Paul Crispen, MD, discusses the Bladder Preservation program at Uf Health Shands Hospital. He examines current indications for radical cycstectomy when treating bladder cancer. He helps us to understand the current indications for radical cycstectomy when treating bladder cancer.
He defines BCG refractory disease and treatment options outside of radical cystectomy for BCG refractory disease, and very importantly he shares patient and tumor characteristics that are associated with improved outcomes.
Selected Podcast
Bladder Preservation Program
Featuring:
At University of Florida Health, he is the associate chair of clinical affairs and an associate professor of urology. Dr. Crispen specializes in the treatment of cancers involving the kidney, bladder, testis and penis. His clinical interests focus on the surgical management of renal and bladder cancer, including minimally invasive techniques. He has extensive experience with bladder removal surgery and urinary diversion. While Dr. Crispen’s practice focuses on the surgical management of urologic malignancies, he places emphasis on multidisciplinary cancer care involving medical and radiation oncologists.
His research focuses on improving the evaluation and treatment of patients with urologic malignancies. Dr. Crispen is an advocate for enrollment of patients in clinical trials to enhance their own care, in addition to providing essential information for prospective patients who may benefit from such treatment in the future.
Dr. Crispen is an active member of the UF Health Cancer Center, and serves as the research leader for the Genitourinary Disease Site Group as well as chairman of the Scientific Review and Monitoring Committee.
Paul Crispen, MD
Paul Crispen, MD, is board-certified in urology. He earned his medical degree and completed his urology residency at Temple University School of Medicine in Philadelphia and completed his fellowship in urologic oncology at the Mayo Clinic in Rochester.At University of Florida Health, he is the associate chair of clinical affairs and an associate professor of urology. Dr. Crispen specializes in the treatment of cancers involving the kidney, bladder, testis and penis. His clinical interests focus on the surgical management of renal and bladder cancer, including minimally invasive techniques. He has extensive experience with bladder removal surgery and urinary diversion. While Dr. Crispen’s practice focuses on the surgical management of urologic malignancies, he places emphasis on multidisciplinary cancer care involving medical and radiation oncologists.
His research focuses on improving the evaluation and treatment of patients with urologic malignancies. Dr. Crispen is an advocate for enrollment of patients in clinical trials to enhance their own care, in addition to providing essential information for prospective patients who may benefit from such treatment in the future.
Dr. Crispen is an active member of the UF Health Cancer Center, and serves as the research leader for the Genitourinary Disease Site Group as well as chairman of the Scientific Review and Monitoring Committee.
Transcription:
The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of .25 AMA PRA category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome. I’m Melanie Cole and today we’re talking about bladder preservation. We’re examining current indications for radical cystectomy when treating bladder cancer. We’re going to discuss BCG refractory disease and treatment options outside of radical cystectomy and patient and tumor characteristics that are associated with improved outcomes. Today with me, is Dr. Paul Crispen. He's an Associate Professor of Urologic Surgical Oncology at the University of Florida and he practices at UF Health Shands Hospital in Gainesville. Dr. Crispen, it’s a pleasure to have you join us. Please let’s start with the prevalence of bladder cancer and the incidence, the burden; tell us a little bit about this particular type of cancer.
Paul Crispen, MD (Guest): Bladder cancer is very prevalent in the United States. It’s the fourth most common malignancy in males and it’s in the top ten in females in our area around UF Health Urology. So, we have a lot of interest in this disease and would like to do a lot more better to improve the outcomes. The average age of patients that are diagnosed currently is 73 years old in the state of Florida. And there are going to be about 80,000 new cases of bladder cancer throughout the year in the United States.
Now when patients, when we first diagnose them with bladder cancer, the majority are going to have localized disease or stage one disease and then the other 30 to 40% of patients are going to have more locally advanced or even metastatic disease based upon their presentation.
Host: Well thank you for opening with that Dr. Crispen. So, help us to understand the current indications for radical cystectomy when treating bladder cancer and some of the outcomes associated with neoadjuvant chemotherapy.
