Adequate BCG Therapy for Very High-Risk Non-Muscle-Invasive Bladder Cancer: A Multicenter Analysis - José Daniel Subiela Henriquez
June 17, 2024
José Daniel Subiela Henriquez presented findings from his multicenter study on BCG therapy for very high-risk non-muscle-invasive bladder cancer (NMIBC). Dr. Subiela's research evaluates the effectiveness of BCG in a group where the European Association of Urology (EAU) had recommended radical cystectomy due to high progression risks. His study, involving 640 patients over 13 years, suggests that BCG therapy provides significantly better outcomes than previously estimated by EAU guidelines, with a five-year progression-free survival rate of 80%, contrasting the EAU's predicted 44%. Despite this, Dr. Subiela cautions that BCG should not replace cystectomy for all very high-risk patients but highlights its potential as an alternative, especially for those without additional high-risk factors. His findings underscore the importance of tailored treatment approaches and the need for continuous follow-up to refine patient management strategies.
Biographies:
José Daniel Subiela Henriquez, MD, PhD, Urologist, Hospital Universitario Ramón y Cajal, Universidad e Alcalá, Madrid, Spain
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Biographies:
José Daniel Subiela Henriquez, MD, PhD, Urologist, Hospital Universitario Ramón y Cajal, Universidad e Alcalá, Madrid, Spain
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Read the Full Video Transcript
Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. Today we're going to have Dr. Jose Subiela coming to us and sharing with us the data that he has published on unlocking the potential of adequate BCG therapy in the very high-risk non-muscle-invasive bladder cancer. This is a multicenter analysis of oncologic outcomes and risk dynamics. Dr. Subiela, looking forward to hearing what you have to say.
José Daniel Subiela Henriquez: Good afternoon to all, and thank you, Dr. Kamat and UroToday for the opportunity. Without further ado... In 2021, the European Association of Urology updated risk stratification for the non-muscle invasive bladder carcinoma management. One cornerstone of this classification was the creation of the novel risk group named very high-risk group, with at least a risk of progression at five years of 20%. As a result, a novel risk group, the very high-risk group, was created with a risk of progression at five-year follow-up of 44%. Under this condition, the European Association of Urology recommends upfront radical cystectomy for all patients in the very high-risk group. But there was no data on BCG for the patient in the novel risk group because all the patients treated with BCG were excluded from the EAU21 risk groups construction.
Previous studies, one from our group and one from the group of Dr. Kamat with Niyati Lobo as the first author, showed that the EAU21 risk group overestimated the risk of patients treated with BCG. This is especially true for patients in the very high-risk group. Motivated by this, we performed this multicenter observational retrospective study, including patients classified as very high-risk group. These are the baseline features of our study. We included 640 patients in a timeframe of 13 years. Most of these were T1, all had associated CIS, 80% underwent second transurethral resection, all received adequate BCG therapy, and the median follow-up was 47 months. Sorry.
Probably this plot summarizes well our study. In purple, we found the theoretical risk of progression according to the EAU21 risk group of 44% in the patient in the very high-risk group, and in green the progression-free survival probability from our work. The probability of progression at five-year follow-up from our study was 20%. Many will agree with me that under this condition, to offer an upfront radical cystectomy for all patients in the very high-risk group probably is overtreatment.
Other analyses from our study were the high-grade recurrence risk, which is 44% at five-year follow-up, and the cancer mortality risk. Under the competing risk analysis, the cancer mortality risk from our cohort was 13% at five years of follow-up.
Additionally, in the conditional survival probability, we found that all outcomes improved over time. For example, for progression, the probabilities improve from 20% at diagnosis to 4% for all patients who remain disease-free for at least four years. Probably this information could be useful for the planning of follow-up, but further studies are needed.
In conclusion, our study does not offer enough evidence to support BCG as the first-line therapy for all patients in the very high-risk group. But the patients in the very high-risk group who receive adequate BCG therapy have a better prognosis than predicted by EAU21 risk group. Probably in this context, maintenance therapy with BCG could be an alternative to radical cystectomy in these patients. An upfront radical cystectomy may be reserved for the patient with additional risk factors not accounted for in the EAU21 risk group, such as: T1b or c substaging, lymphovascular invasion, histological subtypes, prostatic urethral invasion, residual T1 tumors in second transurethral resection, and even the patient with Lynch syndrome. Thank you very much. Thank you very much again for UroToday and Dr. Kamat.
