JCOG1019 Trial Examines Watchful Waiting vs BCG for High-Grade T1 Bladder Cancer - Hiroshi Kitamura
October 9, 2024
Zachary Klaassen interviews Hiroshi Kitamura about the JCOG1019 study, examining watchful waiting versus BCG therapy in high-grade T1 bladder cancer patients with no residual tumor after second TUR. Dr. Kitamura explains the trial design and key results, highlighting that watchful waiting demonstrates non-inferiority to BCG in relapse-free survival for T1 or deeper recurrence. The study shows similar overall survival and metastasis-free survival between groups, with BCG showing a slight advantage in intravesical recurrence-free survival. Dr. Kitamura discusses the implications for patient care, suggesting watchful waiting as a potential new standard for select patients, particularly older or more comorbid individuals. They explore how these findings might help address BCG shortages and guide patient counseling. Dr. Kitamura states that 90% of watchful waiting patients avoided BCG during follow-up, supporting its viability as a treatment approach.
Biographies:
Hiroshi Kitamura, MD, PhD, Professor and Chairman, Department of Urology, Faculty of Medicine, University of Toyama, Toyoma, Japan
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Hiroshi Kitamura, MD, PhD, Professor and Chairman, Department of Urology, Faculty of Medicine, University of Toyama, Toyoma, Japan
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Hiroshi Kitamura from the University of Toyama in Japan. Hiroshi, thanks very much for joining us today for this discussion.
Hiroshi Kitamura: Thank you for having me.
Zachary Klaassen: So we are going to discuss data that you presented at ESMO, really thought-provoking and interesting data from JCOG1019, where you looked at basically a randomized phase 3 study of watchful waiting versus BCG in patients with high-grade T1 but then had a T0 on the second TUR specimen. So I would love for you to pull up your slides and walk us through the background, the trial design, and the key results.
Hiroshi Kitamura: Okay. As you know, T1 bladder cancer comprises about 20% of non-muscle invasive bladder cancer. This presents a particular clinical challenge due to the aggressive biological behavior and elevated risks of recurrence and progression to muscle invasion or metastatic disease.
The TURBT followed by a second TUR and intravesical BCG has been the standard treatment of T1 bladder cancer, regardless of the pathological diagnosis on the second TUR. However, there is no evidence showing whether intravesical BCG is necessary for patients with high-grade T1 bladder cancer who have pT0 histology after second TUR.
So we conducted a randomized phase 3 trial called JCOG1019. This is the study design of JCOG1019; this is a phase 3, multi-institutional, open-label, randomized controlled trial powered for non-inferiority. The protocol addressed a clinical question regarding the standard treatment in patients who have a histopathological diagnosis of high-grade T1 bladder cancer on the initial TURBT and no residual tumor on the second TUR specimen.
Participants who underwent a TURBT and the histopathological diagnosis was high-grade T1 bladder cancer were eligible for the first registration. And then, the participants underwent a second TUR, and if they had a histopathologically proven pT0 on the second TUR, they were enrolled in the second registration. The participants were randomized in a one-to-one ratio to undergo watchful waiting or to receive intravesical BCG, eight courses every week.
The primary endpoint was relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death. This is a non-inferiority designed randomized trial.
So the statistical plan; please take a look at the bottom here. Non-inferiority was shown if the upper limit of the two-sided 90% confidence interval of the hazard ratio was less than 1.6. So we conducted the phase 3 study, including a planned sample size for randomization was 216. And finally, we obtained 263 patients. This is the primary endpoint, relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death.
As you can see, watchful waiting was non-inferior to intravesical BCG with respect to RFS. The hazard ratio was 0.69, and the upper limit was at 1.08. This was smaller than 1.6. That means that non-inferiority is statistically significant. And, as you can see, the watchful waiting arm seems to be better than the intravesical BCG in terms of relapse-free survival.
This is one of the secondary endpoints, overall survival. The hazard ratio was 0.64, and in overall survival, the watchful waiting seems to be not only non-inferior but also superior to the intravesical BCG group.
And this is the metastasis-free survival graph. The relationship between the two arms is similar to relapse-free survival and overall survival.
In contrast, in terms of intravesical recurrence-free survival including Ta or Tis intravesical recurrence, the intravesical BCG arm seems to be superior to the watchful waiting arm. The hazard ratio was 1.33, and there is no statistical significance, but the three-year intravesical recurrence-free survival of the intravesical BCG arm was 80%, and the three-year intravesical RFS of watchful waiting was 70%.
This is the safety profile of BCG treatment-related adverse events. The frequency of adverse events including fever, fatigue, hematuria, urinary frequency, and urinary tract pain was similar to that previously reported. Grade 3 anemia, urinary tract pain and renal infection, cytokine release syndrome, and vesicular dermatitis and arthritis were observed, but no deaths occurred during the protocol treatment or within 30 days of the last treatment.