Dr. Crispen: There are two main groups of patients who have indications to undergo bladder removal surgery. The first of which, are patients who have stage one bladder cancer that have not responded to standard therapy and that standard therapy is BCG in the United States. And those patients, the reason we move to cystectomy is really they have poor treatment options once we see that BCG is ineffective. And so, when we look at the medications or the current therapies beyond BCG currently, they are very limited with most having less than a 20% success rate at one year, thus a lot of these stage one patients will be offered cystectomy immediately when we consider them BCG refractory.
The second population of patients which are commonly recommended to undergo bladder removal surgery or cystectomy are those who are presenting with stage two and three disease. And that’s defined as patients where the cancer is invading into the deep musculature of the bladder or just going into the fat around the bladder and can be also in the lymph nodes in the pelvis.
For patients who have metastatic disease, we do not typically recommend bladder removal surgery. Now, with these patients, we expect the long term outcomes in patients with the stage one indications or the BCG refractory indications to do very well long term in terms of survival and we’d expect a high cure rate associated with those patients with the bladder removal surgery. Unfortunately, in the patients with stage two and three disease; those patients have a potentially deadly cancer where most patients who undergo even maximal therapy may not live beyond five years.
And that brings us to your question of neoadjuvant chemotherapy. We do know that if we give patients chemotherapy, usually it’s about three to four months’ worth before their surgery, they will have improved survival compared to patients who do not undergo chemotherapy. This improvement in survival can be quite dramatic. If you look at some of the clinical trials that evaluated this, if a patient on average would have just the bladder removal surgery alone; their average life expectancy would be about four years. If they get chemotherapy first, that could extend their life expectancy by about one and a half to two years. And so that’s the real important piece about neoadjuvant chemotherapy and when we like to give it while we can with our medical oncologists because we know patients will do better in the long run. It’s more treatment up front, however, I think the outcomes justify it.
Now with the neoadjuvant chemotherapy, the patients who do the best, are the ones when we take their bladder out after the chemotherapy; that they have no residual disease left in their bladder. And that’s something we have to be upfront with with patients right away. We have to prepare them to know we could take out their bladder and then they go – when we get the pathology report back, there’s no evidence of cancer, and that will often lead to patients saying well why did you need to take my bladder out if we got rid of it with the chemotherapy?
That’s how well the neoadjuvant chemotherapy can work. And that will happen in about 30 to 40% of patients who receive neoadjuvant chemotherapy prior to cystectomy.
Host: Wow that is so interesting Dr. Crispen. So, then based on what you just said, tell us about bladder preservation. When is this indicated or contraindicated? And tell us about the cancer-free and overall survival of patients in these populations.
Dr. Crispen: Certainly and again, I’ll start with the two separate populations. The BCG refractory stage one patients, then move on to the muscle invasive cancer patients. And so, for the stage one patients, we would like to avoid the bladder removal surgery as much as we can because we know that bladder removal is extremely complicated both short term and long term. And so, some of those immediate complications would be bleeding, infection, high 30 day readmission rates and it can also have very long term complications as well impacting patient’s quality of life. Some patients can have recurrent urinary tract infections, have a tremendous impact on their sexual function and their ability to work.
And so, when we look at all of these things when we talk to patients, it’s a really big deal. Especially if they have the BCG refractory stage one disease. And so for what it means in those patients, bladder preservation therapy would be discovering new medications or new techniques to replace BCG and to replace cystectomy all together. And that can be putting the medications directly into the bladder or putting medications into the vein where they go systemically. But again, as I pointed out earlier, these current medications are very limited with a low likelihood of success, however, they can be used to preserve the bladder in patients with this low stage disease. However, unfortunately, they are just not that successful at this time.
In regard to muscle invasive bladder cancer, there are several different options for those patients for bladder preservation. Those would include something called trimodal therapy where we combine maximal endoscopic resection and then concomitant chemotherapy and radiation therapy which is given over a six week period. And that’s probably the best form of bladder preservation therapy we have.
Other options would include maximal endoscopic resection, or chemotherapy alone.
Host: Well thank you for that explanation. So, as we’re talking about radical cystectomy, why is this one of the most challenging procedures performed by urologic surgeons and does it carry with it, significant risks of complications, hospital readmissions, things like that?
Dr. Crispen: Yes, absolutely. And that’s why I always tell my patients when counseling them about bladder removal surgery or cystectomy, that it’s a surgery that I do often, and I enjoy doing but only do it when it’s absolutely indicated because it has such a tremendous impact on a patient’s life. Now, the surgery is complex, however, there’s a very low mortality rate associated with it. And so, the surgery itself isn’t risky in terms of taking a patient’s life, but there are as you stated, multiple complications can occur commonly in patients.
