Beyond Clinical Trials: Real-World Success with Trimodality Therapy in Bladder Cancer - Sean Sachdev & Praneet Polineni
June 30, 2021
Sean Sachdev and Praneet Polineni delve into their paper on trimodality therapy for muscle-invasive bladder cancer. Dr. Sachdev highlights the growing evidence supporting trimodality therapy as a viable option, especially for older patients who may not be good candidates for surgical intervention. Dr. Polineni offers details on their study, which involved 32 patients with a mean age of 73. The treatment outcomes were promising, even for a cohort with advanced disease and other risk factors. The talk also touches upon the SWOG/NRG 1806 trial, which aims to explore the efficacy of chemoradiation with or without atezolizumab. Both guests agree that the study offers real-world insights into the effectiveness of bladder preservation therapies, thus adding to the growing body of literature supporting this approach for muscle-invasive bladder cancer.
Biographies:
Sean Sachdev, MD, Radiation Oncologist, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Praneet Polineni, BA, Fourth Year Medical Student, Northwestern University Feinberg School of Medicine
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.
Biographies:
Sean Sachdev, MD, Radiation Oncologist, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Praneet Polineni, BA, Fourth Year Medical Student, Northwestern University Feinberg School of Medicine
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.
Read the Full Video Transcript
Alicia Morgans: Hi, my name is Alicia Morgans. I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University. I'm so excited to talk today with a good friend and colleague, Dr. Sean Sachdev, an Assistant Professor of Radiation Oncology at Northwestern University, as well as fourth-year medical student Praneet Polineni, who is here with us today, both of them, to talk with us a little bit about their paper recently published in Advances in Radiation Oncology, describing their response rates, disease control rates, for patients treated with trimodality therapy for muscle-invasive bladder cancer, all treated here at Northwestern University. Thank you both for being here with me today.
Sean Sachdev: Well, thank you so much for having us, Alicia.
Alicia Morgans: You're welcome.
Praneet Polineni: Thank you very much.
Alicia Morgans: Wonderful. So, Dr. Sachdev, why don't you start off-
Sean Sachdev: Sure.
Alicia Morgans: ... by just telling us a little bit about the importance of trimodality, or chemoradiation therapy approaches, in muscle-invasive bladder cancer?
Sean Sachdev: Absolutely. There is now a growing body of data that supports more utilization of trimodality therapy, bladder preservation therapy, for patients who have muscle-invasive bladder cancer. And frankly, there are also some very good data that show that, especially in older patients who are not good candidates for surgical therapy, with a radical cystectomy, trimodality and bladder preservation therapy, which are synonymous, is somewhat underutilized. So we decided to go back and take a deep dive, and look at our institutional outcomes for patients who are largely treated in a more or less uniform manner, spanning many years, all diagnosed with muscle-invasive bladder cancer, and oftentimes patients who would typically not be deemed great candidates for the therapy, because they have very advanced disease, or they have incomplete risk protection.
We basically reported on our results, and we found that even when a suboptimal cohort of patients was treated with trimodality therapy, we actually had very good results. And these were largely in line with what has been reported in the literature before, including a pooled cooperative group analysis of [inaudible] patients, as well as a large single-institution series from Harvard, the group that is most well-known for pursuing this technique, as our results were largely comparable. Our hope was to add to this growing body of literature, in hopes of continuing to support this being a viable modality of important organ preservation.
Alicia Morgans: Well, thank you for setting that up, and also, for really acknowledging that this is an important treatment modality, but really also emphasizing that in the US at least, there has been sort of a subset of institutions that have owned trimodality therapy, or at least have been pioneering, in terms of defining how we proceed with these treatments. What I think is so special and important about this population is that yes, of course, we are at an academic institution, and so already, of course, have a leg up in that way, in terms of ensuring that patients are receiving the sort of topmost understanding of radiation therapy delivery. However, it ultimately is a real-world application of these treatment approaches. Despite that, you really seemed to find that you had great effects in terms of disease control.
So, Praneet, why don't we move to you, and just really have you explain to us, what exactly did you do in this study? How did you follow these patients? What treatments did they receive, and who were these patients? And then, of course, we can move on to the results in terms of disease control.