In summary, watchful waiting demonstrated a statistically significant non-inferiority to intravesical BCG in relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death in patients with bladder cancer with high-grade pT1 at the initial TURBT and pT0 at second TUR.
Overall survival and metastasis-free survival with bladder preservation were similar in both groups. Intravesical BCG tended to show better intravesical relapse-free survival than did watchful waiting. The safety profile of watchful waiting was better than that of intravesical BCG.
In conclusion, the results support watchful waiting as a potential new standard of care for patients with high-grade T1 bladder cancer without residual tumors at the second TUR.
Thank you for your attention.
Zachary Klaassen: Thank you so much, Hiroshi. That was fantastic and really, really thought-provoking data. So congratulations on the data and the ESMO presentation.
So just a couple of discussion questions. My first one is that across the globe, especially in parts of the United States, we have had prolonged BCG shortages. Would you say that this data sort of gives us a bit of an idea of maybe patients we can target versus maybe withhold BCG?
Hiroshi Kitamura: We focused on the survival benefit of patients with high-grade T1 bladder cancer. The big event for them is cancer death and metastasis and radical cystectomy. From such a point of view, we strongly recommend watchful waiting if the second TUR specimen shows no residual tumor. But I think in some cases, in some patients who want to avoid Ta or Tis intravesical recurrence—in such cases, we still recommend intravesical BCG if the second TUR specimen shows no residual tumor.
Zachary Klaassen: Yeah, no, that's a good answer. When I look at the patients that may be best fit for watchful waiting, perhaps maybe they are the more comorbid patients—the patients that are going to have difficulty getting through the therapy.
How are you counseling your patients with regards to this data? Are you looking for the older, more comorbid patients for watchful waiting? Maybe the younger ones you're still treating? How are you counseling your patients based off of this data?
Hiroshi Kitamura: Oh yes, the age and the comorbidity and performance status—we have to totally think about everything. I personally think that in elderly patients, especially 80 years old or older, and I personally think 70 years also, watchful waiting is strongly recommended. I think in patients in their 50s, and in some cases 60s, we have to offer intravesical BCG with our data, and we have to discuss with patients the optimal treatment for them.
Zachary Klaassen: Yeah, absolutely. It's been a great discussion. I have enjoyed it. If you could maybe just provide a couple of take-home messages for our listeners today.
Hiroshi Kitamura: Yes, thank you. Finally, I would say 13 of 130 patients in the watchful waiting arm received intravesical BCG as subsequent therapy—that is 10%. So in other words, 90% of patients in the watchful waiting arm were able to avoid intravesical BCG during a median seven years follow-up. So I believe that watchful waiting can be a standard of care for patients with high-grade T1 bladder cancer whose second TUR specimens show no residual tumor.
Zachary Klaassen: Fantastic. Very well done. Thanks so much for joining us, Hiroshi, and congratulations again on JCOG1019.
Hiroshi Kitamura: Thank you so much. Thank you, too.
Zachary Klaassen: Thank you.
Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Hiroshi Kitamura from the University of Toyama in Japan. Hiroshi, thanks very much for joining us today for this discussion.
Hiroshi Kitamura: Thank you for having me.
Zachary Klaassen: So we are going to discuss data that you presented at ESMO, really thought-provoking and interesting data from JCOG1019, where you looked at basically a randomized phase 3 study of watchful waiting versus BCG in patients with high-grade T1 but then had a T0 on the second TUR specimen. So I would love for you to pull up your slides and walk us through the background, the trial design, and the key results.
Hiroshi Kitamura: Okay. As you know, T1 bladder cancer comprises about 20% of non-muscle invasive bladder cancer. This presents a particular clinical challenge due to the aggressive biological behavior and elevated risks of recurrence and progression to muscle invasion or metastatic disease.
The TURBT followed by a second TUR and intravesical BCG has been the standard treatment of T1 bladder cancer, regardless of the pathological diagnosis on the second TUR. However, there is no evidence showing whether intravesical BCG is necessary for patients with high-grade T1 bladder cancer who have pT0 histology after second TUR.
So we conducted a randomized phase 3 trial called JCOG1019. This is the study design of JCOG1019; this is a phase 3, multi-institutional, open-label, randomized controlled trial powered for non-inferiority. The protocol addressed a clinical question regarding the standard treatment in patients who have a histopathological diagnosis of high-grade T1 bladder cancer on the initial TURBT and no residual tumor on the second TUR specimen.
Participants who underwent a TURBT and the histopathological diagnosis was high-grade T1 bladder cancer were eligible for the first registration. And then, the participants underwent a second TUR, and if they had a histopathologically proven pT0 on the second TUR, they were enrolled in the second registration. The participants were randomized in a one-to-one ratio to undergo watchful waiting or to receive intravesical BCG, eight courses every week.
