Chapters Transcript Video Small Cell: LS-SCLC OK, I'm gonna talk a little bit about biology. Well, biology has been mostly talked about, so I'll skip through that pretty quickly. We kind of just go back to staging and limited and a new quasi-concept of very limited small cell, and I'll discuss the ever popular issue of uh PCI and see if I can insult somebody I haven't already insulted. So staging, um, You know, so small cell lung cancer, this is lung cancer staging made ridiculously simple. Limited is really, and, and these are, you know, a couple of staging editions ago, but, you know, anything that's 12, 3A, 3B other than. You know, which used to have malignant effusions is limited small cell. So your typical limited small cell was somebody with a, you know, like a softball size primary, uh, and then, you know, extensive mediastinal nodes. That was your typical limited small cell. And the official definition from the mid-1960s in the VA, uh, lung group was something that could be encompassed within a tolerable radiation therapy port, uh, unquote, uh, never really defined. So limited actually has had a variety of definitions over the years and may or may not include supraclavicular nodes, ipsilateral or contralateral, usually not if it's in the cooperative group and extensive is pretty much anything else. But at times, for example, malignant effusion was considered within limited small cell. I know this because I ran. An NC uh, what was it? CLGB or SWA study, SWAG study that allowed effusion. So, um, as limited disease. So, this is the staging. So just figure that everything that stages 1 through 3, but you'll see pretty soon that really the earlier, the particularly stage 1s really need to be factored out. So, this is the, uh, you know, the, uh, what, what launched 1000 ships, this study over here. This was an intergroup study, and it compared platinum metoposide and radiation of 45 gray, which was the standard because it's an extremely radiosensitive malignancy to 45 gray BID. I've had this slide for, I don't know, 30 some odd years now. And uh showed that the BID radiation was better than the daily radiation. And, you know, contrary to the prior speaker, relapse is not inevitable in small cell as he even he showed, um, you know, there are patients who are cured of limited small cell lung cancer. And they are cured, um, you know, with chemo radiation. Again, notice that this is before the era of immunotherapy, target therapy, etc. and using what we would now consider very primitive, uh, radiation and really not so great supportive care. So, you know, but this evolved a whole series of questions in radiation in particular, which is, do we really need to go to BID or maybe we should go to maximum tolerated dose because we know from non-small cell, you can certainly go well beyond 60 gray, which is our standard over there. So why don't we try 66 or even 70? Do I hear 72? Um, and, uh, you know, all of these were, were looked at over the years, um, you know, to do daily radiation. And there are reasons both for the patients who don't like sitting around 6 hours and for the radiation oncologist who doesn't want to keep their machine, you know, uh, busy twice a day with the same patient. And then the issue also comes up about what about very limited small cell, and I'm gonna get into that in a little bit. So this is a European study called the Convert trial. They looked at 45 BID versus 66 grade with concurrent chemotherapy. Well done study. This study was designed to show the superiority of 66. It did not. It showed, in fact, if you look closely, you'll see that the red dash line, which is the BID, does do better than the 66. Um, nevertheless, the Politically correct thing to say is that these were comparable. They certainly were not equivalent. In fact, it was a failure, you know, the study, the hypothesis was not proven and one defaults back to BID, which remains the best approach, you know, for these patients. But the higher dose radiation, you know, in the right, you know, in certain situations is not completely ridiculous, um. And, uh, so, you know, the other thing to always remember is both arms did better than predicted staging techniques. We suddenly have PET scans, better radiation therapy. It's not, you know, your father's, you know, BID radiation is certainly not what it is today, you know, it's gotten a lot easier and much improved supportive care. So in the United States, uh, we basically asked the same question. This took forever to get a result. Uh, it was 45 BID versus 70 grade QD. Uh, there was a third arm in this, uh, that came from that same interesting large institution in Texas, which, you know, kind of delayed this for many, many years, um. And at the end of the day, uh, showed that once again, the winner and still champion was the BID radiation, not by much. Um, and again, the higher dose daily radiation is another, not unreasonable way to go. Um, so what finally changed was the advent in the use of immunotherapy, as others have stated, immunotherapy definitely improved the outcomes, uh, for, uh, chemo radiation. Uh, similar to the, uh, Pacific trial and, you know, Pacific Adriatic, same sponsor, AstraZeneca, same drug dervalumab, and kind of an interesting trial design, which is you have the black box of the chemo radiation, uh, you finish that, you have stable disease, and then the race begins of, you know, Derva versus the, uh, uh, control arm. So. Not beginning at the same time, but showing a clear advantage for those patients who in fact get uh durvalumab and this is probably, you know, was literally the first progress in, you know, 3 decades in this field. So, you know, that was quite, you know, important and these results are quite mature and show an overall survival advantage. And this is curative therapy. So these patients are clearly cured. One thing I'll put in, uh, very clearly over here is a key issue in supportive care. You know, patients always want to know what can I do for myself. Well, these are the people with small cell. They started to smoke usually when they're about 12. Uh, they smoke heavily, and they got to stop smoking because the rate of second malignancy in. These patients, if they continue to smoke is 5% per year. It's pretty up there. Um, and, you know, frankly, for all of them. I mean, if you look at, for example, the segmentectomy data in non-small cell, after I