Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston MD Anderson Cancer Center. And it's my distinct pleasure to be joined today by a very good friend, Dr. Pradeep P. Rao, who is a true expert in urology and uro-oncology. Dr. Rao is a Professor of Urology at the DY Patil Medical School in Mumbai. And he's the Director and Head of the Department of Urology at the Global Hospital, also in Mumbai. And he's also very active with different organizations, including the Indian Neurologic Association, the SIU, AUA, EAU. Just all around, I'm really pleased to have you here today, Pradeep.

Pradeep Rao: Thanks, Ashish, for the great introduction. I'm very happy to be on this program with you. I've been following your programs and see a lot of great guys on this program. So I'm pretty honored to be invited on. And I think you're doing a fantastic job in pushing bladder cancer and improving the treatments all over the world.

Ashish Kamat: Thanks, Dr. Rao. We're excited to hear what you have to say about bladder cancer, and as your title says, especially in times of COVID. So the show is yours.

Pradeep Rao: So for the last two or three months in Mumbai, we are having a lot of COVID patients and are pretty much locked down. So it's got me thinking about things like bladder cancer. If you see the guidelines released by most of the urological associations, including the Indian Society, cystectomy and nephroureterectomy are the two surgeries, which they recommended should go ahead, even in these times when we are not doing other elective surgeries. But, yes, that shows that bladder cancer is something that you cannot sit on and cannot wait. And that's why I thought I should just give the thoughts on what is happening in bladder cancer in India, as against what you see in the Western world.

Looking at the Indian problem in bladder cancer, one of the main issues that we have in India is a lack of a proper registry, especially in urological cancers. Of course, we have a huge number of oropharyngeal cancers, which is the commonest cancer in India, and breast cancer in women. But if you notice this is the Indian data from two years back, and bladder is pretty low down the list, 18th among cancers, and second among urological cancers after prostate cancer, which is slightly different, I think, from the Western data where it's a lot more common. But I think what this is reflecting is the lack of a registry and lack of documentation because a lot of these cancers are treated where the patients live, which is in the rural areas and the smaller centers, and they are not documented.

So what are the problems we face with treating bladder cancer in India? There are very few reference centers where patients will come and get treated. A lot of them get treated in the periphery, in smaller setups, in nursing homes, a lot by general surgeons and surgical oncologists rather than going to a urologist. Insurance penetration is a huge problem in India, below 5% nationwide, although slightly more in cities. And the majority of patients with bladder cancer are treated at low volume centers, that is low volume for bladder cancer. And the problems that happen when patients are treated in low volume centers for such a disease as bladder cancer, the outcomes definitely tend to be worse.

The specific challenges we face are in getting a good TURBT done, maintenance BCG, neoadjuvant chemo, surgery, and surveillance. And I'll take each of these in turn. Coming to TURBT, we know that it's the mainstay of diagnosis and treatment for bladder cancer. Unfortunately, it's one of the procedures which is really shortchanged in residency programs here in India. I believe that some countries in the West have similar problems. And one of this is a function of, like I said, that a lot of bladder cancers don't necessarily come to the referral centers where there is a residency program and the residents don't really get trained properly as they do get in other surgeries like stones and BPH, of which there is a higher volume.

And this leads to them being inexperienced when they go into private practice. You end up seeing a vast majority of TURBTs, which are very commonly underdone. You don't see muscle in the specimen, which is not necessarily a reflection of the surgery alone, but it's also because pathologists are often ill-trained to report and they tend to confuse the muscularis mucosa and the muscularis propria. And this is another issue. And there's a huge variation across the country of the quality of the TURBT being done, as well as the quality of reporting by oncologists. And the other thing is that a second look TURBT is done very rarely, which of course affects the results overall and the outcomes.

We don't have access to blue light cystoscopy in India at all. I don't think anyone is using it. Narrowband imaging is available at a few urban centers, but not commonly. And again, it's not commonly used in diagnosis of bladder cancer.