If you look at for example, if you would look at the national rate of blood transfusions at the time or immediately after a cystectomy; it’s anywhere from 30 to 40%. And also, there’s a high rate of patients needing to go back and have secondary procedures to correct problems that were missed or occurred at the time of the first surgery. And as you alluded to, there is a high 30 day admission rate, up to 30% of patients will be readmitted after their discharge within 30 days of their hospitalization.
In regard to what makes the surgery this complex; most of these complications aren’t related to the bladder removal portion of the surgery; they are usually related to the portion of the surgery what you call urinary diversion where we have to use a segment of the patient’s bowel to eliminate the urine from their body after the surgery.
Host: It is such an interesting topic Dr. Crispen and when you discuss the surgery itself, yes, so complicated; so what is the role of BCG in bladder carcinoma in situ treatment and when you’re discussing that, tell us what BCG refractory disease is and some of the treatment options that you might consider outside of radical cystectomy.
Dr. Crispen: Certainly and so, for carcinoma in situ of the bladder, when patients first present with that, BCG is the best treatment we know for those patients. When you look at patients with a carcinoma in situ, their recurrence rate after a endoscopic resection, depending upon your series is going to be 70 to 90% of those patients are going to have the cancer come back. BCG is our best way of controlling that after their initial surgery, however, it only cuts that chance of recurrence in half. And so, if patients have an 80% chance of having the recurrence without the BCG; with the BCG, it only drops that to 40%.
So, we define BCG refractory disease based upon the total amount of BCG treatments a patient has received in their treatment course. So, all patients will have to have at least six weeks of induction BCG and if they recur then; they can get another six weeks of induction BCG before they would be considered BCG refractory. Another common definition of BCG refractory disease is if a patient would have the cancer come back after the initial six week induction course or another three weeks of maintenance therapy. If the cancer would come back within a set time.
Now the importance of this BCG refractory definition cannot be understated and having the key to understanding of what someone needs to become BCG refractory is very important because of the clinical trials being done out there which can give patients another option before going to cystectomy. But these definitions are very rigid for enrollment and so if the BCG isn’t given according to standard guidelines; patients may miss out on bladder preservation being offered through a clinical trial.
In regard to the options outside of going straight to bladder removal surgery in these patients with BCG refractory disease and particularly carcinoma in situ; there are a number of options for them, all of which involve the placement of chemotherapy directly into the bladder. Those chemotherapeutic agents include valrubicin, mitomycin, gemcitabine, thiotepa, docetaxel and there’s others I could add onto the list. And there’s others I could add onto the list. And so, while there’s a large number of those that can be offered; unfortunately, they do fairly poorly again, with success rates at one year of keeping the cancer at bay being less than 20%.
And so, often, patients will try that next step before going on to bladder removal surgery. However, those other options are not very durable at this point.
Host: Good points Dr. Crispen. So, let’s talk a little bit about patient selection. What patient characteristics are important when you are considering improved outcomes with that trimodal therapy for muscle invasive bladder cancer. Tell us how careful patient selection and extensive counseling are paramount to your successful intervention.
Dr. Crispen: Certainly. Yeah, it’s very important to get it right the first time with these treatments. Because secondary treatments can be more complex and so patient selection up front is critical. If we look at a patient to be considered for trimodal therapy; we know that there are certain tumor characteristics that will select patients for the best outcomes. And those would be only having a single tumor in the bladder that can be completely resected, not having carcinoma in situ in the bladder, not having any hydronephrosis or swelling of the kidneys, not having any variant histology on their bladder cancer. So, bladder cancer can come in different types and the pure bladder cancer or pure urothelial carcinoma tend to do better.
And so, when a patient has all of those options, certainly trimodal therapy is an excellent alternative for them compared to bladder removal surgery. However, we know that the recurrence rates in patients who even have been well selected, the recurrence rates of the bladder cancer can be 50 to 60%, at which time, we’d have to look at other agents like bladder removal surgery despite our initial attempt to keep the bladder in place.