Praneet Polineni: We had 32 patients here at Northwestern, who were treated with trimodality therapy. They were at a mean age of 73 years old. For the patient, in tumor characteristics, 22% of the patients in our study had greater than T2 disease, so T3 or T4, and 25% had hydronephrosis at the time of diagnosis.
For the treatment characteristics, 53% of the patients received a visibly complete TURBT, and 37% actually received neoadjuvant chemo, with cisplatin being the most commonly used agent.
In terms of the outcomes, we were able to follow them for a median of 19 months. And for the patients who had survived, we had a median of about 30, and overall survival at five years was 61%, with bladder preserved disease-free survival, at 60% at five years. Also, the salvage cystectomy rates at five years were 9%. Four patients did have locally invasive recurrences, and two of those patients underwent salvage radical cystectomy.
Overall, we were unable to find any particular disease, or patient characteristics, that were associated significantly with recurrence or survival. These results were, as Dr. Sachdev mentioned, in line with other studies that have been done, despite the fact that some of these patients had more comorbidities, and had more significant disease factors, than in other studies.
Alicia Morgans: Great. Thank you so much for sharing that. And Dr. Sachdev, I'd love to hear your thoughts. I do think it's important and interesting in this real-world cohort, that there were a number of patients who actually had higher T scores.
Sean Sachdev: Yeah.
Alicia Morgans: Figuring that they had larger tumors, there were some patients, a small portion, but there were some, who had hydronephrosis.
Sean Sachdev: Yep.
Alicia Morgans: And also some patients who had neoadjuvant chemo, which is not necessarily the approach we would plan if we were planning from the beginning, but there are some patients who undergo neoadjuvant chemotherapy before planned cystectomy and then plans change, and then they end up having chemoradiation. So I'd love to hear your thoughts on the risk of this particular cohort, as it compares to potentially, clinical trial cohorts, where everyone had to really follow the schema defined in the protocol for those clinical trials, and how these disease control rates really map onto those, given these higher risk features.
Sean Sachdev: Because historically, this has not been a very well-utilized modality. We do . not not have a lot of data from multi-institutional studies, or prospective studies, that have matured. So a lot of our understanding of how to do this well has largely come from the Harvard group, and they have done a very nice job maintaining very good follow-up with a large cohort of patients, where they've shown in subsequent studies, who are the ideal candidates. And typically, and now this is reflected in more modern NCTN trials, where we have a trial open now, which is the largest Phase III trial that has ever been conducted, looking at bladder preservation therapy. In specific, Specifically, between SWOG and NRG, we are proud at Northwestern to be the third leading accruer nationally. But a lot of the criteria for the patients that can go on the trial have been shaped by the Harvard data, with mature follow-up, and those data include taking patients who do not have hydronephrosis, or at most, unifocal, or unilateral, I should say, hydronephrosis, patients who don't have T3 or T4 disease, and patients who have a visibly complete TURBT.
But in real life, exactly as you mentioned, oftentimes you'll have patients who are ideal candidates but are not good candidates for a radical cystectomy, because they are too high of surgical surgical risk, for example. Obviously, for those patients, we will offer the treatment and we will treat them. What we found in our data was that even though we have a good number of patients who are ideal candidates, nearly a quarter had T3 or T4 disease. Which, for example, if you have T4 disease, per the recent SWOG and NRG trials, if I recall correctly, that is an exclusion criterion. So we have patients who had much more advanced diseases disease than what would be ideal for this treatment. We had patients who had hydronephrosis and incomplete TURBTs, and they still did very well.
Alicia Morgans: I agree with that. That's why I love these real-world cohorts because I do think they reflect the challenges that we face in everyday treatment. I'd love to hear your thoughts, just before we wrap up, on SWOG 1806, because I do think that this is a trial we should ensure that folks are aware of and that people are considering enrolling on. This is a chemoradiation trial that is quite flexible on its enrollment criteria and is looking, I think, at chemoradiation with, or without atezolizumab. What are your thoughts on that study, Dr. Sachdev?