think it was 5 years, uh, in the CLGB trial, 15% of patients had second malignancies. So, you know, good opportunity for secondary prevention, etc. So, similar to the situation in non-small cell, let's move immunotherapy up earlier, what possibly could go wrong? Well, everything, um, you know, Chris Higgins, uh, had to present the study. It was a disaster in the sense that it showed us, you know, and this was an NRG trial. I was part of this, um, and it showed us that this is not a good idea. And you know that probably because of the extensive radiation to lymphocytes and lymphopenia that I've always kind of ignored over the years is for immunotherapy an important thing and sustained radiation with immunotherapy is not is a pretty bad thing because if you really think about it, this not only was not beneficial, it is the control arm here is not sequential, you know, is, is actually, it, it completely eliminates the benefits that were seen before. So what about very limited disease? Well, there's resectable small cells, so we never used to see this. Why? Because we didn't have a CT scanner on every corner. Um, you know, these days, you know, you stub your toe, you get a CT scan. This produces a lot of extra diagnoses. Furthermore, even though screening is barely, you know, been taken up in the United States, maybe 15% of eligible patients, it does show some small cell patients. And these patients, if they're known negative, are very resectable, and what do you do with these people? Um, so is there a role for adjuvant therapy? So there's, you know, for and against this. This is the best study comes from, uh, Duke University, and it's a review of the National Cancer Database. And the yellow line over there is those patients, they get resection followed by chemotherapy. And so this is like, if there's any fellows in the audience, this is the right answer on the boards, uh, if these patients come up, or they could have another local therapy such as stereotactic radiation, uh, followed by, uh, adjuvant therapy. You notice just those numbers are pretty up there, you know, we're above 50% for some of these people. So very this, what I would call very limited small cell and perhaps the staging system needs to come back into play. And the people who benefit the most for these are the node negative patients. So a patient, we just had one of these last week in our clinic who gets a properly done, uh, and a bronchial ultrasound, really staging their nodes very, very carefully, can go to stereotactic radiation, follow with chemotherapy with clear curative intent. And probably as much as a 50% long term survival, either with the stereotactic radiation or with resection. But no, no randomized studies in this, but this is a biological plausible thing to do. They don't need immunotherapy. There's no evidence for that at this point. And, um, you know, it remains to be seen. I think it would be very hard to ever get a study on that. What about PCI? So PCI. Everybody loves PCI. This was something, this was like a board question for me, I think at least 3 times. I think I had it in my internal medicine. It was in my med on, um, you know, boards probably was even on the HEAM boards. Um, so this was really based on the observation that a lot of patients on their initial relapse would be in the brain. And the experience at that point, remember, this all came up. This was in the late 80s or so, was based on pediatric acute lymphoblastic leukemia, one of our first real, you know, curable diseases that the brain was a sanctuary site and you treat the brain, life will be good, you prevent recurrence. So this relied on two studies, you know, for this something called the OPRA and meta-analysis. Um, this showed this absolute 5% increase in outcome. But remember, none of these patients were staged with an MRI. None were staged with a PET scan, really archaic data. Actually, the first study in this is pre-CT. So, not even remotely resembling the modern era, uh, and the data now with PET and, you know, MRI is that you're probably not really helping anybody. The EURTC sort of launched this idea in in extensive small cell, and what I always tell people is look at what they did. Is this like your practice? In the United States, we stage the brain. We get MRIs of the brain, or at least a CT with contrast routinely. This is not done in Europe. They only did it in patients who are symptomatic. When 1 millimeter brain mats are not symptomatic. So basically they were just treating subclinical disease. And furthermore, you know, there was a survival advantage, but nowhere in their papers, nowhere in any subsequent publications, and actually nowhere, even when I debated this, the, the first author, Doctor Slottman. Uh, could anybody tell me what their second line therapy was because they don't treat the second line. They weren't even getting topotecan, which does show a survival advantage. So I don't think that's analogous, uh, to what we do here. And the guidelines now in the United States are to consider this. But remember, PCI. Comes with a substantial degree of a poten potential um cognitive defect, um, you know, and particularly in patients over 70 is associated with dementia we have enough hospital administrators let's not create any more um so. You know, let's just, you know, there's, and remember, once again, who are the people that you'll be treating with this? They are people who started smoking when they were young, they're lower socioeconomic, uh, they did not live, live a life of good cardiopulmonary health. They are going to have problems, you know, when you treat this. It's something probably to consider would say the occasional younger patient, but, um. Uh, generally, uh, should be considered carefully. Limited small cell is a curable disease. Uh, current standard of care, chemotherapy, concurrent platinumettoposide, radiation, 45 BID preferred, 66 or so, uh, daily, uh, would be OK, followed by immunotherapy with dvalumab. We don't yet know the role of the newer agents tarlatumab, urbinectidine, etc. in a limited stage setting. MPCI should be discussed, but it's certainly not mandatory, but close follow-up with the CNS with MRI is certainly indicated. Thank you. Created by Related Presenters Martin Edelman, MD Department of Hematology/Oncology Chair, Department of Hematology/Oncology, Professor, Department of Hematology/Oncology View full profile
