Mattia Longoni: Thank you, Professor Chang, for the kind presentation, and thank you today for having me here today to present and to share our latest results on the effect of neoadjuvant chemotherapy on years of life lost in patients treated with radical cystectomy for bladder cancer. The story of neoadjuvant chemotherapy, you know, starts back in 2003 with the SWOG-8710 trial and then continues with the medical research council trial, and it's evolving. We are adding now neoadjuvant immunotherapy to that with the NIAGARA trial. And this led over the past 20 years to an increasing adoption of neoadjuvant chemotherapy before radical cystectomy, as you can see in this work by De Angelis et al. But still, some kind of patients, a big slice of patients actually, still are not going to get neoadjuvant chemotherapy, and this is due to many reasons, actually. For sure, one of those is you can argue that neoadjuvant chemotherapy may not be beneficial to some patients, and its benefit may not be universal or not without cost, actually. So what we wanted to do is to look into this kind of issue in a different kind of way. Instead of the usual survival analysis, we wanted to use years of life lost because it's a more tangible metric that we can use to assess this issue and to finally clarify at least whether gains in survival after neoadjuvant chemotherapy justify the risk of this intensification of therapy.
So to do that, we actually retrieved real cases from the SEER dataset. We generated one-to-one cases, controls, sorry, based on age, sex, and year of diagnosis, and we modeled the survival of these cases accordingly based on the SSA life tables. This is the math behind, and thanks to Dr. Fabian Falkenbach, who was one of my co-fellows in Montreal, who did the first statistics. But what you have to understand actually is that the years of life lost is the difference between the age at death of actual cancer patients and the remaining life expectancy of the population controls, until the age of 75 because we cannot do forever, but 75 is this kind of cutoff that we used and the WHO uses for definition of premature death. So coming to our results, we have retrieved around 5,400 patients who did radical cystectomy with T2N0M0. We sort of selected this specific population to have a homogeneous population. So as you can see, the rate of neoadjuvant chemotherapy is around 30%, that is comparable to what we have found in the real-world data, and we also stratified according to year of surgery, sex, and age groups.
And we also did some age distribution analysis to see if there were some differences, and according to treatment and sex or study period and treatment, we did not find actually any difference, so we could actually analyze in those subgroups the differences in years of life lost. So overall, we found that patients undergoing radical cystectomy plus neoadjuvant chemotherapy had 1.3 years of life lost compared to population controls, those undergoing radical cystectomy alone had 2.3. So approximately for patients with neoadjuvant chemotherapy, an advantage of one year relative to radical cystectomy alone. But the most important findings that we observed were in the subgroup analysis. First, younger patients had the highest years of life lost and showed the largest benefit from neoadjuvant chemotherapy, while years of life lost decreased substantially with increasing age. And this is very important because most of the patients that get neoadjuvant chemotherapy are younger and fitter patients. And we also observed a decline in years of life lost across surgical eras in both treatment groups, which is quite understandable because contemporary diagnostic improvements and therapeutic advances, just think about PET-CT scans or neoadjuvant immunotherapy, as I told, are changing, are changing the treatment and the outcome of these patients. And finally, we did not observe any difference according to sex, but that's kind of expected because sex is not a meaningful driver of survival in this case. So of course our findings could not be interpreted without some limitations.
First of all, the lack of comorbidity in the SEER dataset, the inherent stage migration or selection bias because the pT2N0M0 patients after neoadjuvant chemotherapy should probably be a higher stage and represent a downgrading effect of the neoadjuvant chemotherapy. We don't have any details on neoadjuvant chemotherapy regimen or radical cystectomy-related information. And finally, we cannot account for potential cisplatin-ineligible patients. But of course, what we can say is that taken together, we reported quite important findings. First of all, the overall advantage of one year of life actually for patients undergoing neoadjuvant plus radical cystectomy compared to the ones only doing radical cystectomy, that this advantage is particularly strong in young patients, and that finally, it appears that the intensification of staging or systemic therapies will probably result in better years of life lost or higher years of life lost in the future years. So based on this observation, of course, neoadjuvant chemotherapy use should reflect guideline recommendations, but we should be aware as urologists and oncologists that the highest benefit should be observed in the younger group of patients. So this concludes my presentation. Once again, I'm grateful to you today for inviting me and sharing our work, which couldn't have been possible actually without the help of my co-fellows back in Montreal that you can see here in this picture. Thanks again.
Sam Chang: Dr. Longoni, that was a fantastic presentation that... I think the key points are in that last slide, to be able and using... Obviously we have some concerns about SEER data, the limitations that you listed, but it's real world. This is what happens.
Mattia Longoni: Of course.
Sam Chang: And it gives us what we can counsel our patients. At the end of the day, if we look at neoadjuvant use, we gain a year in life, and that's very, very, I think, persuasive. I think as you showed the data by five-year blocks, you could see that the use of neoadjuvant chemotherapy has increased. And in no way are we going to get to that 100% use. We probably shouldn't. Let me focus then on that last point regarding that the advantages seem to be perhaps decreasing with better diagnostics, evaluation with MRI, et cetera. Tell me your thoughts about that decrease over time.
Mattia Longoni: Thank you, Professor. It's a good point to raise because we have discussed that while we were writing and doing the analysis. Of course we explained that by these advancements in diagnosis, also I would say better patient selection, but of course you have also to account for the use of new therapies. The neoadjuvant therapy used in this work trial, it's not the same. It's not the same anymore, of course, and that's good news, right? But I guess that's the most important thing that you can see, that you actually lose some... The years of life lost is decreasing, but the gap between radical cystectomy and neoadjuvant chemotherapy plus radical cystectomy, there is still a gap. And of course we have to say that one of the biggest limitations is that you cannot really know because the more recent years have, of course, less follow-up. So that also impacts differently from survival analysis, but it also impacts on the years of life lost.
Sam Chang: So tell us what you're doing... Now, this is a personal question. What are you doing at Karolinska? What type of research are you doing there?
Mattia Longoni: Actually, I try not to do so much research right now, actually. I prefer to focus on some really nice projects and improve my skills in the OR. So actually, I'm a clinical fellow here and working in radical cystectomy with Professor Richmond as head of research or unit. And all of the guys here are fantastic and they really know what to do, how to do it, so I'm going to steal some skills from them.
Sam Chang: Very good. Very good. Well, we look forward to your future contributions. I know at some point... I know you say you're just a resident; you're much more than that, much more than that. And the work that you've put together during your research time has been quite incredible, and we look forward to future contributions. And yet, like I said, another superstar from San Raffaele will be there as well. So thank you again, and we appreciate very much your contributions and look forward to spending some more time together in the future.
Mattia Longoni: Me too, Professor. You're too kind. But thanks again, and for sure there will be some other occasions.