Sean Sachdev: I think it is a very important study, which is why we are enthusiastic and happy at Northwestern, to try to get as many patients on. Just as you mentioned, this is really a trial looking at chemoradiation using established standard practices from the RTOG, and from the Harvard group, plus or minus infusional immunotherapy where they chose atezolizumab. Whether or not we find that the atezolizumab helped in terms of disease control outcomes, it's still an important study, because it is a large prospective Phase III trial, which has a lot of important endpoints, including patient-reported outcomes, as well as a lot of key translational scientific endpoints. I think regardless of the conclusion as to whether or not it's helpful to add infusional immunotherapy to this treatment, I think these will be just valuable data, nonetheless.
Alicia Morgans: I would agree with you. I think that it is going to be so important too because this is a trial that actually expands chemoradiation across so many academic and community sites throughout the whole country. I would be remiss if I called it just a SWOG study, as you said, it's an NRG study as well, so I do want to give credit where credit is due. It's really a collaboration between those two really phenomenal cooperative groups, and actually, Alliance and ECOG are very heavily engaged in this, as well. It's really everybody coming together to understand how this approach to treating muscle-invasive bladder cancer can be really deployed on a larger scale, in a way that allows people to maintain their bladder. So really an exciting study.
So now let's wrap up. And Praneet, I'd love to hear from you. What are your final words, or a summary of your message from this paper that you've recently published?
Praneet Polineni: Yeah. I think the take-home message for me would be that it's exciting to see good results with patients who might have been at a higher risk and that this treatment modality could be beneficial in making sure that patients receive curative treatment for their bladder cancer, but also are able to preserve native bladder function.
Alicia Morgans: Fantastic. And Dr. Sachdev, what is your final word?
Sean Sachdev: I think that was well put. We were very happy to show that for a cohort of patients treated largely and informally and uniformly, we can add to the growing body of data that supports organ preservation. And if we look historically, there are other disease science sites where previously, organ preservation was not a routine part of the standard treatment conversation. Cancers, such as anal cancer, or cancers of the larynx, are now uniformly treated with a goal for organ preservation. If one is able to pursue a curative treatment while retaining their bladder, I think that is a win for patients, and that is a win for physicians who can deliver that treatment. We're just really happy that we can add to that body of data, which will be further enhanced in the future, ideally from the results of the SWOG/NRG 1806 trial.
Alicia Morgans: Wonderful. Well, thank you both so much for your time for putting together this real-world cohort, so that we understand how well chemoradiation can work, even in a higher risk population. As we do offer this bladder-sparing approach to our patients, it's meaningful to them and certainly meaningful to all of us. I really commend you for your efforts in this regard.
Thank you so much for your time today as well, in explaining it.
Praneet Polineni: Thank you.
Sean Sachdev: Thank you for having us.
Alicia Morgans: Hi, my name is Alicia Morgans. I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University. I'm so excited to talk today with a good friend and colleague, Dr. Sean Sachdev, an Assistant Professor of Radiation Oncology at Northwestern University, as well as fourth-year medical student Praneet Polineni, who is here with us today, both of them, to talk with us a little bit about their paper recently published in Advances in Radiation Oncology, describing their response rates, disease control rates, for patients treated with trimodality therapy for muscle-invasive bladder cancer, all treated here at Northwestern University. Thank you both for being here with me today.
Sean Sachdev: Well, thank you so much for having us, Alicia.
Alicia Morgans: You're welcome.
Praneet Polineni: Thank you very much.
Alicia Morgans: Wonderful. So, Dr. Sachdev, why don't you start off-
Sean Sachdev: Sure.
Alicia Morgans: ... by just telling us a little bit about the importance of trimodality, or chemoradiation therapy approaches, in muscle-invasive bladder cancer?
Sean Sachdev: Absolutely. There is now a growing body of data that supports more utilization of trimodality therapy, bladder preservation therapy, for patients who have muscle-invasive bladder cancer. And frankly, there are also some very good data that show that, especially in older patients who are not good candidates for surgical therapy, with a radical cystectomy, trimodality and bladder preservation therapy, which are synonymous, is somewhat underutilized. So we decided to go back and take a deep dive, and look at our institutional outcomes for patients who are largely treated in a more or less uniform manner, spanning many years, all diagnosed with muscle-invasive bladder cancer, and oftentimes patients who would typically not be deemed great candidates for the therapy, because they have very advanced disease, or they have incomplete risk protection.