The primary endpoint was relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death. This is a non-inferiority designed randomized trial.
So the statistical plan; please take a look at the bottom here. Non-inferiority was shown if the upper limit of the two-sided 90% confidence interval of the hazard ratio was less than 1.6. So we conducted the phase 3 study, including a planned sample size for randomization was 216. And finally, we obtained 263 patients. This is the primary endpoint, relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death.
As you can see, watchful waiting was non-inferior to intravesical BCG with respect to RFS. The hazard ratio was 0.69, and the upper limit was at 1.08. This was smaller than 1.6. That means that non-inferiority is statistically significant. And, as you can see, the watchful waiting arm seems to be better than the intravesical BCG in terms of relapse-free survival.
This is one of the secondary endpoints, overall survival. The hazard ratio was 0.64, and in overall survival, the watchful waiting seems to be not only non-inferior but also superior to the intravesical BCG group.
And this is the metastasis-free survival graph. The relationship between the two arms is similar to relapse-free survival and overall survival.
In contrast, in terms of intravesical recurrence-free survival including Ta or Tis intravesical recurrence, the intravesical BCG arm seems to be superior to the watchful waiting arm. The hazard ratio was 1.33, and there is no statistical significance, but the three-year intravesical recurrence-free survival of the intravesical BCG arm was 80%, and the three-year intravesical RFS of watchful waiting was 70%.
This is the safety profile of BCG treatment-related adverse events. The frequency of adverse events including fever, fatigue, hematuria, urinary frequency, and urinary tract pain was similar to that previously reported. Grade 3 anemia, urinary tract pain and renal infection, cytokine release syndrome, and vesicular dermatitis and arthritis were observed, but no deaths occurred during the protocol treatment or within 30 days of the last treatment.
In summary, watchful waiting demonstrated a statistically significant non-inferiority to intravesical BCG in relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence or death in patients with bladder cancer with high-grade pT1 at the initial TURBT and pT0 at second TUR.
Overall survival and metastasis-free survival with bladder preservation were similar in both groups. Intravesical BCG tended to show better intravesical relapse-free survival than did watchful waiting. The safety profile of watchful waiting was better than that of intravesical BCG.
In conclusion, the results support watchful waiting as a potential new standard of care for patients with high-grade T1 bladder cancer without residual tumors at the second TUR.
Thank you for your attention.
Zachary Klaassen: Thank you so much, Hiroshi. That was fantastic and really, really thought-provoking data. So congratulations on the data and the ESMO presentation.
So just a couple of discussion questions. My first one is that across the globe, especially in parts of the United States, we have had prolonged BCG shortages. Would you say that this data sort of gives us a bit of an idea of maybe patients we can target versus maybe withhold BCG?
Hiroshi Kitamura: We focused on the survival benefit of patients with high-grade T1 bladder cancer. The big event for them is cancer death and metastasis and radical cystectomy. From such a point of view, we strongly recommend watchful waiting if the second TUR specimen shows no residual tumor. But I think in some cases, in some patients who want to avoid Ta or Tis intravesical recurrence—in such cases, we still recommend intravesical BCG if the second TUR specimen shows no residual tumor.
Zachary Klaassen: Yeah, no, that's a good answer. When I look at the patients that may be best fit for watchful waiting, perhaps maybe they are the more comorbid patients—the patients that are going to have difficulty getting through the therapy.
How are you counseling your patients with regards to this data? Are you looking for the older, more comorbid patients for watchful waiting? Maybe the younger ones you're still treating? How are you counseling your patients based off of this data?
Hiroshi Kitamura: Oh yes, the age and the comorbidity and performance status—we have to totally think about everything. I personally think that in elderly patients, especially 80 years old or older, and I personally think 70 years also, watchful waiting is strongly recommended. I think in patients in their 50s, and in some cases 60s, we have to offer intravesical BCG with our data, and we have to discuss with patients the optimal treatment for them.
Zachary Klaassen: Yeah, absolutely. It's been a great discussion. I have enjoyed it. If you could maybe just provide a couple of take-home messages for our listeners today.
Hiroshi Kitamura: Yes, thank you. Finally, I would say 13 of 130 patients in the watchful waiting arm received intravesical BCG as subsequent therapy—that is 10%. So in other words, 90% of patients in the watchful waiting arm were able to avoid intravesical BCG during a median seven years follow-up. So I believe that watchful waiting can be a standard of care for patients with high-grade T1 bladder cancer whose second TUR specimens show no residual tumor.
Zachary Klaassen: Fantastic. Very well done. Thanks so much for joining us, Hiroshi, and congratulations again on JCOG1019.
Hiroshi Kitamura: Thank you so much. Thank you, too.
Zachary Klaassen: Thank you.