Having the TURBT, we know from the Western data, even in the West, a single TURBT understages from 20 to 70%. That's a huge variation there itself. Obviously in a center like MD Anderson, which is a main oncology center that specializes in treating bladder cancer, you would have much better outcomes than in the smaller centers in the United States as well. But in India, this problem is a lot more. We don't have specific data from India which is published on the amount of understaging, so I'm showing the Western data.

You get residual diseases in 27% of TURBTs without a second look, and a repeat resection significantly reduces recurrences. We know that re-resection also has prognostic significance, with a five-year muscle invasion at 82%, with a residual T1 tumor as against a T0 or CIS. And this data would be similar or even worse in India, but we don't have any documentation.

How do we improve outcomes? So TURBT, even if it has not been taught in residency, the one thing which we have found recently, which seems to work better, is teaching people how to do an en-bloc TURBT. We have started doing this and we have started pushing this at meetings that patients where an en-bloc can be done, you find it easier to teach, the outcome seems to be more standardized, of course, as well as some papillary tumors. It's an extension of skills from prostate enucleation, so the surgeons are a little more familiar, the younger guys. Obviously it's not suitable in all cases, but where it is, we find it helps people to keep the tumor intact and get it all completely.

I'll just show a small video on en-bloc resection of the bladder tumor. This is the device that I use, which is a loop, which has, I think, this particular one is from Olympus, but the other companies also make something similar. It's actually a prostate enucleation loop. The advantage of the cutting loop, you can use to incise the mucosa and the whole donut, which can be used to push the tumor away, allows you access to the deeper structures.

I prefer not to take the muscle along with en-bloc and take the chip of muscle separately once the bed is completely exposed and the tumor is away. As you can see, we incise the mucosa and then push it away. It's fairly easy to see the main region of the muscle here, but we will still take a deep muscle biopsy at the end to make sure that you're not missing any invasion. This is a fairly large tumor. So this can be done in larger tumors as well. But you need tumors which are papillary. You don't want to be trying this in a solid sessile tumor.

Would you guys also be doing en-bloc regularly, Ashish?

Ashish Kamat: Yeah, I mean, I use en-bloc quite routinely, but as you mentioned, mainly for papillary tumors. And of course, then the size is an important criterion because even if it's a large tumor, you can clearly resect the tumor, but then extracting it ends up being more problematic for the patient and of course for us.

Pradeep Rao: Right.

Ashish Kamat: So, I mean, this is obviously a technique that is good to teach the residents and fellows early on so they can adopt it in their own practice.

Pradeep Rao: We do morcellation if it's a very large tumor as well because we have access to the morcellator which we use for BPH. And not to spread the tumor, it just sucks it in. And obviously bladder tumors are a lot easier to morcellate than the prostate itself, just takes a minute or so.

As you can see, we go all the way to the bed of the tumor. And now we added the mucosal already at the other end. A small bit is left behind here, which also can be taken off in the same way. And any small lesions just at the periphery can just be fulgurated that way. And right at the end, once the whole bed is exposed, we just take a muscle biopsy of the bed just to make sure there's nothing in that.

So that was a small video. I hope it was informative. If you see the meta-analysis and review of en-bloc versus conventional TURBT, it shows all the outcome parameters are similar or better than a conventional TUR. Again, this is not for every case, but in the cases where it can be done, it's a pretty useful technique. The complications also seem to be lower. We have had a good effect with obturator jerk also being a little less, reducing the chance of bladder perforation. So it's important to remember that a systematic well-done TURBT, with a proper second look two to six weeks later, significantly improves the prognosis of the patient with bladder cancer.

Coming to maintenance BCG. Most patients in India tolerate the first six doses of BCG fairly well, but we have real problems with maintenance. I know, Ashish, that you worked a lot on maintenance in the past, but Indian patients don't tolerate maintenance cycles well at all. We have hardly 30% of patients who can take a full course of maintenance. I don't know the exact reason for this. It could be that a lot of Indian patients that are exposed to tuberculosis through their lifetime, and that's one of the reasons we also react very badly to a Mantoux test, a tuberculin skin test. And the moment you start a maintenance cycle of BCG, many of them react very badly. They don't go beyond the first dose. And a lot of them, in fact, require treatment for a month or so before they can get rid of the symptoms.