Host: What about the tumor itself Dr. Crispen? What characteristics are associated with improved outcomes in that regard?
Dr. Crispen: Volume of disease, certainly has a lot to do with it. The more tumor we can resect and clear with the scope before they get chemotherapy or trimodal therapy; we know that will improve outcomes. There is evidence that tumors with certain genetic mutations will be more sensitive to chemotherapy and for those patients; there’s currently trials available including one here with UF Health Urology where if a patient has specific mutations within their tumor; and we believe that they will have a complete response based upon that; we can enroll them in the trial to see if we can give them chemotherapy and then not have to take their bladder out or not have to give them radiation as part of their treatment of their muscle invasive bladder cancer.
Host: Well as long as you brought up trials, doctor, tell us about some ongoing research being evaluated to improve bladder preservation therapy in patients with BCG refractory disease and muscle invasive disease. What research is going on? What would you like other providers to know that you are doing there?
Dr. Crispen: Certainly. And so, we kind of have a top down approach for trying to improve our outcomes with patients with bladder cancer. And that starts really in our labs. Part of a lab where I collaborate with, with Dr. Serge Kusmartsev, we are looking at things in the petri dish and in animal models trying to look at the tumor microenvironment or the way that the tumor or the cancer impacts cells around it, impacts the fluid around it to kind of push the immune system away or turn off the immune system at the level of the tumor. And we do know that immunotherapy can be successful in bladder cancer but it’s only successful for about 30% of patients and so what our research is looking at is looking at ways that we can change the tumor microenvironment, increase our understanding to then make these cancers more susceptible to currently available immunotherapy.
Now while this type of research is in its very early stages and we’d be years away from being able to actually treat patients with these types of techniques that we are evaluating; we do have multiple clinical trials open for patients with both the stage one BCG refractory disease and for those patients presenting with muscle invasive disease. And so, with our patients with the stage one disease; one of the obvious ways that we would think to try to improve that is avoiding patients for becoming BCG refractory. So, is it giving better BCG, is it improving a patient’s immune system prior to giving them BCG so they have an improved response rate.
Currently, we are involved with a nationwide trial which we’ve been very good in. It will be over 900 patients at which we are one of the top three accruing sites to this trial where we are looking at bringing in a new type of BCG into the United States and helping to improve outcomes for all patients and helping to improve the availability of BCG to all patients. And so, that’s one method where we are trying to actually just prevent the patients forever needing to be considered for a cystectomy.
Another option we have for these patients is avoid offering patients unique treatments when they really are BCG refractory. We’ve been involved in a number of clinical trials there looking at immunotherapy that’s given systemically through an IV infusion and these medications have been shown to be very successful in patients with advanced bladder cancer. We’re just trying to move that type of therapy early in their treatment to try to keep their bladder in place.
Another fascinating area for clinical trials and what’s being used in bladder cancer now are the trials that we’ve helped complete in looking at putting an adenovirus, an altered adenovirus or the common cold virus in someone’s bladder, having that virus infect the cells of the bladder, then make those cancer cells kill themselves or secrete products that will lead to their death and be able to keep these patients away from having their bladder removed.
In regards to our clinical trials for muscle invasive disease; we look to again, improve current therapies by offering additional therapy after trimodal therapy. So, instead of getting that 50 to 60% chance of the cancer coming back after standard trimodal therapy; trying to offer additional medications after they have completed their radiation therapy to decrease that chance of recurrence maybe even as much as 25%.
And again, I mentioned one trial a little earlier where we are looking to avoid having to perform bladder removal surgery in patients who have a complete response to chemotherapy and developing other markers which can predict that complete response to help patients avoid cystectomy.
Host: So, exciting. Absolutely fascinating. Dr. Crispen as we wrap up, do you have any final thoughts or information you would like other providers to know about the bladder preservation program and what you are doing there at UF Health Shands Hospital?
Dr. Crispen: Certainly. I think that there’s other ways that we could improve our treatment of bladder cancer and again, within standard therapies, even outside of clinical trials; the one thing is just for us to do as best job we can to treat these patients up front. And example again, would be optimizing treatment in patients with stage one disease so they do not develop BCG refractory disease or not progress to muscle invasive disease. We always are looking at our quality and one quality measure is to make sure that patients get the proper chemotherapy placed in their bladder after their endoscopic resections because we know that that can decrease bladder cancer recurrences in the future.