We basically reported on our results, and we found that even when a suboptimal cohort of patients was treated with trimodality therapy, we actually had very good results. And these were largely in line with what has been reported in the literature before, including a pooled cooperative group analysis of [inaudible] patients, as well as a large single-institution series from Harvard, the group that is most well-known for pursuing this technique, as our results were largely comparable. Our hope was to add to this growing body of literature, in hopes of continuing to support this being a viable modality of important organ preservation.
Alicia Morgans: Well, thank you for setting that up, and also, for really acknowledging that this is an important treatment modality, but really also emphasizing that in the US at least, there has been sort of a subset of institutions that have owned trimodality therapy, or at least have been pioneering, in terms of defining how we proceed with these treatments. What I think is so special and important about this population is that yes, of course, we are at an academic institution, and so already, of course, have a leg up in that way, in terms of ensuring that patients are receiving the sort of topmost understanding of radiation therapy delivery. However, it ultimately is a real-world application of these treatment approaches. Despite that, you really seemed to find that you had great effects in terms of disease control.
So, Praneet, why don't we move to you, and just really have you explain to us, what exactly did you do in this study? How did you follow these patients? What treatments did they receive, and who were these patients? And then, of course, we can move on to the results in terms of disease control.
Praneet Polineni: We had 32 patients here at Northwestern, who were treated with trimodality therapy. They were at a mean age of 73 years old. For the patient, in tumor characteristics, 22% of the patients in our study had greater than T2 disease, so T3 or T4, and 25% had hydronephrosis at the time of diagnosis.
For the treatment characteristics, 53% of the patients received a visibly complete TURBT, and 37% actually received neoadjuvant chemo, with cisplatin being the most commonly used agent.
In terms of the outcomes, we were able to follow them for a median of 19 months. And for the patients who had survived, we had a median of about 30, and overall survival at five years was 61%, with bladder preserved disease-free survival, at 60% at five years. Also, the salvage cystectomy rates at five years were 9%. Four patients did have locally invasive recurrences, and two of those patients underwent salvage radical cystectomy.
Overall, we were unable to find any particular disease, or patient characteristics, that were associated significantly with recurrence or survival. These results were, as Dr. Sachdev mentioned, in line with other studies that have been done, despite the fact that some of these patients had more comorbidities, and had more significant disease factors, than in other studies.
Alicia Morgans: Great. Thank you so much for sharing that. And Dr. Sachdev, I'd love to hear your thoughts. I do think it's important and interesting in this real-world cohort, that there were a number of patients who actually had higher T scores.
Sean Sachdev: Yeah.
Alicia Morgans: Figuring that they had larger tumors, there were some patients, a small portion, but there were some, who had hydronephrosis.
Sean Sachdev: Yep.
Alicia Morgans: And also some patients who had neoadjuvant chemo, which is not necessarily the approach we would plan if we were planning from the beginning, but there are some patients who undergo neoadjuvant chemotherapy before planned cystectomy and then plans change, and then they end up having chemoradiation. So I'd love to hear your thoughts on the risk of this particular cohort, as it compares to potentially, clinical trial cohorts, where everyone had to really follow the schema defined in the protocol for those clinical trials, and how these disease control rates really map onto those, given these higher risk features.
Sean Sachdev: Because historically, this has not been a very well-utilized modality. We do . not not have a lot of data from multi-institutional studies, or prospective studies, that have matured. So a lot of our understanding of how to do this well has largely come from the Harvard group, and they have done a very nice job maintaining very good follow-up with a large cohort of patients, where they've shown in subsequent studies, who are the ideal candidates. And typically, and now this is reflected in more modern NCTN trials, where we have a trial open now, which is the largest Phase III trial that has ever been conducted, looking at bladder preservation therapy. In specific, Specifically, between SWOG and NRG, we are proud at Northwestern to be the third leading accruer nationally. But a lot of the criteria for the patients that can go on the trial have been shaped by the Harvard data, with mature follow-up, and those data include taking patients who do not have hydronephrosis, or at most, unifocal, or unilateral, I should say, hydronephrosis, patients who don't have T3 or T4 disease, and patients who have a visibly complete TURBT.
