific trial and such other great trials as new adjunct blada, Niagara, Niagara. Any trial that's named after a body of water I think is devalue map, that's the giveaway. Yeah, there's no Indian Ocean one yet, but it might come. There will be, there've got to be running out of things. They've done Caspian, Adriatic Pacific, they'll run out of bodies of water soon. And so rather than me lamenting about the fact I'm thinking of the line which in the wardrobe at the moment, you know, Prince Caspian. Let's talk about this drug. Quality reference there, Josh, quality reference. I always knew you were a man of culture. Devalue map is a antibody binding to the programmed it like N1, it's got a high affinity. It's like every other immunotherapy drug that activates CD80 and it interacts with the mechanism essentially upregulating the immune system. Michael already spoke about the Caspian trial, which was Derva devalue map plus etoposide and platinum improved overall survival in the extensive stage setting and Pacific as well in that sort of stage three undersectoral disease for the non-small cell lung cancer. But this study is a little bit different. There are three arms. We're talking about the first two, which is once randomized will be devalue map or placebo. There is a third arm, which is a tremolimumab and devalue map, but that hasn't read out yet. And for those that are interested, tremolimumab is a CTLA14 inhibitor. - It's like saying Mississippi isn't it? - And so it's a phase three randomized double blind trial, stage one to stage three limited stage cancer, good performance status has not progress following concurrent chemo radiotherapy and that's a set yet. And you're given four cycles of the platinum and etoposide three were permitted and radiotherapy. And then you'll randomized, I think it's one to one to one and there are about 730 patients involved with the primary dual endpoints being that of overall survival and progression free survival. And the secondary endpoints was devalue map plus tremolimumab versus placebo. First thing I didn't love about this is that I don't think they compared devalue map versus devalue map and tremolimab. I would have liked that. - Yeah, I was gonna ask because this seems like one of those trials where they have three arms and then don't actually compare all of the arms together, which is frustrating when you're trying to tease out the responses. - The nuances, but I don't think the third arm is actually read out Michael. So maybe we will see some non statistically derived analysis from that. So 939 patients are actually enrolled. The above full mention number was randomized, median age, 60s, most were former smokers, that's 68% and current smokers are 22% and 87 had stage three disease, which highlights the fact that this stuff is found pretty late, like you don't get tiny little baby stage ones a lot of the time. The 33% of the intervention and 26% of the control arm completed treatment, placebo as well, so they're like not bad. And the primary reason for discontinuation was disease progression about half and second reason for discontinuation was an AE in 16% and 10% in the control arm. So overall survival was 0.73, that was your hazard ratio. So that's 27% better than the SOC or standard of care. This favored devalue map, with a median overall survival of 55.9 months, versus 33.4 months in the placebo group. - That seems pretty long for limited stage, considering the relapse rates. - 100%, 100%. So you're definitely seeing some benefit. And then the overall survival of 24 months, which I really like, was 68% versus 58%. So you're getting a 10% benefit at that two-year mark. It's good for patients, I think this is to say, you know, what does that actually mean for me? It's like, well, you know, an extra 10% of patients are alive at the two-year mark because of our intervention. And then the progression for survival was longer in the devalue map arm, about 25% better, with a median PFS of 16.6 months, versus 9.2 months, which is good as well. And at the 18 month mark, it was 48% had not had disease progression, and 36% in the placebo one. So then it's already about 12% better. And at 24 months, it's about 46 versus 34%. So you see that continued benefit at the two-year mark. An objective response rate was similar in both arms, and the median duration response was slightly better in the intervention arm. Adverse events was not dissimilar between the two groups. I think that's probably a high light and the importance of that. Due to drug, I said DERG, but in my notes, but DERG, or placebo use, or 67% in the devalue map, and 48.7% in those of the control arm. And I think when you look at the treatment-related adverse events, sometimes you get mixed up with that of just, or adverse events, including issues when it comes to disease and other such problems. So you're just looking at like a 20% increase in toxicity, but also quite a significant improve OS. One final thing is that the incident of pneumonitis or radiation pneumonitis