Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center. And it's a pleasure to welcome today Dr. Shen Tan, who is going to talk to us on the updated consensus definition and management recommendations from the International Bladder Cancer Group when it comes to intermediate-risk, non-muscle invasive bladder cancer. Dr. Tan has graduated from his residencyin the UK and now is actually right here in Houston at MD Anderson Cancer Center as a urologic oncology fellow. But during the writing and publication of his manuscript, he functioned to pull together a group from the International Bladder Cancer Group, and hence has a flavor of the recommendations from both the US and the UK perspective. So, Shen, looking forward to hearing what you have to say, and then our discussion.

Wei Shen Tan: Thank you very much Dr. Kamat, for the kind introduction as well as UroToday for having me here today. As Dr. Kamat mentioned, what I will be doing today is  presenting data on the IBCG recent consensus on definition and management for the intermediate-risk non-muscle-invasive bladder cancer. I have only got one conflict of interest to declare which is not relevant for today’s discussion. This represents an updated consensus from Dr. Kamat's previous publication back in 2014, where we reviewed existing literature with the IBCG group panel to formulate a new consensus document. As most of the audience  would know, non-muscle-invasive bladder cancer is often categorized based on risk groups. And while the low- and the high-risk groups are pretty well defined, there is a gray area for the intermediate-risk groups. And often this group represents patients who do not fulfill the low- or the high-risk definition.

And as a result, while some of these features are quite common between the guidelines, several contentious issue such as low-grade T1 disease and high-grade pTa <3cm. These are the issues that we will be discuss in the coming slides. This represents a Venn diagram of defining intermediate-risk non-muscle-invasive bladder cancer based on the different guidelines and definitions from the EAU definition to the AUA/SUO, the NCCN, NICE from the UK, as well as the IBCG previous recommendation.  There is some degree of variation. However, most guidelines would agree that if a patient has recurrent low-grade pTa disease, primary or recurrent multifocal low-grade pTa disease, primary or recurrent solitary, but more than three-centimeter tumor with LGpTa disease, these patients would be defined as intermediate-risk patients. And as the audience well lknows, typically these patients are managed by a TUR followed by a single installation, postoperative chemotherapy, and a review of histology.

Once they have been defined as an intermediate-risk disease, these patients would then be offered treatment, either in a form of adjuvant intravesical chemotherapy, or BCG with maintenance for about a year or so. And in the coming slides, we will review some of the reasons for these recommendations and which patients within the intermediate-risk group patients would benefit from specific intravesical treatments. One of the important points to point out is that BCG is superior to chemotherapy. And in this meta-analysis by Bohle et al.,  they found that the benefit for BCG was only evident in lowering the risk of disease recurrence when BCG was given as maintenance therapy for at least a year. This benefit was not seen when induction only BCG was given. So, induction-only BCG is  similar essentially to intravesical chemotherapy.

Another thing to point out is that there is no difference in disease progression, even when maintenance BCG was used in this study of intermediate-risk patient cohort. And what about the duration of BCG? In this randomized study by Oddens et al., patients were randomized to four different groups where they were either given full dose of BCG, one-third dose, one year of BCG, or three years of BCG. And what they found was that in the intermediate-risk patients, there was no difference  whether patients were given one year versus three years of full dose BCG, hence the recommendation for at least a year of BCG. The Lamm protocol where BCG is given for three years is typically  used in the high-risk patients however, we do not  need three years for intermediate-risk patients.

Moving on, in terms of our recommendation from the IBCG recently, we defined intermediate-risk patients based on different risk groups to minimize the heterogeneity of this patient cohort. Patients are then classified to whether they have multifocal disease, early recurrence, frequent recurrence, increased tumor size, or failure from previous intravesical treatments. And based on these five risk factors,  if a patient has got no risk factors, essentially these patients should be treated with as similar to low-risk patients where they are just given a single installation post-intravesical treatment, and they would not need adjuvant treatment. If you have got one to two risk factors, this patient cohort would benefit from adjuvant chemotherapy and if you have more than three risk factors, the highest number of risk factors, these are the patients that would benefit from BCG with at least one year of maintenance. And in the following slides, we are going to go through some of the issues that might arise and discuss the  variation between the different guidelines.