And again, if you look at national numbers for the use of that type of what I consider standard therapy; less than 25% of urologists are using that routinely throughout the country and our rates are well over 70%. And again, that’s just our dedication to really try to avoid the need for bladder removal surgery.
Another, I think important component of this is keeping up with widely available technology. There’s new technology that has been approved for the last year for use in patients with a stage one bladder cancer called Blue Light Cystoscopy and we’re happy to be able to offer that to our patients with UF Health Urology. And what that technology consists of is us putting the medication in the bladder so when we look in the bladder with a cystoscope; we are going to be able to detect tumors with greater sensitivity. And studies have shown, when you use that on a routine basis; the time to recurrence increases and the total amount of recurrences decrease as well. So, again, that’s part of our strategy of doing the best job we can to get to the point we never even have to discuss bladder removal surgery with a patient.
Host: It is such an interesting topic. Dr. Crispen, thank you so much for great information. That concludes this episode of UF Health MedEd Cast with UF Health Shands Hospital. To learn more about cancer clinical trials available at the UF Health Cancer Center, please visit www.ughealth.org/navigator. And to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit www.ufhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital Podcasts. Until next time, I’m Melanie Cole.
The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of .25 AMA PRA category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome. I’m Melanie Cole and today we’re talking about bladder preservation. We’re examining current indications for radical cystectomy when treating bladder cancer. We’re going to discuss BCG refractory disease and treatment options outside of radical cystectomy and patient and tumor characteristics that are associated with improved outcomes. Today with me, is Dr. Paul Crispen. He's an Associate Professor of Urologic Surgical Oncology at the University of Florida and he practices at UF Health Shands Hospital in Gainesville. Dr. Crispen, it’s a pleasure to have you join us. Please let’s start with the prevalence of bladder cancer and the incidence, the burden; tell us a little bit about this particular type of cancer.
Paul Crispen, MD (Guest): Bladder cancer is very prevalent in the United States. It’s the fourth most common malignancy in males and it’s in the top ten in females in our area around UF Health Urology. So, we have a lot of interest in this disease and would like to do a lot more better to improve the outcomes. The average age of patients that are diagnosed currently is 73 years old in the state of Florida. And there are going to be about 80,000 new cases of bladder cancer throughout the year in the United States.
Now when patients, when we first diagnose them with bladder cancer, the majority are going to have localized disease or stage one disease and then the other 30 to 40% of patients are going to have more locally advanced or even metastatic disease based upon their presentation.
Host: Well thank you for opening with that Dr. Crispen. So, help us to understand the current indications for radical cystectomy when treating bladder cancer and some of the outcomes associated with neoadjuvant chemotherapy.
Dr. Crispen: There are two main groups of patients who have indications to undergo bladder removal surgery. The first of which, are patients who have stage one bladder cancer that have not responded to standard therapy and that standard therapy is BCG in the United States. And those patients, the reason we move to cystectomy is really they have poor treatment options once we see that BCG is ineffective. And so, when we look at the medications or the current therapies beyond BCG currently, they are very limited with most having less than a 20% success rate at one year, thus a lot of these stage one patients will be offered cystectomy immediately when we consider them BCG refractory.
The second population of patients which are commonly recommended to undergo bladder removal surgery or cystectomy are those who are presenting with stage two and three disease. And that’s defined as patients where the cancer is invading into the deep musculature of the bladder or just going into the fat around the bladder and can be also in the lymph nodes in the pelvis.
For patients who have metastatic disease, we do not typically recommend bladder removal surgery. Now, with these patients, we expect the long term outcomes in patients with the stage one indications or the BCG refractory indications to do very well long term in terms of survival and we’d expect a high cure rate associated with those patients with the bladder removal surgery. Unfortunately, in the patients with stage two and three disease; those patients have a potentially deadly cancer where most patients who undergo even maximal therapy may not live beyond five years.