was relatively high. It's like 38% in the DERG group, DERG value map, and 30% in the placebo group. Grade three or grade four, pretty mild. So only about 3 and 2.6% respectively in one patient diet, but also a lot of people progress. So you have to kind of take that into account. We're still waiting for some final readouts. I think that's it. Are there any biomarkers that help influence what we do? What's the optimal timing and role of proflected cranial radiation? And long-term survivors and outcomes of that. So we still need a little bit of nuance, I think, to figure out. I mean, definitely it's a good drug, and it is the standard care, right? The healthcare system and your country will pay for it. If I was me and I had that, I'd be like, yes, please give me the dwelling map, because that 10 to 15% is really, really important. I think looking at the numbers from your notes here, Josh, there are a couple of things that do jump out at me. I mean, number one is the fact that the median overall survival in the DERG group was 55 months. And the overall survival in the placebo group was 33 months, which, to me, does seem a bit longer. Considering, as we'll see next week, the survival for extensive stage small cell is absolutely abysmal, it's less than a third of that. But it also seems like if you are a responder sort of at that 18 to. Yeah, probably about 18 to 24 month mark. The likelihood of dropping, because overall survival was 68% at 24 months, and then you've got a median overall survival of 55, or almost 56 months. So between those two, you know, almost two years, you've only had an 18% drop in patient survival and similar with PFS. So there is hope if you are one of those responders, and it seems like it's a good response, it has not been approved in Australia yet. I suspect that's because our system is a bit slow, but you do have a couple of good questions here, which is, you know, what's the optimal timing with PCI in the DERB era? We know as well that there's interactions, and you mention them between humanitists and radiation, humanitists being worse in volume, you know, therapy. So a couple of considerations there. Yeah, I think that's it. Michael, I don't want to us to talk too long, otherwise I would keep rambling about this. But I think for though you're right, those are who respond. This is definitely will be a potential game changer, because I think when we get more follow-up time, it will show how we actually cure the cohort of these patients, and if that's the case, that's the aim. And it looks like there is a decent. The cap on my coat shows something nice. We've mentioned this in the non-small cell space as well, but it will be interesting in Australia to see how the lung cancer screening program goes with potentially picking up these ones. I suspect it will be less game-changing if it's going to make any difference at all, because small cell can have a very small primary that just sort of bolts very quickly and goes to the lungs, goes to the brain without a huge burden of disease in the lungs. So it might not be as effective, but we don't know. Well, Michael, let's go back to 1999 when the matrix came out. Everyone was partying apparently. That's it. And the Sydney Olympics were just around the corner. I remember watching the Sydney Olympics from a hotel room somewhere. I think it was on Golgas. Anyway. So the study that I'm going to be talking about is about prophylactic cranial irradiation or PCI. And the reason I wanted to talk about this one is that it is a bit uncertain, from center to center, there are differences in terms of the utility of PCI. Fortunately, or power, I hope I'm pronouncing that correctly, et al in 1999, did a meta-analysis, which we love. We love meta-analysis. The background for this is that the CNS is a known sanctuary type of metastasis. We've mentioned this sort of obliquely in the past. Almost 50% of patients will develop brain metastasis during the course of their disease. And 36% will develop brain metastasis within 12 months of treatment without prophylactic cranial irradiation. As with every radiotherapy, this is not designed. It's for systemic treatment. This is prevention of a very specific area of recurrence. So basically, this meta-analysis was looking at studies that enrolled patients with small cell lung cancer in complete remission. And I guess that is important to note because you can have complete remission in extensive stage. You can have an incredible response. You just have a late recurrence. Patients were randomly assigned in the analyzed trials to PCI versus no PCI that have no evidence of brain metastasis before randomization and no previous cranial irradiation. Very hard to irradiate the brain twice. The window for enrollment was between 1965 and 1995. The primary endpoint was overall survival. Secondary endpoints were disease-free survival. The cumulative incidence of brain metastasis. The cumulative incidence of other metastasis and the cumulative incidence of local or regional