The first of them is low-grade T1 disease. It is important to understand that this patient cohort is incredibly rare. In the Swedish Bladder Cancer Registry, when they analyzed more than 10 years’ worth of patients, they identified 98 cases of patients that were recorded as Grade 1 pT1 patients. They then retrospectively reviewed all of these patients and found that they were all actually inaccurately recorded. So essentially, there was no patients actually with low-grade pT1 disease.

Hopkins, did a similar study and looked through more than 10 years' worth of patients. They identified about 37 low-grade T1 patients. And they found that the risk of progression is pretty low in this patient cohort, and this  mirrors intermediate-risk patients rather than high-risk patients. Finally, it is important to understand that the rarity of this patient cohort should mean that this should be flagged up and  reviewed by a uropathologist rather than a standard pathologist to make sure that you are defining the patient appropriately, and categorizing them appropriately so that they receive the recommended treatment.

In terms of high-grade Ta disease, some of the guidelines would suggest that these patients would fulfill intermediate-risks if they are less than 3 cm in diameter. However, based on Dr. Kamat's group recent publication in Journal of Urology, they looked at patients with high-grade Ta disease, and they found that this patient cohort had a very high risk of disease progression, including to progression to muscle-invasive disease or metastasis. This risk of progression is similar to patients with high-risk disease patients. Hence any patients with high-grade disease, even those with  Ta disease, should be treated as high-risk and not intermediate-risk.

In terms of the clinical features such as multifocality, tumor size, and prior recurrence rates, these are very well validated clinical features associated with increased risk of disease recurrence, as well as progression. One of the most cited studies would be the Sylvester et al. EORTC nomogram, where  patients with multifocal disease, higher tumor size, as well as increased recurrence rate were associated with an increased risk of recurrence as well as progression. And this is what we incorporated into our recommendations as well.

. In terms of the other  clinical features such as early risk of recurrence, we  recognized that patients who recur early, particularly at the three months cystoscopy are much more likely to develop subsequent disease recurrence. In since some of these studies, the risk of future disease recurrence vary from 70 to 90% if you' have got disease recurrence at three months. Hence, we incorporated this in our recommendation as well.

And finally, if you have had disease recurrence following intravesical treatment, you are more likely to develop disease recurrence in the future. In this randomized study by Malmstrom et al., 250 patients were randomized to mitomycin or BCG. In patients who then developed disease recurrence, there was crossover of treatment, where the BCG patients had mitomycin and vice versa. Here patients treated with  salvage mitomycin and  BCG, and the risk of disease recurrence is much higher compared to their primary treatment. It's important to understand that patients initially treated with mitomycin  were  salvaged  nearly 40% of the time with BCG.

To validate our different risk factor groups, we then incorporate these risk factors in the EORTC Sylvester 2006 nomogram, and we found a stepwise increase in the increased risk of recurrence and progression at one year and five years, as you can see here.

Finally, I would like to thank Dr. Kamat as well as the other members of the IBCG group for the opportunity to lead on this study, and for their time and their efforts in reviewing the literature with me as well. Thank you very much for your time.

Ashish Kamat: Thanks, Shen. That was a nice, concise summary of the findings and recommendation from the panel. If you could share with our audience members, some of the key points. And I know you did that already in the presentation, but from a practical standpoint, if you see a patient in the clinic, and the patient has non-muscle-invasive bladder cancer, what are some of the lessons or recommendations from this consensus publication to the practicing urologist as to factors that they should consider when they're thinking of risk classifying patients?

Wei Shen Tan: The salient  points in terms of the recommendations would be:  After a TUR, patients at least should have single installation postoperative intravesical chemotherapy, provided personal contraindications. And following histology review, in your mind, you should risk classify these patients, because they are quite heterogeneous, whether to give them adjuvant intravesical chemotherapy or BCG. And in the lower risk factor patients, treat them with intravesical chemotherapy because they might not need the additional advantage of BCG. BCG also has  tolerability issues and also issues with supply, particularly in the current climate, where there is a shortage of BCG.Hence, you want to reserve your BCG for the patients who are actually need it.