So we have been very wary of using maintenance BCG and against the recommendations in the West where the maintenance is given regularly for up to two years.

Ashish Kamat: Dr. Rao, have you tried dose reduction? Because as you mentioned in populations that have had prior exposure to BCG, whether it's because of tuberculosis vaccination, or even low-level TB in the population, one thing that works really well is cutting down the dose to one-third, one-tenth, even down to one-hundredth, because the BCG colony-forming units is in logs of a million.

Pradeep Rao: Right.

Ashish Kamat: Has that been tried, those reductions?

Pradeep Rao: Oh yes. We don't do one-hundredth, but we do half and one-third of what we normally give. I've not tried going below that. But what I've found is that we find out that the patient is reacting badly when we give him the first maintenance dose. And then some of them react so badly that they have a fever for a month. They just have severe urinary symptoms. They don't come back and they're scared to try another dose. Because it's such a high proportion of patients, maybe we should look at the starting of the maintenance on a very low dose. And maybe if they tolerate, maybe we can push up the dose later. That would be something worth trying, I'm sure. We have tried with a half dose and one-third dose because that's what's the recommendations. But yes, the first dose is where the problem occurs.

Ashish Kamat: Right. And just something to consider, because if you actually look at the CFUs use from batch to batch of BCG, there's a natural variation of up to tenfold. So even if you're giving someone half a dose, you might actually be giving them a full dose, just depending on which batch the BCG comes from. And something really to consider in your patient population is dropping the dose down all the way to one-tenth.

Pradeep Rao: We should definitely look at that. I think we should put that across to people, that this is something that should be tried. And we'll look at that going forward. Thank you.

Coming to neoadjuvant chemotherapy again. MVAC, although it's preferred, most of the places in the West, it's very expensive in India. It's not tolerated well. And a lot of our oncologists are not keen on getting MVAC to patients, especially older patients. They use mainly platinum-based chemotherapy. But many patients cannot afford the cost of chemo and surgery, and given the choice of one or the other, I think surgery is more useful in these patients. Other than costs, time is also a factor for patients because chemo is available mostly in the cities and if they come for chemo and they're to keep coming, then they're not able to come to the surgery later.

So we do use neoadjuvant chemotherapy in the patients who are affording in the cities. But it's not so common in the patients who have traveled to get surgery done. And their follow-up is poor, so that remains a recurrent problem in India. We have 70% of our population living in rural areas. And these are the guys who do not find it easy to take neoadjuvant chemotherapy. And of course, the data shows that patients do much better with neoadjuvant chemotherapy than with surgery alone or with surgery straight up.

Coming to surgery itself, MIS and robotics are very poor penetration. But again, this is not prostate cancer or kidney cancer and outcomes of open cystectomy are just as good as MIS or robotics. Many cases are done by surgical oncologists who are not trained urologists. And this is different from, I think, in the Western world.

But that also leads to a predominance of ileal conduit. I would say 90 to 95% of the diversions done in India are ileal conduits. A few of the high volume centers run by uro-oncologists would be doing neobladders but these are very much in the minority in India.

Counseling of patients is very poor. Again, where urologists are not involved, we find the counseling of bladder cancer patients is extremely poor and the patients are not aware of what they're going in for. And this is something that we should improve if we want to improve our outcomes in bladder cancer.

Now the issue with surveillance and follow-up. Obviously, after TURBT, there is a very strict regimen for surveillance of these patients. And one of the main problems in India, the lack of availability of flexible cystoscopy. It makes it cumbersome and expensive to do surveillance on the patient. It is being done, but obviously more availability of this device would help for better surveillance. Ashish, would you say in the United States all surveillance is by flexible cystoscopy on an outpatient basis?

Ashish Kamat: Yes. I would say in the US almost 95, if not higher, percentage of surveillance cystoscopy is done as an outpatient with a flexible cystoscope. And clearly, having used both in patients and having chatted with many of them who've gone through the years, done the rigid and then moved on to flexible, it's, from a patient perspective, night and day.