records. Lots of accumulations here. Basically, in terms of results, they identified seven trials. Three trials constituted 84% of patients. So basically, three big trials, four small trials. In terms of the overall survival, the risk ratio for disease progression or death was 0.84. And this was similar after they adjusted for the extent of disease, gender, age, the type of introduction therapy, performance status and time between the start of induction therapy and randomization. So regardless of what you do, PCI is going to reduce the risk of brain metastasis and therefore improve overall survival. There was a trend to a greater effect of PCI on the incidence of brain metastasis in patients who were randomized quicker. So basically, you finish your systemic therapy and bang, you go onto PCI as soon as physically possible. But this did not have an impact in overall survival. So while you are potentially, we're talking about a trend here, so take it with a grain of salt. While you potentially are reducing the number of brain metastasis, you're not improving overall survival. There was also a bit of variability amongst the trials in terms of the dose of radiotherapy, which was ranging from 24 to 40 grays, which was given in 8 to 20 fractions. So different ways to give the PCI. This did not significantly impact survival either. The pooled relative risk of brain metastases was 0.46, sorry, hazard ratio, I should say, the relative risk. So if you have a PCI, you are more than halving your likelihood of developing brain metastasis. There was improved disease-free survival from a brain metastasis perspective, but obviously because we're focusing on the brain here, there was no effect on other metastases or local or regional recurrence. So basically, PCI is now the standard of care for patients who have a complete or near-complete response in both limited stage and extensive stage of small cell lung cancer. However, as anyone who has given or seen patients with PCI will tell you, it is recommended only in patients with good functional and neurocognitive status. There are significant issues with memory, significant issues with emotional state that can arise from PCI. There are a couple of studies which I won't go into in any great detail, but they demonstrated improved toxicity when the PCI regimen spared the hippocampus, which I guess anatomically makes sense. This specifically was manifested as improvements in delayed free-requel, total-requel, and this did not impact the overall survival quality of life. So basically, yep, the summary of this meta-analysis is PCI, you should have it in limited stage and in extensive stage, if you are one of these patients, it has a really good response. But you should always select your patients carefully, we say that pretty much every episode, and always discuss with your friendly neighborhood, MDM, because the degree of response, these meta-analyses, mandated a complete response, but the degree of response will influence whether it's sort of worth it. If you can reduce the morbidity for these patients, then yeah, absolutely, standard of care. Seal of approval for PCI. - That's great, Michael, I was looking at, yeah, I was looking at like 30 years to recruit, I'm like, wow, just the number of trials. Really interesting though, 'cause the technology has changed so much with radiation that I suspect is probably better now than what it was, but also was there much on the tox? - There wasn't much in the study, but the toxicity is pretty standard, as I mentioned, issues with neurocognitive and emotional status as the main thing, energy is people frequent to get significant fatigue, apathy, those sorts of neurocognitive symptoms, as you say, radiotherapy has come a long way, and with the mRNA machines now, you'd hope that it would be a bit more precise, and our understanding of what is contributing to the toxes is these probably improved as well. - That's it, and speaking of coming a long way, Michael, our next episode, we're moving into the extensive stage, small cell lung cancer. What was probably very much an orphan cancer up until a couple of years ago, I think I'm not gonna give away the drug that we've all used and how things are changing, I think it's gonna be a great and interesting conversation. - I think it's gonna be a very interesting episode. - That's it, and don't forget to like and subscribe for Michael's sake. - For my sake, absolutely, because apparently I've got a bald spot. - I'm kidding, I think I've got the bald spot. We'll see you next week. - See you next week. (upbeat music) - Thank you for listening to this episode of oncology for the inquisitive mind. Produced by ADC Productions with the assistance of education grants from Pfizer, Gilead Pharmaceuticals, and the Merc Pharmaceuticals. As always, these companies do not receive early previews or editorial input of any kind. The opinions expressed in this episode are our own and the facts are, well, the facts. 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