But in real life, exactly as you mentioned, oftentimes you'll have patients who are ideal candidates but are not good candidates for a radical cystectomy, because they are too high of surgical surgical risk, for example. Obviously, for those patients, we will offer the treatment and we will treat them. What we found in our data was that even though we have a good number of patients who are ideal candidates, nearly a quarter had T3 or T4 disease. Which, for example, if you have T4 disease, per the recent SWOG and NRG trials, if I recall correctly, that is an exclusion criterion. So we have patients who had much more advanced diseases disease than what would be ideal for this treatment. We had patients who had hydronephrosis and incomplete TURBTs, and they still did very well.
Alicia Morgans: I agree with that. That's why I love these real-world cohorts because I do think they reflect the challenges that we face in everyday treatment. I'd love to hear your thoughts, just before we wrap up, on SWOG 1806, because I do think that this is a trial we should ensure that folks are aware of and that people are considering enrolling on. This is a chemoradiation trial that is quite flexible on its enrollment criteria and is looking, I think, at chemoradiation with, or without atezolizumab. What are your thoughts on that study, Dr. Sachdev?
Sean Sachdev: I think it is a very important study, which is why we are enthusiastic and happy at Northwestern, to try to get as many patients on. Just as you mentioned, this is really a trial looking at chemoradiation using established standard practices from the RTOG, and from the Harvard group, plus or minus infusional immunotherapy where they chose atezolizumab. Whether or not we find that the atezolizumab helped in terms of disease control outcomes, it's still an important study, because it is a large prospective Phase III trial, which has a lot of important endpoints, including patient-reported outcomes, as well as a lot of key translational scientific endpoints. I think regardless of the conclusion as to whether or not it's helpful to add infusional immunotherapy to this treatment, I think these will be just valuable data, nonetheless.
Alicia Morgans: I would agree with you. I think that it is going to be so important too because this is a trial that actually expands chemoradiation across so many academic and community sites throughout the whole country. I would be remiss if I called it just a SWOG study, as you said, it's an NRG study as well, so I do want to give credit where credit is due. It's really a collaboration between those two really phenomenal cooperative groups, and actually, Alliance and ECOG are very heavily engaged in this, as well. It's really everybody coming together to understand how this approach to treating muscle-invasive bladder cancer can be really deployed on a larger scale, in a way that allows people to maintain their bladder. So really an exciting study.
So now let's wrap up. And Praneet, I'd love to hear from you. What are your final words, or a summary of your message from this paper that you've recently published?
Praneet Polineni: Yeah. I think the take-home message for me would be that it's exciting to see good results with patients who might have been at a higher risk and that this treatment modality could be beneficial in making sure that patients receive curative treatment for their bladder cancer, but also are able to preserve native bladder function.
Alicia Morgans: Fantastic. And Dr. Sachdev, what is your final word?
Sean Sachdev: I think that was well put. We were very happy to show that for a cohort of patients treated largely and informally and uniformly, we can add to the growing body of data that supports organ preservation. And if we look historically, there are other disease science sites where previously, organ preservation was not a routine part of the standard treatment conversation. Cancers, such as anal cancer, or cancers of the larynx, are now uniformly treated with a goal for organ preservation. If one is able to pursue a curative treatment while retaining their bladder, I think that is a win for patients, and that is a win for physicians who can deliver that treatment. We're just really happy that we can add to that body of data, which will be further enhanced in the future, ideally from the results of the SWOG/NRG 1806 trial.
Alicia Morgans: Wonderful. Well, thank you both so much for your time for putting together this real-world cohort, so that we understand how well chemoradiation can work, even in a higher risk population. As we do offer this bladder-sparing approach to our patients, it's meaningful to them and certainly meaningful to all of us. I really commend you for your efforts in this regard.
Thank you so much for your time today as well, in explaining it.
Praneet Polineni: Thank you.
Sean Sachdev: Thank you for having us.