And that brings us to your question of neoadjuvant chemotherapy. We do know that if we give patients chemotherapy, usually it’s about three to four months’ worth before their surgery, they will have improved survival compared to patients who do not undergo chemotherapy. This improvement in survival can be quite dramatic. If you look at some of the clinical trials that evaluated this, if a patient on average would have just the bladder removal surgery alone; their average life expectancy would be about four years. If they get chemotherapy first, that could extend their life expectancy by about one and a half to two years. And so that’s the real important piece about neoadjuvant chemotherapy and when we like to give it while we can with our medical oncologists because we know patients will do better in the long run. It’s more treatment up front, however, I think the outcomes justify it.
Now with the neoadjuvant chemotherapy, the patients who do the best, are the ones when we take their bladder out after the chemotherapy; that they have no residual disease left in their bladder. And that’s something we have to be upfront with with patients right away. We have to prepare them to know we could take out their bladder and then they go – when we get the pathology report back, there’s no evidence of cancer, and that will often lead to patients saying well why did you need to take my bladder out if we got rid of it with the chemotherapy?
That’s how well the neoadjuvant chemotherapy can work. And that will happen in about 30 to 40% of patients who receive neoadjuvant chemotherapy prior to cystectomy.
Host: Wow that is so interesting Dr. Crispen. So, then based on what you just said, tell us about bladder preservation. When is this indicated or contraindicated? And tell us about the cancer-free and overall survival of patients in these populations.
Dr. Crispen: Certainly and again, I’ll start with the two separate populations. The BCG refractory stage one patients, then move on to the muscle invasive cancer patients. And so, for the stage one patients, we would like to avoid the bladder removal surgery as much as we can because we know that bladder removal is extremely complicated both short term and long term. And so, some of those immediate complications would be bleeding, infection, high 30 day readmission rates and it can also have very long term complications as well impacting patient’s quality of life. Some patients can have recurrent urinary tract infections, have a tremendous impact on their sexual function and their ability to work.
And so, when we look at all of these things when we talk to patients, it’s a really big deal. Especially if they have the BCG refractory stage one disease. And so for what it means in those patients, bladder preservation therapy would be discovering new medications or new techniques to replace BCG and to replace cystectomy all together. And that can be putting the medications directly into the bladder or putting medications into the vein where they go systemically. But again, as I pointed out earlier, these current medications are very limited with a low likelihood of success, however, they can be used to preserve the bladder in patients with this low stage disease. However, unfortunately, they are just not that successful at this time.
In regard to muscle invasive bladder cancer, there are several different options for those patients for bladder preservation. Those would include something called trimodal therapy where we combine maximal endoscopic resection and then concomitant chemotherapy and radiation therapy which is given over a six week period. And that’s probably the best form of bladder preservation therapy we have.
Other options would include maximal endoscopic resection, or chemotherapy alone.
Host: Well thank you for that explanation. So, as we’re talking about radical cystectomy, why is this one of the most challenging procedures performed by urologic surgeons and does it carry with it, significant risks of complications, hospital readmissions, things like that?
Dr. Crispen: Yes, absolutely. And that’s why I always tell my patients when counseling them about bladder removal surgery or cystectomy, that it’s a surgery that I do often, and I enjoy doing but only do it when it’s absolutely indicated because it has such a tremendous impact on a patient’s life. Now, the surgery is complex, however, there’s a very low mortality rate associated with it. And so, the surgery itself isn’t risky in terms of taking a patient’s life, but there are as you stated, multiple complications can occur commonly in patients.
If you look at for example, if you would look at the national rate of blood transfusions at the time or immediately after a cystectomy; it’s anywhere from 30 to 40%. And also, there’s a high rate of patients needing to go back and have secondary procedures to correct problems that were missed or occurred at the time of the first surgery. And as you alluded to, there is a high 30 day admission rate, up to 30% of patients will be readmitted after their discharge within 30 days of their hospitalization.
In regard to what makes the surgery this complex; most of these complications aren’t related to the bladder removal portion of the surgery; they are usually related to the portion of the surgery what you call urinary diversion where we have to use a segment of the patient’s bowel to eliminate the urine from their body after the surgery.
Host: It is such an interesting topic Dr. Crispen and when you discuss the surgery itself, yes, so complicated; so what is the role of BCG in bladder carcinoma in situ treatment and when you’re discussing that, tell us what BCG refractory disease is and some of the treatment options that you might consider outside of radical cystectomy.