Pradeep Rao: Absolutely. No question about it. So we do use flexible cystoscope in the city, in my center and one or two others. But most of the centers are just still doing rigid cystoscopy. And that makes it cumbersome to do surveillance on these patients.

The other issue is distances and poorly educated patients, significant investments to follow. It's hard to convince them. And you know that unless you do regular followup, you may end up with advanced disease the next time you see the patient.

To sum up, we lack an effective registry of cases in all urological cancers, which would immensely help in documenting as well as prognosticating our patients going forward.

Lack of insurance coverage in India is a huge concern, especially where the treatment is expensive and time-consuming, as in bladder cancer.

Many of the newer drugs like checkpoint inhibitors and some of the immunotherapeutic agents are prohibitively expensive, out of reach of all but the elite. The drugs for kidney cancer, which are older, have come down in price, but not the ones that are being used for bladder cancer so far. And this should change in the future to help us treat these patients better.

The mainstay of treatment for bladder cancer in India and most developing countries remains surgery, which tends to be the cheapest of the options available to the patient. Thank you.

Ashish Kamat: So that was an excellent overview of the whole situation as it pertains to India. But not only India. Any country where you don't have the facilities, as you outlined, it would be appropriate for that patient and surgeon population to hear this talk as well.

A couple of points. You brought up the fact that blue light is not available in India, which I understand, and I totally am aware of. But one thing that a lot of folks forget is that there is something that's, I guess, known as a poor man's blue light, which is just using a vital stain such as methylene blue, put in the bladder for about 30 minutes before you start the cystoscopy, and then you wash it out. And any cells that are rapidly dividing will pick up this methylene blue. It's obviously not been studied head to head with Cysview® or blue light, because those studies just will never be done. But back in the day before we had blue light available, that's what I used to use. Put some methylene blue in the bladder in areas that are CIS or have high perforative rate will take up the methylene blue. So just something to consider.

Pradeep Rao: Interesting, I didn't know that actually. The only way for me would be doesn't it end up staining just about everything?

Ashish Kamat: It has to be diluted and put in the bladder. And of course, then you have to wash it out. It'll stain the tissue that you want it to stain, but it won't stain the rest because once you drain it out-

Pradeep Rao: And you don't need a different light for this, right?

Ashish Kamat: No, not at all.

Pradeep Rao: Just a regular white light.

Ashish Kamat: Just regular white light. Exactly.

Pradeep Rao: That's interesting.

Ashish Kamat: And the other thing of course that you mentioned is the BCG and the dose reduction. The thing about the neoadjuvant chemotherapy, obviously, the data suggests the neoadjuvant chemotherapy helps patients that are having radical cystectomy.

Pradeep Rao: Right.

Ashish Kamat: But even at our center here at MD Anderson, we try to select out which patients would be better served with chemotherapy versus those that might be better served with surgery upfront.

So the dogma that everybody has to get chemotherapy is appropriate in infrastructures where you can give that safely. But in a place like in India, going straight to surgery, so long as the patient does have node-positive disease, of course, or clearly unresectable disease makes perfect sense. And I don't think that's actually a negative, but just something to track, like you said, in a registry so you can actually see what the outcomes are in the patient population, in the country of interest.

Pradeep Rao: Absolutely. In my center, there's no problem. We do neoadjuvant chemotherapy in many patients. But I also go to the medical college where obviously we have a lot of poor population and those guys just can't afford it. They can't afford the time also. It's not just the chemotherapy itself. So you have to pick and choose. Some patients, obviously, here would get it, but others would not.

Ashish Kamat: Great. And so again, I really truly appreciate you taking the time off from your busy schedule. I know Mumbai is starting to see an uptick in COVID cases, as is a lot of cities in different parts of the world. So I really appreciate you taking the time. But once again, thank you so much, Dr. Rao. This is truly a very informative session and I know our audience and listeners and viewers will really appreciate hearing your perspective.

Pradeep Rao: Ashish, I'm privileged to be on with a superstar like you. It was a pleasure to be on the show.

Ashish Kamat: Thank you again.