In the higher risk, non-intermediate-risk patients, these are the patients that you can treat with one year BCG. Of course, for patients with no risk factors, we can treat them as low-risk disease because there's a good chance that it might not have any recurrence again in the future. Hence, you do not really need to treat them with adjuvant intravesical treatment. These  are some of the salient recommendations. In terms of the histopathological features, as we discussed previously, if you have got a low-grade T1, this is an incredibly rare group of patients. For the purpose of clinical trials, we would recommend that we exclude this patient cohort to minimize disease heterogeneity. Also any high-grade disease, even Ta patients, these patients  should be treated as high-risk disease. So, they should not follow this protocol.

Ashish Kamat: Again, you pretty much summarized everything in one response, which is great. Just to break it down for our audience, one of the things I would always emphasize is that when we are risk classifying patients, the goal of the risk classification is in many ways to make the counseling and discussion with our patients, and of course the [inaudible] recommendations a little bit simpler, rather more complicated. And that's why, of course, the recommendation from the International Bladder Cancer Group, the IBCG, that you published, shows that if a patient has low-grade disease, and it's a first-time solitary small tumor, those patients are best considered to be low-risk. And also if a patient has the risk criteria to fall in the intermediate-risk category, but has zero of the risk factors, as you mentioned earlier, then that patient too should be treated like a low-risk patient. Which means there's less need to over-treat these patients because the natural history of the disease is unlikely to cause progression or adverse events that would potentially put the patient's life at risk.

Ashish Kamat: On the other hand, if a patient has high-grade disease, including a small first-time Ta high-grade disease, that patient's risk is essentially the same as somebody that has a high-grade disease period. And that's why classifying those patients more towards the high-risk category is appropriate. And then that opens up the whole intermediate-risk category of patients in whom you could do the zero, zero to... One to two, and more than three years factors. So, keeping that in mind, the recommendation for intravesical BCG versus chemotherapy, could you highlight some of the findings from the literature review and the publication as to in whom would you recommend BCG over chemotherapy, and in which patients that have intermediate-risk disease, would chemotherapy be an appropriate option?

Wei Shen Tan: The patients that would benefit from intravesical chemotherapy typically would be patients that would be the middle-risk groups. One to two risk factors. The role for chemotherapy is actually to reduce the disease risk of recurrence of disease.Chemotherapy, as we well know, is better tolerated compared to BCG. These patients might not need BCG treatment. However, in the  small subgroup of these patients who develop disease recurrence, then it would be very reasonable to treat these patients with BCG. BCG we feel should be reserved for  the higher-risk, intermediate-risk patients, especially in today's current climate.  These patients should be treated for at least one year of BCG maintenance, as the benefit from the studies that we discussed previously would suggest that the benefit of BCG in lowering disease recurrence is actually only evident when we give maintenance BCG. Hence, induction BCG alone does not add any advantage compared to chemotherapy.

Ashish Kamat: Yeah. Great point. And then finally, of course, one of the reasons that we always put forward risk stratification for patients, especially in bladder cancer, is to make the conduct and interpretation of clinical trials a little bit more easier and homogeneous. And from that perspective, if we are looking at agents that are directed towards this large basket of patients that are intermediate-risk, but we don't in many ways factor in the sub-classification of patients, it makes the sample size a lot larger.

If you have patients that really have zero risk factors, the event rate will be low enough that the sample size will be much larger. On the other hand, if you're looking to do a relatively shorter study with less number of patients than enriching for the higher risk amongst the intermediate-risk category patients would be advantageous. And you touched upon that, but I just wanted to highlight that as well. So, Shen, it's been great to have you discuss this paper with our audience, and with the members of UroToday. I'll give you the last 30 seconds to a minute to leave the audience with your thoughts, and some of your top-level message from this paper.

Wei Shen Tan: Thanks again, Dr. Kamat and UroToday for having me. So, it has been a privilege to work on this, and  the IBCG group feels that it's important to risk classify intermediate-risk patients because they represent a very heterogeneous patient population. It's important to tailor treatment appropriately to these patients, minimize overtreatment, and also try to rationalize BCG use, especially to today's current climate of BCG shortage. Thank you very much.

Ashish Kamat: Great. Thank you.