Dr. Crispen: Certainly and so, for carcinoma in situ of the bladder, when patients first present with that, BCG is the best treatment we know for those patients. When you look at patients with a carcinoma in situ, their recurrence rate after a endoscopic resection, depending upon your series is going to be 70 to 90% of those patients are going to have the cancer come back. BCG is our best way of controlling that after their initial surgery, however, it only cuts that chance of recurrence in half. And so, if patients have an 80% chance of having the recurrence without the BCG; with the BCG, it only drops that to 40%.
So, we define BCG refractory disease based upon the total amount of BCG treatments a patient has received in their treatment course. So, all patients will have to have at least six weeks of induction BCG and if they recur then; they can get another six weeks of induction BCG before they would be considered BCG refractory. Another common definition of BCG refractory disease is if a patient would have the cancer come back after the initial six week induction course or another three weeks of maintenance therapy. If the cancer would come back within a set time.
Now the importance of this BCG refractory definition cannot be understated and having the key to understanding of what someone needs to become BCG refractory is very important because of the clinical trials being done out there which can give patients another option before going to cystectomy. But these definitions are very rigid for enrollment and so if the BCG isn’t given according to standard guidelines; patients may miss out on bladder preservation being offered through a clinical trial.
In regard to the options outside of going straight to bladder removal surgery in these patients with BCG refractory disease and particularly carcinoma in situ; there are a number of options for them, all of which involve the placement of chemotherapy directly into the bladder. Those chemotherapeutic agents include valrubicin, mitomycin, gemcitabine, thiotepa, docetaxel and there’s others I could add onto the list. And there’s others I could add onto the list. And so, while there’s a large number of those that can be offered; unfortunately, they do fairly poorly again, with success rates at one year of keeping the cancer at bay being less than 20%.
And so, often, patients will try that next step before going on to bladder removal surgery. However, those other options are not very durable at this point.
Host: Good points Dr. Crispen. So, let’s talk a little bit about patient selection. What patient characteristics are important when you are considering improved outcomes with that trimodal therapy for muscle invasive bladder cancer. Tell us how careful patient selection and extensive counseling are paramount to your successful intervention.
Dr. Crispen: Certainly. Yeah, it’s very important to get it right the first time with these treatments. Because secondary treatments can be more complex and so patient selection up front is critical. If we look at a patient to be considered for trimodal therapy; we know that there are certain tumor characteristics that will select patients for the best outcomes. And those would be only having a single tumor in the bladder that can be completely resected, not having carcinoma in situ in the bladder, not having any hydronephrosis or swelling of the kidneys, not having any variant histology on their bladder cancer. So, bladder cancer can come in different types and the pure bladder cancer or pure urothelial carcinoma tend to do better.
And so, when a patient has all of those options, certainly trimodal therapy is an excellent alternative for them compared to bladder removal surgery. However, we know that the recurrence rates in patients who even have been well selected, the recurrence rates of the bladder cancer can be 50 to 60%, at which time, we’d have to look at other agents like bladder removal surgery despite our initial attempt to keep the bladder in place.
Host: What about the tumor itself Dr. Crispen? What characteristics are associated with improved outcomes in that regard?
Dr. Crispen: Volume of disease, certainly has a lot to do with it. The more tumor we can resect and clear with the scope before they get chemotherapy or trimodal therapy; we know that will improve outcomes. There is evidence that tumors with certain genetic mutations will be more sensitive to chemotherapy and for those patients; there’s currently trials available including one here with UF Health Urology where if a patient has specific mutations within their tumor; and we believe that they will have a complete response based upon that; we can enroll them in the trial to see if we can give them chemotherapy and then not have to take their bladder out or not have to give them radiation as part of their treatment of their muscle invasive bladder cancer.
Host: Well as long as you brought up trials, doctor, tell us about some ongoing research being evaluated to improve bladder preservation therapy in patients with BCG refractory disease and muscle invasive disease. What research is going on? What would you like other providers to know that you are doing there?
Dr. Crispen: Certainly. And so, we kind of have a top down approach for trying to improve our outcomes with patients with bladder cancer. And that starts really in our labs. Part of a lab where I collaborate with, with Dr. Serge Kusmartsev, we are looking at things in the petri dish and in animal models trying to look at the tumor microenvironment or the way that the tumor or the cancer impacts cells around it, impacts the fluid around it to kind of push the immune system away or turn off the immune system at the level of the tumor. And we do know that immunotherapy can be successful in bladder cancer but it’s only successful for about 30% of patients and so what our research is looking at is looking at ways that we can change the tumor microenvironment, increase our understanding to then make these cancers more susceptible to currently available immunotherapy.