Ashish Kamat: Thank you very much for that presentation, Jose. That was very well done. It's great that you were able to validate the findings of our publication, which you did reference earlier in your talk, because one of the things that came about when that very high-risk subgroup was defined by the EAU was a lot of people did not realize that those patients were not treated with BCG, right? So that's the natural history of the disease. And of course, when you're counseling patients, you do want to counsel them on the natural history of disease, but of course, patients are more interested in what their outcome is at a particular time point if they get treated as well. So I think our results, and of course your results now in a large multicenter validation, really help us understand the disease and counsel the patient. You had a nice conclusion slide where you show the risk factors where you would recommend a radical cystectomy. Just to clarify, those risk factors were not assessed directly in your study, were they?
José Daniel Subiela Henriquez: No. Only we have the residual T1 tumors in second transurethral resection. This is a limitation of our study because, although the database was performed to collect all this data, the data is not collected for all institutions. No conclusion can we make about this.
Ashish Kamat: And also there's a selection bias, right? Because at least at our center, if somebody has T1b disease, if they have lymphovascular invasion, if they have, say, micropapillary disease, we don't really recommend that they get BCG therapy. So it's hard for us to know how they would do with BCG other than looking at other publications that we and others have put forward where clearly, T1b, T1 on restaging, lymphovascular invasion, all those are negative prognostic factors. Do you have any sense, looking at the literature when you were writing this paper, as to which are the ideal candidates that you would recommend BCG for in that very high-risk population? Because I know you looked at the entire population, and you showed, and we showed too, that the risk of progression is relatively low, but it's still not zero, right? It's still in the 15, 20% range. So are there any clues, within your subgroup analyses, as to which patients are doing much better and which ones are leaning towards saying, "Well, you're probably going to progress. We should consider radical cystectomy sooner rather than later"?
José Daniel Subiela Henriquez: We identified that the tumor size was the only risk factor for a major risk of progression in our study, but probably we didn't identify other risk factors because the factors could be included in the stratification of the patients during the recruitment for a study.
Ashish Kamat: Right. Well, I want to thank you once again for doing this fine work, publishing it, and leading such an important effort. And just to summarize for the audience, I think it's very important that people recognize that, in patients that have very high-risk disease as defined by the EAU, or even the AUA for that matter, BCG is still a very good option, and the risk of progression with treatment is much lower than the risk of progression predicted by the calculators. So that's a very important piece of information that we have to always discuss with our patients, and it's very important for shared decision-making and health literacy of our patients of course. So once again, Jose, I want to thank you for your time and thank you for joining us.
José Daniel Subiela Henriquez: Thank you.
Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. Today we're going to have Dr. Jose Subiela coming to us and sharing with us the data that he has published on unlocking the potential of adequate BCG therapy in the very high-risk non-muscle-invasive bladder cancer. This is a multicenter analysis of oncologic outcomes and risk dynamics. Dr. Subiela, looking forward to hearing what you have to say.
José Daniel Subiela Henriquez: Good afternoon to all, and thank you, Dr. Kamat and UroToday for the opportunity. Without further ado... In 2021, the European Association of Urology updated risk stratification for the non-muscle invasive bladder carcinoma management. One cornerstone of this classification was the creation of the novel risk group named very high-risk group, with at least a risk of progression at five years of 20%. As a result, a novel risk group, the very high-risk group, was created with a risk of progression at five-year follow-up of 44%. Under this condition, the European Association of Urology recommends upfront radical cystectomy for all patients in the very high-risk group. But there was no data on BCG for the patient in the novel risk group because all the patients treated with BCG were excluded from the EAU21 risk groups construction.
Previous studies, one from our group and one from the group of Dr. Kamat with Niyati Lobo as the first author, showed that the EAU21 risk group overestimated the risk of patients treated with BCG. This is especially true for patients in the very high-risk group. Motivated by this, we performed this multicenter observational retrospective study, including patients classified as very high-risk group. These are the baseline features of our study. We included 640 patients in a timeframe of 13 years. Most of these were T1, all had associated CIS, 80% underwent second transurethral resection, all received adequate BCG therapy, and the median follow-up was 47 months. Sorry.
Probably this plot summarizes well our study. In purple, we found the theoretical risk of progression according to the EAU21 risk group of 44% in the patient in the very high-risk group, and in green the progression-free survival probability from our work. The probability of progression at five-year follow-up from our study was 20%. Many will agree with me that under this condition, to offer an upfront radical cystectomy for all patients in the very high-risk group probably is overtreatment.
Other analyses from our study were the high-grade recurrence risk, which is 44% at five-year follow-up, and the cancer mortality risk. Under the competing risk analysis, the cancer mortality risk from our cohort was 13% at five years of follow-up.
Additionally, in the conditional survival probability, we found that all outcomes improved over time. For example, for progression, the probabilities improve from 20% at diagnosis to 4% for all patients who remain disease-free for at least four years. Probably this information could be useful for the planning of follow-up, but further studies are needed.
In conclusion, our study does not offer enough evidence to support BCG as the first-line therapy for all patients in the very high-risk group. But the patients in the very high-risk group who receive adequate BCG therapy have a better prognosis than predicted by EAU21 risk group. Probably in this context, maintenance therapy with BCG could be an alternative to radical cystectomy in these patients. An upfront radical cystectomy may be reserved for the patient with additional risk factors not accounted for in the EAU21 risk group, such as: T1b or c substaging, lymphovascular invasion, histological subtypes, prostatic urethral invasion, residual T1 tumors in second transurethral resection, and even the patient with Lynch syndrome. Thank you very much. Thank you very much again for UroToday and Dr. Kamat.
Ashish Kamat: Thank you very much for that presentation, Jose. That was very well done. It's great that you were able to validate the findings of our publication, which you did reference earlier in your talk, because one of the things that came about when that very high-risk subgroup was defined by the EAU was a lot of people did not realize that those patients were not treated with BCG, right? So that's the natural history of the disease. And of course, when you're counseling patients, you do want to counsel them on the natural history of disease, but of course, patients are more interested in what their outcome is at a particular time point if they get treated as well. So I think our results, and of course your results now in a large multicenter validation, really help us understand the disease and counsel the patient. You had a nice conclusion slide where you show the risk factors where you would recommend a radical cystectomy. Just to clarify, those risk factors were not assessed directly in your study, were they?
José Daniel Subiela Henriquez: No. Only we have the residual T1 tumors in second transurethral resection. This is a limitation of our study because, although the database was performed to collect all this data, the data is not collected for all institutions. No conclusion can we make about this.
Ashish Kamat: And also there's a selection bias, right? Because at least at our center, if somebody has T1b disease, if they have lymphovascular invasion, if they have, say, micropapillary disease, we don't really recommend that they get BCG therapy. So it's hard for us to know how they would do with BCG other than looking at other publications that we and others have put forward where clearly, T1b, T1 on restaging, lymphovascular invasion, all those are negative prognostic factors. Do you have any sense, looking at the literature when you were writing this paper, as to which are the ideal candidates that you would recommend BCG for in that very high-risk population? Because I know you looked at the entire population, and you showed, and we showed too, that the risk of progression is relatively low, but it's still not zero, right? It's still in the 15, 20% range. So are there any clues, within your subgroup analyses, as to which patients are doing much better and which ones are leaning towards saying, "Well, you're probably going to progress. We should consider radical cystectomy sooner rather than later"?
José Daniel Subiela Henriquez: We identified that the tumor size was the only risk factor for a major risk of progression in our study, but probably we didn't identify other risk factors because the factors could be included in the stratification of the patients during the recruitment for a study.
Ashish Kamat: Right. Well, I want to thank you once again for doing this fine work, publishing it, and leading such an important effort. And just to summarize for the audience, I think it's very important that people recognize that, in patients that have very high-risk disease as defined by the EAU, or even the AUA for that matter, BCG is still a very good option, and the risk of progression with treatment is much lower than the risk of progression predicted by the calculators. So that's a very important piece of information that we have to always discuss with our patients, and it's very important for shared decision-making and health literacy of our patients of course. So once again, Jose, I want to thank you for your time and thank you for joining us.
José Daniel Subiela Henriquez: Thank you.