Now while this type of research is in its very early stages and we’d be years away from being able to actually treat patients with these types of techniques that we are evaluating; we do have multiple clinical trials open for patients with both the stage one BCG refractory disease and for those patients presenting with muscle invasive disease. And so, with our patients with the stage one disease; one of the obvious ways that we would think to try to improve that is avoiding patients for becoming BCG refractory. So, is it giving better BCG, is it improving a patient’s immune system prior to giving them BCG so they have an improved response rate.
Currently, we are involved with a nationwide trial which we’ve been very good in. It will be over 900 patients at which we are one of the top three accruing sites to this trial where we are looking at bringing in a new type of BCG into the United States and helping to improve outcomes for all patients and helping to improve the availability of BCG to all patients. And so, that’s one method where we are trying to actually just prevent the patients forever needing to be considered for a cystectomy.
Another option we have for these patients is avoid offering patients unique treatments when they really are BCG refractory. We’ve been involved in a number of clinical trials there looking at immunotherapy that’s given systemically through an IV infusion and these medications have been shown to be very successful in patients with advanced bladder cancer. We’re just trying to move that type of therapy early in their treatment to try to keep their bladder in place.
Another fascinating area for clinical trials and what’s being used in bladder cancer now are the trials that we’ve helped complete in looking at putting an adenovirus, an altered adenovirus or the common cold virus in someone’s bladder, having that virus infect the cells of the bladder, then make those cancer cells kill themselves or secrete products that will lead to their death and be able to keep these patients away from having their bladder removed.
In regards to our clinical trials for muscle invasive disease; we look to again, improve current therapies by offering additional therapy after trimodal therapy. So, instead of getting that 50 to 60% chance of the cancer coming back after standard trimodal therapy; trying to offer additional medications after they have completed their radiation therapy to decrease that chance of recurrence maybe even as much as 25%.
And again, I mentioned one trial a little earlier where we are looking to avoid having to perform bladder removal surgery in patients who have a complete response to chemotherapy and developing other markers which can predict that complete response to help patients avoid cystectomy.
Host: So, exciting. Absolutely fascinating. Dr. Crispen as we wrap up, do you have any final thoughts or information you would like other providers to know about the bladder preservation program and what you are doing there at UF Health Shands Hospital?
Dr. Crispen: Certainly. I think that there’s other ways that we could improve our treatment of bladder cancer and again, within standard therapies, even outside of clinical trials; the one thing is just for us to do as best job we can to treat these patients up front. And example again, would be optimizing treatment in patients with stage one disease so they do not develop BCG refractory disease or not progress to muscle invasive disease. We always are looking at our quality and one quality measure is to make sure that patients get the proper chemotherapy placed in their bladder after their endoscopic resections because we know that that can decrease bladder cancer recurrences in the future.
And again, if you look at national numbers for the use of that type of what I consider standard therapy; less than 25% of urologists are using that routinely throughout the country and our rates are well over 70%. And again, that’s just our dedication to really try to avoid the need for bladder removal surgery.
Another, I think important component of this is keeping up with widely available technology. There’s new technology that has been approved for the last year for use in patients with a stage one bladder cancer called Blue Light Cystoscopy and we’re happy to be able to offer that to our patients with UF Health Urology. And what that technology consists of is us putting the medication in the bladder so when we look in the bladder with a cystoscope; we are going to be able to detect tumors with greater sensitivity. And studies have shown, when you use that on a routine basis; the time to recurrence increases and the total amount of recurrences decrease as well. So, again, that’s part of our strategy of doing the best job we can to get to the point we never even have to discuss bladder removal surgery with a patient.
Host: It is such an interesting topic. Dr. Crispen, thank you so much for great information. That concludes this episode of UF Health MedEd Cast with UF Health Shands Hospital. To learn more about cancer clinical trials available at the UF Health Cancer Center, please visit www.ughealth.org/navigator. And to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit www.ufhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital Podcasts. Until next time, I’m Melanie Cole.